course description

NEW DRUG DELIVERY TECHNOLOGIES

ONLINE INFORMATION SOURCES & SEARCH STRATEGIES

Bonnie SnowDirector, Pharmaceutical Markets, Dialog

Course Description

Recent advances in drug delivery involve combinations of drugs or biologics with medical devices. Searching for information to support the development of new hybrid products and assessment of their business implications is challenging. This session will survey the broad spectrum of online databases typically needed, including bioengineering and biomaterials, clinical, and competitive intelligence information sources. Sample searches will also illustrate techniques for constructing effective keyword strategies for retrieving relevant data in a rapidly evolving discipline where little standardized indexing vocabulary is available.

SLA Annual Conference – Toronto, June 2005

© Bonnie Snow, 2005

Pharmaceutical & Health Technology

Division

Special Libraries Association

Table of Contents

Background 2 - 9

Case Studies in MEDLINE & EMBASE

INFUSE Bone Graft 10 - 24CYPHER Drug-Eluting Stent 25 - 31PEGASYS – Drug Combination for Hepatitis C Therapy 32 - 40Observations – Indexing Policies & Search Techniques 41

Extending Your Reach: Other Biomedical Bibliographic Files

Adis Clinical Trials Insight 42 - 47BIOSIS Previews 48 - 49Derwent Drug File 50International Pharmaceutical Abstracts 51 - 52Complementary Resources: SciSearch, CA Search, JICST, Pascal 52

Extending Your Reach: Engineering Literature Resources

EI Compendex 53 - 55INSPEC 56 - 58A Pertinent Dialindex/OneSearch Category 59MEDITEC: Biomedical Engineering 59

Drug Pipeline Databases: Will They Help in Identifying Products That Incorporate New Drug Delivery Technology?

Introductory Overview 60Pharmaprojects 61 - 66IMS R&D Focus 67 - 72Adis R&D Insight 73 - 76

Full-Text Subject Specialty News Sources for Monitoring Drug Delivery Developments

PHIND 77-84ESPICOM Pharmaceutical & Medical Device News 85 - 86Prous Science Daily Essentials 87FDA News 88 - 89NewsRx Weekly Reports 90Gale Group Newsletter Database 91 - 94

Other Sources of Drug Delivery & Combination Product Information:Syndicated Market Research Reports & Investment Analysts’ Reports 95-97

Page 1

Background

Drug Delivery = Dispensing mechanism/technology incorporated into a pharmaceutical product that controls the precise anatomical location and timing of the release of a therapeutic compound with the purpose of optimizing its safety and efficacy.

Familiar (widely accepted) applications– Oral controlled- or sustained-release formulations (e.g., enteric-coated tablets)– Topical preparations for localized delivery of medications to body site affected (e.g., antibacterial, cortisone sprays, ointments, or creams for skin conditions)

Emerging advanced applications– Transdermal patches– Inhalables– Long-acting depot injections– Needle-free injections– Nanotechnology

Recent developments in drug delivery also involve, in increasing numbers, combinations of drugs + biologics, drugs + medical devices, or drugs + biologics + devices.

Examples of “hybrid” products:– Antibiotic bone cement– Bandage or wound dressing that incorporates a pain-reducing medication– Photodynamic therapy - Pharmacologically inactive agents administered topically or systemically are converted to active metabolites when exposed to a proprietary light source– Radioimmunotherapy - isotope-labeled monoclonal antibodies– Antimicrobial-coated catheters– Drug-eluting stents

Impetus for increased interest in drug delivery technology development? Need to…

Administer new chemical entities consisting of insoluble small molecules or [sometimes unstable] macromolecules arising from biotechnology Avoid or mitigate effects of metabolic process associated with oral ingestion of a medication (possible reduction in bioavailability, delayed onset of action, systemic side effects) Improve dosing regimen for less frequent administration Increase patient compliance & quality of life by introducing more “user-friendly” dosage forms (e.g., inhalable versus injectable insulin, transdermal patch administration in Parkinson’s disease, Alzheimer’s, arthritis) Reduce healthcare costs (keep patients ambulatory, enable self-care, limit hospitalization and/or need for ongoing monitoring/tests, decrease risk of disease recurrence or severe adverse effects) Prolong product life cycle, “rescue” drugs nearing patent expiration Rejuvenate pipeline, re-examine previously investigated products where further development was suspended due to inadequate efficacy. Can delivery enhancement using emerging technology more fully exploit the compound’s potential benefits? Block/delay competition by employing new modes of drug delivery that will make it more difficult and expensive for would-be generic competitors to achieve comparable bioavailability

Page 2

Gauging Commercial Potential Through Analysis of Patents

In a Scrip Report on The Future of Pharmaceutical Innovation published in 2004, PJB discusses results of their analysis of U.S. patent data from January 2000 through June 2003

Total number of patents granted that were directly related to pharmaceutical, biotech, or medical processes, products, or services = 69,823

– 1/3 of these were for devices, diagnostics, or equipment– Another 30% claimed formulations & therapeutic applications (outnumbering those granted for new chemical entities)

Indicator of greater concentration on reformulations and extendedindications than on new compound development?

– 6.5% of patents issued over the 3.5-year period were directly related to drug delivery technology platforms (4,543 in all)

Source – Scrip-Online-Plus record in the Pharmaceutical & Healthcare Industry News Database - PHIND (T 00831852/9 in File 129 on Dialog)

The Marketplace

Drug delivery technologies increased from 9.6% of total worldwide pharmaceutical sales in 1995 to 31% of total in 2002, when drug delivery revenue reached $38 billion. It has been estimated that drug delivery technology will account for 39% of pharmaceutical sales by 2007.

Source – Drug Delivery 2003 report from Visiongain, highlighted in an M2 Presswire record in the Gale Group Newsletter Database (T 05574544/9 in File 636 on Dialog)

Business Communications Company (BCC) estimated the U.S. market for advanced drug delivery systems in 2003 at $43.7 billion, expected to rise at an average annual growth rate of 11.3% to reach $74.5 B by 2008.

Source – May 2004 Biotechnology Industry Review in BCC Market Research database (T 00239427/9 in File 764 on Dialog)

SG Cowen Securities estimates that the U.S. drug-eluting stent market will grow to $3.315 billion in 2005 and $3.46B in 2006

Source – July 2004 report entitled Medical Supplies & Devices: The New World Order in Investext (Report Number 9773565, page 18)

Sun Trust predicts that the worldwide market for drug-eluting stents will reach $5.26B in 2005

Source – Aug 2003 report entitled Medical Devices - Drug-Eluting Stents: Place Your Bets Here! in Investext (Report Number 7572590, page 5)

vFinance Investments (NY) predicts that the drug-eluting stent market in the U.S. will grow to $6.3 billion by 2008

Source – “Drug-Eluting Stent Battle Picks Up Speed,” Hospital Materials Management, May 2004, in the Gale Group Newsletter Database (T 05794001/9 in File 636)

Page 3

Searching for information to support the development of new hybrid products is challenging

Drug delivery is an interdisciplinary science, drawing on expertise in chemistry, biology, physics, mathematics, engineering, and electronics.

Developments may be reported in the literature of any of these subject areas, requiringaccess to a broad cross-section of online resources—many of which represent “unfamiliar territory” for biomedical searchers

Retrieving information on specific products is difficult, particularly when a medical device is involved.

Brand names for devices are not as well controlled as those for drugs, where regulatoryauthorities examine names for possible confusion from similarity with existing products. Many device brand names are ambiguous, especially when searched in non-biomedicalsources (e.g. ENDEAVOR)

Abbreviations commonly used in the literature are also non-exclusive and can lead to irrelevant retrieval (e.g., DES).

The new breed of combination products typically employ proprietary technology originating from several different companies, any of which may or may not be cited.

– CYPHER drug-eluting stent includes a Johnson & Johnson (Cordis) BX VELOCITY stent modified to deliver a Wyeth drug, via a polymer coating forsustained elution developed by Surmodics.– INFUSE Bone Graft delivers a Wyeth biologic on Integra’s absorbable collagen sponge, embedded in a surgically implanted device produced by Medtronic.

Given this context, determining patent status/intellectual property protection can be arduous.

Monitoring licensing & partnership agreements, m&a activities is particularly important when assessing business implications and the competitive landscape

As in any relatively new subject specialty, controlled (standardized & predictable) vocabulary is often unavailable in indexing provided by a given database.

The concept of drug delivery and its specific components (chemical compounds, other mechanisms) is frequently overlooked in indexing.

The term “combination product” can be misleading.

Heretofore, it has been used to describe drugs with two or more active ingredients.

The FDA’s recent decision to use the phrase for drug/biologic/device combinations does not change its meaning and application in extant database indexing.

As a result, the situation is quite confusing (and annoying) from the searcher’sperspective, necessitating extra care in strategy formulation.

Page 4

U.S. regulatory definition of a “combination product”

A product composed of two or more components, each of which is regulated by a separate FDA Center (administrative division)

Drug + Device Biologic + Device Drug + Biologic Drug + Device + Biologic

The product’s components can be physically, chemically, or otherwise combined or mixed, e.g…..

1) produced as a single entity (monoclonal antibody + chemotherapy drug)

2) components remain separate, but are packaged together for administration as a unit (e.g., lumbar fusion device marketed with bone morphogenetic protein)

3) components packaged separately, but labeled for use only with another specified product, where both are required to achieve the intended purpose, indication, or effect, e.g.,

– diagnostic test designed for use with specific drug – Herceptin– branded biologic for concurrent use with drug to achieve synergistic therapeutic effect

Note that this regulatory definition does not apply to combination drug-drug products

Excludes CADUET (Pfizer’s combination of its lipid-lowering agent LIPITOR with anantihypertensive, NORVASC, for simultaneous treatment of high blood pressure and highcholesterol)

or to drug delivery devices developed for administration of unspecified agents (syringes, infusion pumps)

Key Regulatory Issue (Worldwide, not just in USA): Jurisdiction

Traditionally, separate divisions (“Centers”) within government agencies are responsible for marketing authorization of drugs, devices, or biologics.

When a hybrid product is proposed, regulatory jurisdiction is controversial.

FDA’s Office of Combination Products (OCP) was established in December 2002 to assist in determining which Center will be responsible for premarket review of a product candidate & its post-market surveillance, once approved.

– OCP also tracks statistics related to the process, monitoring timeliness (published in an annual report to U.S. Congress)

– Produces relevant Guidance documents for industry

Page 5

Regulatory Jurisdiction Decision & Consequent Road to Market based on…

Product’s Primary Mode of Action to achieve its principal therapeutic effect

Relies on chemical action within or on the body, metabolism of agent administered? Example: biodegradable polymer wafer implanted for antineoplastic drug delivery

– CDER (Center for Drug Evaluation & Research)or

– CBER (Center for Biologics Evaluation & Research)

NDA or BLA submission required for marketing authorization

More & larger clinical trials, longer application review times, extensive post-marketing surveillance mandated, as well as higher user fees

Primary intended purpose not dependent on metabolism or chemical action?Example: Coronary stent coated with a drug

– CDRH (Center for Devices & Radiological Health)

PMA or 510(k) submission, depending on “class” (risk category) of device

One relatively small clinical trial, shorter review time, lower user fees, post-marketing surveillance focused on production process quality control

If PMOA cannot be determined (too early in development process or dual action)…

– Premarket review assigned to Center responsible for reviewing similar products in the past (historical precedents)

– If no similar product heretofore, assigned to Center likely to have most expertise in reviewing the product’s component that poses more questions regarding safety & efficacy

Example: Contact lens combined with glaucoma drug (CDER)Example: Powered catheter that uses ultrasound energy and thrombolytic agent

to break up clots (CDRH)

Source – Patterson, N. “Faster Approvals for Drug and Device Combination Products.” The BBI Newsletter, Sept 2003, in Gale Group Newsletter Database (T 05636250/9 in File 636 on Dialog). Extracts from this 7-page, 3,658-word article shown below…

FDA Centers and Approved Product Categories

Primary FDA FDA Consulting Center Examples Approval Center

CDRH (device) CDER (drugs) Bone cement containing antimicrobial agent Cardiac pacemaker lead with steroid coated tip Condom or diaphragm with contraceptive or Antimicrobial agent Drug eluting stent Dental device with fluoride

Page 6

FDA Centers and Approved Product Categories [continued]

Primary FDA FDA Consulting Center Examples Approval Center

CDRH (device) CBER (biologic) Spinal-fusion cage with recombinant human bone morphogenic protein Catheters that deliver angiogenesis gene to heart muscle CBER (biologic) CDRH (device) Plasmapheresis devices Blood banking equipment CDER (drug) CDRH (device) Photoactivated drugs with proprietary light source * Oxygen tank for therapy Prefilled syringe Transdermal patch CDRH (device) None Devices that calculate drug dosages Glucose monitor device/insulin pump

combination Drug delivery pump and/or catheter infusion pump for implantation ** Iontophoreses device ** Nebulizer ** Small particle aerosol generator for ventilated patient Splitter block for mixing nitrous oxide and oxygen Syringe: jet injector; storage and dispensing equipment ** Ultrasound infusion catheters **

* Resulted in a new drug approval for the drug and several separate PMA approvals for the device ** Combination products requiring CDER/CBER consultation when prefilled or labeled for a specific drug

Comparison Between Device and Drug/Biologic Product Regulatory Process

Review Requirements Device Drug/Biologic

Can use prototype in clinical trial Yes No

Product life cycle Short Long

Ease of in vitro assessment High Low

Influence of physician technique on results High Low

Ability to visualize performance after use High Low

Number of full-scale clinical studies usually required 1 2

Number of regulatory classes 3 1

Extent of clinical data required Low High

Average number patients in clinical trial Hundreds Thousands

Average time to FDA approval once all required testing complete and submitted for review 510(k) 30-90 days PMA (Includes IDE study) 2 to 5 years NDA/BLA (pharmaceutical) 7 to 10 years (Includes IND studies)

Page 7

Comparison Between Device and Drug/Biologic Product Regulatory Process [continued]

Post-approval reporting requirements to the FDA

510(k) Low

PMA Moderate to High

NDA/BLA (pharmaceutical) High

Approximate clinical trial costs

510(k) $300,000-$500,000

PMA $2 million-$4 million

NDA/BLA (pharmaceutical) $200 million-$300 million

Sources: Semih Oktay, PhD, president, CardioMed Device Consultants, Martha Feldman, president, Drug and Device Development Co.

Regulatory Situation in European Union (2nd largest world market)

No separate agency dedicated to determining jurisdiction

Manufacturers/applicants can select least burdensome route to approval (if device involved: easier to obtain CE Mark than to complete the marketing authorization process for drugs/biologics)

CE Mark

– Indicates that manufacturer has conformed with European regulatory requirements– Applicant selects one of more than 60 Notified Bodies to handle evaluation of safety/efficacy/quality control data. Certification by one constitutes authorization to market throughout the EU

Source – Murphy, P. Understanding How Medical Devices are Approved in the U.S., Europe and Canada, RBC Capital Markets report issued January 2003. Fulltext available in Investext (Report Number 7440396)

Source – Patterson, N. “Faster Approvals for Drug and Device Combination Products.” The BBI Newsletter, Sept 2003, in Gale Group Newsletter Database (T 05636250/9 in File 636). Also cited previously as source of extracts shown above.

Selected Web Resources for Additional Background Information

FDA Office of Combination Productshttp://www.fda.gov/oc/combination/

Combination Products Primary Mode of Action. Proposed Rule: May 7, 2004, Federal Registerhttp://www.fda.gov/OHRMS/DOCKETS/98fr/04-10447.htm

MX [magazine for medical device executives]Sumner, K. “Attitude Adjustment.” June 2003http://www.devicelink.com/MX/archive/03/05/sumner.html

Medical Device & Diagnostic Industry [magazine] Feature Articles…

Page 8

Sall, B; Lassoff, P; Babbitt, B. “Getting Started with a Combination Product: Part I.” March 2003.http://www.devicelink.com/mddi/archive/03/03/018.html

--------. “Getting Started with a Combination Product Part II: European Regulations.” April 2003.http://www.devicelink.com/mddi/archive/03/04/019.html

Swain, E. “Blazing New Paths for Product Introductions.” Oct 2003. http://www.devicelink.com/mddi/archive/03/09/001.html

Loob, W. “Combination Products Enhance Capabilities, Pose New Challenges.” (May 2000).http://www.devicelink.com/mddi/archive/00/05/009.html

Special Libraries Association – Pharmaceutical & Health Technology Division Presentations…

Rosenberg, B. “Breaking New Ground: Combination Products & Information Strategies.”http://www.sla.org/division/dpht/Annual2004/presentations2004/CombProducts_Rosenberg.ppt

White, B. “Breaking New Ground: Combination Products & Information Needs.”http://www.sla.org/division/dpht/Annual2004/presentations2004/CombProducts_White.ppt

Meisner, C and White, B. “Beyond Science Fiction: Medical Technology in the 21st Century.”http://www.sla.org/division/dpht/Annual2003/presentations2003/cindy_meisner.ppt

What’s Next?

Three “case studies,” each focusing on an approved combination product, conducted to explore major biomedical database indexing characteristics and illustrate search strategy construction.

Followed by…

A survey of additional, complementary bibliographic resources in medicine & engineering.

Detailed examination of drug pipeline database indexing of combination products & sample search strategies.

A final section highlighting major full-text subject specialty news sources

Page 9

Example #1: Biologic Drug - Device Combination with Orthopedic Applications

INFUSE Bone Graft – Delivers recombinant human bone morphogenetic protein-2 via an absorbable collagen sponge embedded in a biodegradable medical device surgically implanted at the body site where bone regeneration is needed. Currently approved in the U.S. for use with the LT-CAGE Lumbar Tapered Fusion Device as an alternative to autologous bone transplants (autografts) to achieve spinal fusion, enabling shorter post-operative recovery time.

File 154:MEDLINE(R) 1990-2004/Sep W2 (c) format only 2004 The Dialog Corp.

Set Items Description --- ----- -----------? S INFUSE AND BONE()GRAFT 394 INFUSE 281798 BONE 106284 GRAFT 4260 BONE(W)GRAFT S1 6 INFUSE AND BONE()GRAFT

? T S1/9/1-6

1/9/1DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.

16774640 PMID: 15198497 Lumbar interbody fusion after treatment with recombinant human bone morphogenetic protein-2 added to poly(L-lactide-co-D,L-lactide) bioresorbable implants. Lanman Todd H; Hopkins Thomas J DBA California Spine Group, and Century City Hospital, Los Angeles,California, USA. [email protected] Neurosurg Focus (United States) Mar 15 2004, 16 (3) pE9, ISSN1092-0684 Journal Code: 100896471 Document type: Case Reports; Clinical Trial; Journal Article Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS Object. To evaluate the effectiveness of recombinant human bonemorphogenetic protein-2 (rhBMP-2) combined with a bioresorbable implant, the authors conducted a prospective study of 43 patients with degenerative lumbar disc disease who underwent transforaminal lumbar interbody fusion.Methods. The authors used Infuse bone graft, which consisted of rhBMP-2applied to an absorbable collagen sponge and contained within a HYDROSORBTelamon bioresorbable implant to perform the fusion. Multilevel fusions were performed in 30% of the 43 patients, for a total of 57 levels. At 6 months postoperatively, x-ray films and computerized tomography (CT) scans demonstrated solid fusion in 98% of 41 patients. Improvement from the baseline Oswestry Disability Rating was demonstrated at 6 months postoperatively in 68% of the patients, based on the Oswestry Disability Questionnaire. At 12 months all 11 patients in whom CT scans were obtained showed complete bridging of bone; there were no device-related complications. Conclusions. Results in this series provide evidence of the feasibility of using HYDROSORB Telamon bioresorbable spacers in combination with Infuse bone graft for lumbar spine fusion. Tags: Female; Human; Male

[record continues on next page]

Page 10

Trial using a different implantable device

1st in a series of “test searches” for information on recently approved combination products, conducted to explore database indexing characteristics and illustrate strategy construction

Descriptors: *Absorbable Implants; *Bone Morphogenetic Proteins--administration and dosage--AD; *Intervertebral Disk Displacement--therapy--TH; *Lumbar Vertebrae--surgery--SU; *Polyesters--administration anddosage--AD; *Spinal Fusion--methods--MT; Adolescent; Adult; Aged; BoneTransplantation; Collagen--administration and dosage--AD; Follow-Up Studies; Intervertebral Disk--surgery--SU; Intervertebral Disk Displacement--diagnosis--DI; Intervertebral Disk Displacement--surgery--SU; Length ofStay; Materials Testing; Middle Aged; Orthopedic Fixation Devices;Osseointegration--drug effects--DE; Prospective Studies; RecombinantProteins CAS Registry No.: 0 (Bone Morphogenetic Proteins); 0 (Polyesters); 0 (Recombinant Proteins); 0 (bone morphogenetic protein 2); 26969-66-4 (poly(lactide)); 9007-34-5 (Collagen) Record Date Created: 20040616 Record Date Completed: 20040826


16774637 PMID: 15198494 Early findings in a pilot study of anterior cervical interbody fusion in which recombinant human bone morphogenetic protein-2 was used with poly(L-lactide-co-D,L-lactide) bioabsorbable implants. Lanman Todd H; Hopkins Thomas J California Spine Group, Century City Hospital, Los Angeles, California, USA. Neurosurg Focus (United States) Mar 15 2004, 16 (3) pE6, ISSN1092-0684 Journal Code: 100896471 Document type: Evaluation Studies; Journal Article Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS OBJECT: The goal of this study was to assess the efficacy of bioabsorbable interbody spacers in cervical spine fusion. METHODS: The authors report on a prospective examination of 20 patients with degenerative cervical disc disease who underwent anterior cervical fusion at 28 total levels. The authors used Infuse bone graft (that is, recombinant human bone morphogenetic protein-2 applied to an absorbable collagen sponge and contained within a Cornerstone-HSR bioabsorbable spacer. Multiple-level fusions were performed in 30% of these patients. At 3 months postfusion, radiographs and computerized tomography scansdemonstrated bridging bone in 100% of the patients. Improvement from baseline scores in physical functioning, mental health, and bodily pain was demonstrated at 3 months postoperatively according to results of the Short Form-36 Version 2 health survey. There were no device-related complications. CONCLUSIONS: The results in this series indicate that the use of Cornerstone-HSR as a bioabsorbable interbody spacer in combination with Infuse bone graft may be an alternative treatment for cervical spine fusion. Tags: Female; Human; Male Descriptors: *Absorbable Implants; *Bone Morphogenetic Proteins--administration and dosage--AD; *Cervical Vertebrae--surgery--SU; *Polyesters--administration and dosage--AD; *Spinal Fusion--methods--MT; Adult; Cervical Vertebrae--pathology--PA; Cervical Vertebrae--radiography--RA; Follow-Up Studies; Intervertebral Disk--surgery--SU; Intervertebral Disk Displacement--diagnosis--DI; Intervertebral Disk Displacement--surgery--SU; Materials Testing; Middle Aged; Orthopedic Fixation Devices; Osseointegration--drug effects--DE; Pilot Projects; Prospective Studies; Recombinant Proteins CAS Registry No.: 0 (Bone Morphogenetic Proteins); 0 (Polyesters); 0 (Recombinant Proteins); 0 (bone morphogenetic protein 2); 26969-66-4 (poly(lactide)) Record Date Created: 20040616 Record Date Completed: 20040826

Page 11

Another study using an alternative device implant

Specific protein indexed under broad class terms. Delivery mechanisms & their major chemical components identified.

Indexing omits reference to delivery vehicle (collagen)


15536816 PMID: 12811263 A prospective, randomized, controlled cervical fusion study using recombinant human bone morphogenetic protein-2 with the CORNERSTONE-SR allograft ring and the ATLANTIS anterior cervical plate. Baskin David S; Ryan Patrick; Sonntag Volker; Westmark Richard; WidmayerMarsha A Department of Neurosurgery, Baylor College of Medicine, and VeteransAffairs Medical Center, Houston, Texas 77030, USA. [email protected] Spine (United States) Jun 15 2003, 28 (12) p1219-25; discussion 1225, ISSN 1528-1159 Journal Code: 7610646 Document type: Clinical Trial; Journal Article; Randomized Controlled Trial Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS STUDY DESIGN: A prospective, randomized, pilot clinical trial comparedrecombinant human bone morphogenetic protein-2 (rhBMP-2) with iliac crestautograft bone for the treatment of human cervical disc disease. OBJECTIVE:To examine the safety and effectiveness of using INFUSE Bone Graft (rhBMP-2applied to an absorbable collagen sponge), as compared with an autogenous iliac crest bone graft placed inside the CORNERSTONE-SR fibular allograft, in anterior cervical discectomy and interbody fusion. SUMMARY OF BACKGROUNDDATA: Recombinant human bone morphogenetic protein-2 is an osteoinductiveprotein that induces a reliable fusion in the lumbar spine, but it has notbeen studied in patients with degenerative cervical disc disease. METHODS:For this study, 33 patients with degenerative cervical disc disease wererandomly assigned to investigational or control groups. The investigationalgroup received a fibular allograft (CORNERSTONE-SR Allograft Ring) with anrhBMP-2-laden collagen carrier inside the graft along with an ATLANTIS anterior cervical plate. The control group received a fibular allograft with cancellous iliac crest autograft placed inside it, along with an ATLANTIS anterior cervical plate.

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Tags: Comparative Study; Female; Human; Male; Support, Non-U.S. Gov't Descriptors: *Bone Morphogenetic Proteins--administration and dosage--AD;*Bone Transplantation--methods--MT; *Cervical Vertebrae--surgery--SU;*Ilium--transplantation--TR; *Spinal Diseases--surgery--SU; *Spinal Fusion--methods--MT; Cervical Vertebrae--radiography--RA; Diskectomy; Middle Aged; Osseointegration; Osteogenesis--drug effects--DE; Pilot Projects; Prospective Studies; Recombinant Proteins--administration and dosage--AD; Safety; Spinal Diseases--radiography--RA; Tomography, X-Ray Computed; Transplantation, Autologous; Treatment Outcome CAS Registry No.: 0 (Bone Morphogenetic Proteins); 0 (RecombinantProteins); 0 (bone morphogenetic protein 2) Record Date Created: 20030617 Record Date Completed: 20040129

Page 12

Study focused on efficacy of biologic drug-induced osteogenesis versus bone transplantation (autograft). Delivery mechanism ignored in indexing.


12318614 PMID: 12679664 Is INFUSE bone graft superior to autograft bone? An integrated analysis of clinical trials using the LT-CAGE lumbar tapered fusion device. Burkus J Kenneth; Heim Stephen E; Gornet Matthew F; Zdeblick Thomas A Spine Service, The Hughston Clinic, Columbus, Georgia, [email protected] Journal of spinal disorders & techniques (United States) Apr 2003, 16 (2) p113-22, ISSN 1536-0652 Journal Code: 101140323 Document type: Journal Article; Meta-Analysis Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS Multicenter human clinical studies of patients undergoing anterior lumbar fusion have been conducted using recombinant bone morphogenetic protein orrhBMP-2 on an absorbable collagen sponge, marketed as INFUSE Bone Graft, orautograft implanted in the LT-CAGE Lumbar Tapered Fusion device. An integrated analysis of multiple clinical studies was performed …

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. Tags: Comparative Study; Female; Human; Male Descriptors: *Bone Substitutes; *Bone Transplantation--statistics andnumerical data--SN; *Spinal Diseases--epidemiology--EP; *Spinal Fusion--statistics and numerical data--SN; *Transplantation, Autologous--statistics and numerical data--SN; Analysis of Variance; Bone Substitutes--therapeutic use--TU; Bone Transplantation--methods--MT; Clinical Trials--statistics and numerical data--SN; Collagen--therapeutic use--TU; Spinal Diseases--surgery--SU; Spinal Fusion--instrumentation--IS; Spinal Fusion--methods--MT; Transplantation, Autologous--methods--MT CAS Registry No.: 0 (Bone Substitutes); 9007-34-5 (Collagen) Record Date Created: 20030407 Record Date Completed: 20030604


12110870 PMID: 12438990 Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Burkus J Kenneth; Transfeldt Ensor E; Kitchel Scott H; Watkins Robert G;Balderston Richard A Hughston Spine Service, The Hughston Clinic, Columbus, Georgia31908-9517, USA. [email protected] Spine (United States) Nov 1 2002, 27 (21) p2396-408, ISSN 1528-1159Journal Code: 7610646 Document type: Clinical Trial; Journal Article; Multicenter Study;Randomized Controlled Trial Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS STUDY DESIGN: A prospective, nonblinded, multicenter study of outcomes inpatients undergoing single-level anterior lumbar discectomy and interbodyfusion with InFUSE Bone Graft. OBJECTIVE: To determine the safety andeffectiveness of InFUSE Bone Graft applied to an absorbable collagen spongein anterior lumbar interbody fusion with threaded cortical allografts.

[remainder of abstract omitted here. Indexing shown on next page]

Page 13

Indexing fails to identify composition of bone substitute (recombinant protein).

Descriptors: *Bone Morphogenetic Proteins--administration and dosage--AD;*Bone Transplantation--methods--MT; *Lumbar Vertebrae--drug effects--DE;*Lumbar Vertebrae--surgery--SU; *Osteogenesis--drug effects--DE; *SpinalFusion--methods--MT; Adult; Aged; Bone Morphogenetic Proteins--adverseeffects--AE; Collagen--administration and dosage--AD; Diskectomy; DrugCarriers--administration and dosage--AD; Drug Implants--administration anddosage--AD; Ilium--transplantation--TR; Intervertebral Disk Displacement--complications--CO; Intervertebral Disk Displacement--surgery--SU; Low Back Pain--etiology--ET; Low Back Pain--surgery--SU; Lumbar Vertebrae--radiography--RA; Middle Aged; Prospective Studies; Recombinant Proteins--administration and dosage--AD; Recombinant Proteins--adverse effects--AE; Spinal Fusion--adverse effects--AE; Spinal Fusion--instrumentation--IS; Tomography, X-Ray Computed; Treatment Outcome CAS Registry No.: 0 (Bone Morphogenetic Proteins); 0 (Drug Carriers);0 (Drug Implants); 0 (Recombinant Proteins); 0 (bone morphogenetic protein 2); 9007-34-5 (Collagen) Record Date Created: 20021119 Record Date Completed: 20030113


12082246 PMID: 12408742 BMP 2--Genetics Institute/Medtronic-Sofamor Danek/Integra. Bone morphogenetic protein 2--Genetics Institute/Medtronic-Sofamor Danek/Integra, INFUSE Bone Graft, recombinant human bone morphogenetic protein 2--Genetics Institute/ Medtronic-Sofamor Danek/Integra, RhBMP 2--Genetics Institute/Medtronic-Sofamor Danek/Integra. BioDrugs - clinical immunotherapeutics, biopharmaceuticals and genetherapy (New Zealand) 2002, 16 (5) p376-7, ISSN 1173-8804Journal Code: 9705305 Document type: Journal Article Languages: ENGLISH Genetics Institute (Wyeth) is collaborating with Medtronic-Sofamor Danek (which specialises in spinal reconstruction) and Integra Life Sciences todevelop a BMP 2 product [INFUSE Bone Graft] for use in spinal reconstruction in North America. The INFUSE Bone Graft product has been approved for use in lumbar interbody spinal fusion procedures in the USA and is in phase III trials for use in lumbar posterolateral spinal fusion procedures. During the procedure, damaged disc is replaced with a collagen sponge (Integra's Absorbable Collagen Sponge) soaked with BMP 2, which is held in place within an implanted cage device (LT-CAGE Lumbar Tapered Fusion Device); the fusion process subsequently requires several months to complete. However, the patient is able to leave hospital the day after the operation, whereas in conventional spinal surgery a longer recovery time is required. The procedure supersedes the use of autograft bone as it uses a recombinant human bone morphogenic protein, rhBMP-2, which induces the body to grow its own bone where required. Genetics Institute has cloned and expressed bone morphogenic proteins 1-7 and established manufacturing processes by recombinant DNA technology. Bone morphogenic proteins may be useful in the treatment of osteoporosis and orthopaedic trauma. BMP 2 is also being developed for bone regeneration as an implanted device and as an injectable formulation. Genetics Institute is also collaborating with Integra LifeSciences to develop a formulation of BMP 2 with Integra's absorbable collagen-based structures for fracture treatment, which isawaiting approval in the USA. Tags: Human Descriptors: *Bone Morphogenetic Proteins--therapeutic use--TU; *Drug Industry--trends--TD; Clinical Trials--statistics and numerical data--SN;Musculoskeletal Diseases--drug therapy--DT; Musculoskeletal Diseases--metabolism--ME

Page 14

Indexing very general—but highly informative abstract. Demonstrates utility of brand name inclusion in online strategies—augmented with preferred MeSH terms, as shown on next page.

? S BONE MORPHOGENETIC PROTEINS

Page 15

S2 4350 BONE MORPHOGENETIC PROTEINS? S S2 AND RECOMBINANT PROTEINS! 170383 RECOMBINANT PROTEINS! S3 847 S2 AND RECOMBINANT PROTEINS!? S S3 AND SPINAL FUSION 6662 SPINAL FUSION S4 63 S3 AND SPINAL FUSION? S S4 AND (COLLAGEN OR DRUG CARRIERS OR DRUG IMPLANTS OR ABSORBABLE IMPLANTS) 71758 COLLAGEN 7979 DRUG CARRIERS 4126 DRUG IMPLANTS 1349 ABSORBABLE IMPLANTS S5 35 S4 AND (COLLAGEN OR DRUG CARRIERS OR DRUG IMPLANTS OR ABSORBABLE IMPLANTS)? S S5 NOT S1 S6 31 S5 NOT S1

? S RHBMP2 OR RHBMP()2 OR RECOMBINANT()HUMAN()BONE()MORPHOGENETIC()PROTEIN()2 11 RHBMP2 440 RHBMP 2382742 2 411 RHBMP(W)2 336 RECOMBINANT(W)HUMAN(W)BONE(W)MORPHOGENETIC(W)PROTEIN(W)2 S7 494 RHBMP2 OR RHBMP()2 OR RECOMBINANT()HUMAN()BONE()MORPHOGENETIC()PROTEIN()2? S S6 AND S7 S8 23 S6 AND S7? T S8/6/1-6

8/6/116228877 PMID: 15069140 Recombinant human bone morphogenetic protein-2 enhances anterior spinal fusion in a thoracoscopically instrumented animal model.Apr 2004

8/6/216172389 PMID: 14623404 Collagen sponges for bone regeneration with rhBMP-2.Nov 28 2003

8/6/315935452 PMID: 12973141 Lumbar spinal fusion with a mineralized collagen matrix and rhBMP-2 in a rabbit model.Sep 1 2003

8/6/415682262 PMID: 12897477 Bone morphogenetic proteins and spinal surgery.Aug 1 2003

8/6/514529309 PMID: 10528370 Lumbar spinal fusion using recombinant human bone morphogenetic protein in the canine. A comparison of three dosages and two carriers.Oct 1 1999

8/6/614516722 PMID: 10515009 Experimental spinal fusion using sintered bovine bone coated with type I collagen and recombinant human bone morphogenetic protein-2 .Sep 15 1999

Page 16

MeSH scope note

File 72:EMBASE 1993-2004/Sep W2 (c) 2004 Elsevier Science B.V.

Set Items Description --- ----- -----------? S INFUSE AND BONE()GRAFT 237 INFUSE 187285 BONE 103696 GRAFT 6719 BONE(W)GRAFT S1 19 INFUSE AND BONE()GRAFT? T S1/6/ALL

1/6/112755252 EMBASE No: 2004350984 The effectiveness of rhBMP-2 in replacing autograft: An integrated analysis of three human spine studies

1/6/212727550 EMBASE No: 2004319349 Tissue engineering: The current status of this futuristic modality in head neck reconstruction

.

. 1/6/612350876 EMBASE No: 2003469530 Collagen sponges for bone regeneration with rhBMP-2

1/6/712219518 EMBASE No: 2003321207 Clinical applications of recombinant human BMPs: Early experience and future development

.

.After browsing titles, full display of a few sample records enables exploration of EMBASE indexing characteristics…

Page 17

Note higher recall from brand name strategy in EMBASE, compared to MEDLINE (19 versus 6).

1/9/1DIALOG(R)File 72:EMBASE(c) 2004 Elsevier Science B.V. All rts. reserv.

12755252 EMBASE No: 2004350984 The effectiveness of rhBMP-2 in replacing autograft: An integrated analysis of three human spine studies Burkus J.K.; Heim S.E.; Gornet M.F.; Zdeblick T.A. Dr. J.K. Burkus, The Hughston Clinic, 6262 Veterans Pkwy., Columbus, GA 31908-9517 United States Orthopedics ( ORTHOPEDICS ) (United States) 2004, 27/7 (723-728) LANGUAGE: ENGLISH NUMBER OF REFERENCES: 17BRAND NAME/MANUFACTURER NAME: infuse bone graft/Medtronic Sofamor Danek/United StatesMANUFACTURER NAMES: Wyeth/United States; Medtronic Sofamor Danek/UnitedStatesDEVICE BRAND NAME/MANUFACTURER NAME: LT-CAGE Lumbar Tapered Fusion Device/Medtronic Sofamor Danek/United StatesDEVICE MANUFACTURER NAMES: Medtronic Sofamor Danek/United StatesDRUG DESCRIPTORS:*bone morphogenetic protein 2--clinical trial--ct; *bone morphogeneticprotein 2--drug therapy--dt; *bone morphogenetic protein 2--pharmaceutics--pr; *bone morphogenetic protein 2--pharmacology—pd; recombinant protein--clinical trial--ct; recombinant protein--drug therapy--dt; recombinant protein--pharmaceutics--pr; recombinant protein--pharmacology--pd; collagen; drug carrier; antiinflammatory agent—drug therapy--dtMEDICAL DESCRIPTORS:*bone graft; *anterior spine fusion; drug efficacy; lumbar spine; drug delivery system; statistical analysis; treatment outcome; intermethod comparison; autograft; spine disease--diagnosis--di; spine disease--drug therapy--dt; spine disease--surgery--su; spine disease--therapy--th; degenerative disease--diagnosis--di; degenerative disease--drug therapy--dt; degenerative disease--surgery--su; degenerative disease--therapy--th; computer assisted tomography; operation duration; bleeding; hospitalization; work capacity; low back pain—drug therapy--dt; low back pain--surgery--su; low back pain--therapy--th;physiotherapy; drug mechanism; human; male; female; major clinical study;clinical trial; controlled study; aged; adult; articleDRUG TERMS (UNCONTROLLED): infuse bone graftCAS REGISTRY NO.: 9007-34-5 (collagen)SECTION HEADINGS: 027 Biophysics, Bioengineering and Medical Instrumentation 030 Clinical and Experimental Pharmacology 033 Orthopedic Surgery 037 Drug Literature Index 039 Pharmacy

What analysis of initial search results revealsWhat analysis of initial search results reveals

• EMBASE identifies drug & device brand names & manufacturers cited in the full text of the original source – whether or not they also appear in the title and/or abstract– However, not always in TN, MN field (see

record #12 on p. 20)

– Conclusion? Search brand names without field qualification

1/9/6

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DIALOG(R)File 72:EMBASE(c) 2004 Elsevier Science B.V. All rts. reserv.

12350876 EMBASE No: 2003469530 Collagen sponges for bone regeneration with rhBMP-2 Geiger M.; Li R.H.; Friess W. M. Geiger, Drug Product Development, Wyeth BioPharma, One Burtt Road, Andover, MA 01810 United States AUTHOR EMAIL: [email protected] Advanced Drug Delivery Reviews ( ADV. DRUG DELIV. REV. ) (Netherlands)28 NOV 2003, 55/12 (1613-1629) CODEN: ADDRE ISSN: 0169-409X DOCUMENT TYPE: Journal ; Review LANGUAGE: ENGLISH SUMMARY LANGUAGE: ENGLISH NUMBER OF REFERENCES: 108

In the US alone, approximately 500,000 patients annually undergo surgicalprocedures to treat bone fractures, alleviate severe back pain throughspinal fusion procedures, or promote healing of non-unions. Many of theseprocedures involve the use of bone graft substitutes. An alternative tobone grafts are the bone morphogenetic proteins (BMPs), which have beenshown to induce bone formation. For optimal effect, BMPs must be combinedwith an adequate matrix, which serves to prolong the residence time of theprotein and, in some instances, as support for the invading osteoprogenitorcells. Several factors involved in the preparation of adequate matrices,specifically collagen sponges, were investigated in order to test theperformance in a new role as an implant providing local delivery of anosteoinductive differentiation factor. Another focus of this review is thecurrent system consisting of a combination of recombinant human BMP-2(rhBMP-2) and an absorbable collagen sponge (ACS). The efficacy and safetyof the combination has been clearly proven in both animal and human trials.(c) 2003 Elsevier B.V. All rights reserved.

DEVICE BRAND NAME/MANUFACTURER NAME: Osigraft/Howmedica/Ireland; InFuse/medronic sofamor danek/United States; InductOs/Wyeth/United Kingdom;NeOsteo/Sulzer/United StatesDEVICE MANUFACTURER NAMES: Howmedica/Ireland; medtronic sofamor danek/UnitedStates; Wyeth/United Kingdom; Sulzer/United StatesDRUG DESCRIPTORS:*collagen--clinical trial--ct; *collagen--pharmaceutics--pr; *bonemorphogenetic protein 2--clinical trial--ct; *bone morphogenetic protein 2--drug development--dv; *bone morphogenetic protein 2--drug therapy--dt; *bone morphogenetic protein 2--pharmaceutics--pr; *bone morphogeneticprotein 2--pharmacology—pd; formaldehyde; osteogenic protein 1--drug therapy--dt; osteogenic protein 1--pharmaceutics--pr; drug carrier--clinical trial--ct; drug carrier--pharmaceutics--pr; collagen type 1--pharmaceutics--pr; collagen type 4--pharmaceutics--pr; calcium phosphate--pharmaceutics--pr; hydroxyapatite--pharmaceutics--pr; chondroitin 6 sulfate--pharmaceutics--pr; roseolicacid--pharmaceutics--pr; carboxymethylcellulose--pharmaceutics--pr;titanium--pharmaceutics--pr; unclassified drugMEDICAL DESCRIPTORS:*bone regeneration sponge (Porifera); surgical patient; surgical technique; fracture—drug therapy--dt; fracture--surgery--su; backache--drug therapy--dt; backache--surgery--su; spine fusion; fracture healing; bone graft; ossification; drug effect; bone matrix; cell invasion; precursor cell; bone cell; performance; absorption; drug efficacy; drug safety; drug delivery system; cross linking; vapor; thermodynamics; heat treatment; instrumentsterilization; gamma radiation; beta radiation; plastic surgery; toothimplantation; craniofacial morphology; bone transplantation; morphogenesis;biocompatibility; drug mechanism; in vitro study; in vivo study; diseasemodel; treatment outcome; human; nonhuman; clinical trial; review; priorityjournalDRUG TERMS (UNCONTROLLED): recombinant human bone morphogenetic protein 2

Page 19

--clinical trial--ct; recombinant human bone morphogenetic protein 2--drugdevelopment--dv; recombinant human bone morphogenetic protein 2--drugtherapy--dt; recombinant human bone morphogenetic protein 2--pharmaceutics--pr; recombinant human bone morphogenetic protein 2--pharmacology--pd;poly(alpha hydroxy acid)--pharmaceutics--prCAS REGISTRY NO.: 9007-34-5 (collagen); 50-00-0 (formaldehyde); 10103-46-5, 13767-12-9, 14358-97-5, 7758-87-4 (calcium phosphate); 1306-06-5, 51198-94-8 (hydroxyapatite); 25322-46-7 (chondroitin 6 sulfate); 11052-94-1, 603-45-2 (roseolic acid); 8050-38-2, 9000-11-7, 9004-32-4, 9050-04-8 (carboxymethylcellulose); 7440-32-6 (titanium)SECTION HEADINGS: 027 Biophysics, Bioengineering and Medical Instrumentation 030 Clinical and Experimental Pharmacology 033 Orthopedic Surgery 037 Drug Literature Index 039 Pharmacy


12032153 EMBASE No: 2003144118 Is INFUSE Bone Graft superior to autograft bone? An integrated analysis of clinical trials using the LT-CAGE Lumbar Tapered Fusion device Burkus J.K.; Heim S.E.; Gornet M.F.; Zdeblick T.A. Dr. J.K. Burkus, Hughston Clinic, 6262 Veterans Parkway, Columbus, GA 31908-9517 United States AUTHOR EMAIL: [email protected] Journal of Spinal Disorders and Techniques ( J. SPINAL DISORD. TECH. ) ( United States) 2003, 16/2 (113-122) CODEN: JSDTB ISSN: 1536-0652 DOCUMENT TYPE: Journal ; Article LANGUAGE: ENGLISH SUMMARY LANGUAGE: ENGLISH NUMBER OF REFERENCES: 15

Multicenter human clinical studies of patients undergoing anterior lumbarfusion have been conducted using recombinant bone morphogenetic protein orrhBMP-2 on an absorbable collagen sponge, marketed as INFUSE Bone Graft, orautograft implanted in the LT-CAGE Lumbar Tapered Fusion device. Anintegrated analysis of multiple clinical studies was performed using ananalysis of covariance to adjust for preoperative variables in a total of679 patients. Of these patients, 277 had their cages implanted with rhBMP-2on an absorbable collagen sponge and 402 received autograft transferredfrom the iliac crest. The patients treated with rhBMP-2 had statisticallysuperior outcomes with regard to length of surgery, blood loss, hospitalstay, reoperation rate, median time to return to work, and fusion rates at6, 12, and 24 months. Oswestry Disability Index scores and the PhysicalComponent Scores and Pain Index of the SF-36 scale at 3, 6, 12, and 24months showed statistically superior outcomes in the rhBMP-2 group.

DEVICE MANUFACTURER NAMES: Medtronic Sofamor Danek/United StatesDRUG DESCRIPTORS:*recombinant bone morphogenetic protein 2MEDICAL DESCRIPTORS:*bone graft; *autograft; *anterior spine fusion; *intervertebral diskdegeneration--surgery—su; biodegradable implant; iliac crest; treatment outcome; operation duration; bleeding; hospitalization; reoperation; work resumption; disability; pain assessment; follow up; surgical technique; comparative study; device; human; male; female; major clinical study; clinical trial; randomized controlled trial; multicenter study; controlled study; adult; article; priority journal [remainder of record omitted here]

Page 20

Concept of “recombinant” may be identified in the abstract and “uncontrolled” indexing, rather than in the Descriptor field

Cited drug/device brand names omitted in indexing.

What analysis of initial search results revealsWhat analysis of initial search results reveals

• For newer compounds, EMBASE drug descriptors are typically more specific than indexing provided in MEDLINE– Precoordinated term available: “Recombinant Bone

Morphogenetic Protein 2” (record #12)

– “Bone Morphogenetic Protein 2” + “Recombinant Protein” (record #1)

– Or “Bone Morphogenetic Protein 2” + “recombinant”in abstract or “uncontrolled” indexing (record #6)

– Conclusion? Take advantage of the precoordinatedterm, but augment retrieval with “free text” terms

What analysis of initial search results reveals

• “Drug delivery” concept appears to be more systematically identified in EMBASE records, although a variety of Descriptors are used– “Drug Delivery System”

– “Drug Carrier”

– “Biodegradable Implant”

– “Collagen”

• Two alternative Descriptors used for the indication– “Anterior Spine Fusion”

– “Spine Fusion”

• Conclusion? Need to assess term occurrence in a larger sample of results

Page 21

? RANK DEStarted processing RANKCompleted Ranking 19 recordsDIALOG RANK Results--------------------RANK: S1/1-19 Field: /DE File(s): 72(Rank fields found in 19 records -- 495 unique terms) Page 1 of 62

RANK No. Items Term-------- ----- ---- 1 18 HUMAN 2 16 RECOMBINANT BONE MORPHOGENETIC PROTEIN 2 3 15 BONE GRAFT 4 13 CLINICAL TRIAL 5 12 PRIORITY JOURNAL 6 12 SU 7 12 SURGERY 8 10 AUTOGRAFTP = next page Pn = Jump to page nP- = previous page M = More Options Exit = Leave RANK

To view records from RANK, enter VIEW followed by RANK number,format, and item(s) to display, e.g., VIEW 2/9/ALL.

Enter desired option(s) or enter RANK number(s) to save terms.? PDIALOG RANK Results--------------------RANK: S4/1-19 Field: /DE File(s): 72(Rank fields found in 19 records -- 495 unique terms) Page 2 of 62

RANK No. Items Term-------- ----- ---- 9 10 COLLAGEN 10 10 NONHUMAN 11 9 CT 12 9 REVIEW 13 8 CONTROLLED STUDY 14 8 SURGICAL TECHNIQUE 15 7 ARTICLE 16 7 CALCIUM PHOSPHATEP = next page Pn = Jump to page nP- = previous page M = More Options Exit = Leave RANK

? PDIALOG RANK Results--------------------RANK: S4/1-19 Field: /DE File(s): 72(Rank fields found in 19 records -- 495 unique terms) Page 3 of 62

RANK No. Items Term-------- ----- ---- 17 7 PD 18 7 PHARMACOLOGY 19 7 RECOMBINANT BONE MORPHOGENETIC PROTEIN 2 --CLI 20 7 SPINE FUSION 21 6 ADULT 22 6 DRUG THERAPY 23 6 DT 24 5 ANTERIOR SPINE FUSIONP = next page Pn = Jump to page nP- = previous page M = More Options Exit = Leave RANK

Page 22

RANKing Descriptors enables analysis of indexing beyond what can be accomplished through selective browsing.

Item counts assist users in gauging the relative reliability of descriptors when used in follow-up searches.

? PDIALOG RANK Results--------------------RANK: S4/1-19 Field: /DE File(s): 72(Rank fields found in 19 records -- 495 unique terms) Page 4 of 62

RANK No. Items Term-------- ----- ---- 25 5 BONE MORPHOGENETIC PROTEIN 26 5 DRUG DELIVERY SYSTEM 27 5 DRUG EFFICACY 28 5 FEMALE 29 5 LUMBAR SPINE 30 5 MALE 31 5 OSTEOGENIC PROTEIN 1 32 5 RECOMBINANT BONE MORPHOGENETIC PROTEIN 2 –PHA

.

.

. 33 5 TITANIUM 34 5 TREATMENT OUTCOME 35 4 BONE MATRIX 36 4 BONE MORPHOGENETIC PROTEIN 2 37 4 BONE TRANSPLANTATION 38 4 CALCIUM SULFATE 39 4 CO 40 4 COMPLICATION 41 4 COMPUTER ASSISTED TOMOGRAPHY 42 4 DRUG CARRIER 43 4 FIBROBLAST GROWTH FACTOR 44 4 INTERVERTEBRAL DISK DEGENERATION --SURGERY --S 45 4 INTERVERTEBRAL DISK DEGENERATION 46 4 MAJOR CLINICAL STUDY 47 4 PHARMACEUTICS 48 4 PR 49 4 SPINE DISEASE 50 4 TRANSFORMING GROWTH FACTOR BETA 51 3 ADVERSE DRUG REACTION 52 3 AE 53 3 BIODEGRADABLE IMPLANT 54 3 BIOMECHANICS 55 3 BONE CONDUCTION 56 3 BONE MORPHOGENETIC PROTEIN --CLINICAL TRIAL --P = next page Pn = Jump to page nP- = previous page M = More Options Exit = Leave RANK

To view records from RANK, enter VIEW followed by RANK number,format, and item(s) to display, e.g., VIEW 2/9/ALL.

Enter desired option(s) or enter RANK number(s) to save terms.? EXIT

RANK results will be erased; have you saved all the terms of interest?(YES/NO)? YExiting rank... (no terms were saved)

Page 23

EMBASE strategies paralleling those shown earlier in MEDLINE…

? S RECOMBINANT BONE MORPHOGENETIC PROTEIN 2 S2 285 RECOMBINANT BONE MORPHOGENETIC PROTEIN 2

? S BONE MORPHOGENETIC PROTEIN 2 AND (RECOMBINANT OR RHBMP2 OR RHBMP()2)

1144 BONE MORPHOGENETIC PROTEIN 2 114659 RECOMBINANT 7 RHBMP2 330 RHBMP 1497758 2 308 RHBMP(W)2 S3 258 BONE MORPHOGENETIC PROTEIN 2 AND (RECOMBINANT OR RHBMP2 OR RHBMP()2) ? S S2 OR S3 S4 501 S2 OR S3

? S S4 AND SPINE()FUSION/DE 31817 SPINE/DE 15091 FUSION/DE 3862 SPINE/DE(W)FUSION/DE S5 83 S4 AND SPINE()FUSION/DE

? S COLLAGEN OR DRUG CARRIER OR DRUG DELIVERY SYSTEM OR BIODEGRADABLE IMPLANT 44903 COLLAGEN 3292 DRUG CARRIER 19163 DRUG DELIVERY SYSTEM 612 BIODEGRADABLE IMPLANT S6 66235 COLLAGEN OR DRUG CARRIER OR DRUG DELIVERY SYSTEM OR BIODEGRADABLE IMPLANT ? S S5 AND S6 S7 45 S5 AND S6 ? S S7 NOT S1 S8 36 S7 NOT S1

Sample titles…

? T S8/6/1-8 Spinal fusion using bone morphogenetic proteins

Recombinant Human Bone Morphogenetic Protein-2 Enhances Anterior Spinal Fusion in a Thoracoscopically Instrumented Animal Model

Spine fusion by gene therapy

Effect of nano-hydroxyapatite/collagen composite and bone morphogenetic protein-2 on lumbar intertransverse fusion in rabbits

Fusion Biology and Contemporary Graft Options

A cost analysis of bone morphogenetic protein versus autogenous iliac crest bone graft in single-level anterior lumbar fusion

Effect of regional gene therapy with bone morphogenetic protein-2-producing bone marrow cells on spinal fusion in rats

Simple carrier matrix modifications can enhance delivery of recombinant

Page 24

Retrieves additional references to technology pertinent to the product that do not cite the brand name

Augments retrieval from the precoordinated term (set 2) by anticipating assignment of an alternative descriptor, supplemented here with “free text” keywords

Insertion of the proximity operator ( ) ensures retrieval of both “spine fusion” and “anterior spine fusion”.

human bone morphogenetic protein-2 for posterolateral spine fusion

Example #2: Drug - Device Combination with Cardiac Applications

CYPHER Drug-Eluting Stent – Enables local delivery of an immunosuppressive drug at the site of the surgically implanted medical device to reduce the incidence of restenosis. The approved product includes a Cordis (Johnson & Johnson) BX-Velocity stent coated with a sirolimus/synthetic polymer blend for slow release, targeted drug delivery to inhibit proliferation of muscle cells in the artery wall. Because only minimal amounts of the drug enter the bloodstream, systemic adverse effects are avoided.


Set Items Description --- ----- -----------? S CYPHER AND STENT 46 CYPHER 15036 STENT S1 25 CYPHER AND STENT

? T S1/9/1,15 1/9/1DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.

16415064 PMID: 15085373 "Real life" use of sirolimus-eluting coronary stents in Germany. Results from the prospective multi-centre German Cypher Registry. Zahn R; Hamm C W; Zeymer U; Schneider S; Nienaber C A; Richardt G; Kelm M; Levenson B; Bonzel T; Tebbe U; Schobel W A; Sabin G; Senges J Herzzentrum Ludwigshafen, Kardiologie, Bremserstrasse 79, 67063Ludwigshafen, Germany. [email protected] Zeitschrift fur Kardiologie (Germany) Apr 2004, 93 (4) p287-94,ISSN 0300-5860 Journal Code: 0360430 Document type: Clinical Trial; Journal Article; Multicenter Study Languages: ENGLISH Subfile: INDEX MEDICUS BACKGROUND: Drug eluting stents (DES) are currently judged to be a"break-through" technology for the prevention of restenosis after percutaneous coronary interventions (PCI). However, experience is limited to randomised controlled clinical trials (RCT) in selected lesions and the currently available DES are more expensive compared to conventional "bare" stents. Therefore, actual clinical practice may be very different to RCT.METHODS: We analysed the data of the German Cypher trade mark Registry, anationwide registry which was initiated in parallel to the launch of the first DES, the Cypher trade mark sirolimus-eluting coronary stent, in April 2002. RESULTS: From April 2002 until March 2003, 1638 procedures at 88 hospitals were included in the German Cypher trade mark Registry.

.

.

. Tags: Female; Human; Male Descriptors: *Blood Vessel Prosthesis--utilization--UT; *Coronary Disease--epidemiology--EP; *Coronary Disease--surgery--SU; *Coronary Restenosis--epidemiology--EP; *Coronary Restenosis--prevention and control--PC;*Registries; *Sirolimus--administration and dosage--AD; *Stents--utilization--UT; Comorbidity; Coronary Restenosis--drug therapy--DT; Drug Delivery Systems--utilization--UT; Germany--epidemiology--EP; Middle Aged CAS Registry No.: 53123-88-9 (Sirolimus) Record Date Created: 20040415

Page 25

Record Date Completed: 20040630 1/9/15DIALOG(R)File 154:MEDLINE(R)(c) format only 2004 The Dialog Corp. All rts. reserv.

16391936 PMID: 14981005 Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Colombo Antonio; Moses Jeffrey W; Morice Marie Claude; Ludwig Josef;Holmes David R; Spanos Vassilis; Louvard Yves; Desmedt Benny; Di MarioCarlo; Leon Martin B EMO Centro Cuore Columbus, Milan, Italy. Circulation (United States) Mar 16 2004, 109 (10) p1244-9, ISSN1524-4539 Journal Code: 0147763 Document type: Clinical Trial; Journal Article; Randomized Controlled Trial Languages: ENGLISH Record type: Completed Subfile: AIM; INDEX MEDICUS BACKGROUND: A sirolimus-eluting stent (Cypher, Cordis Corp) has been reported to markedly decrease restenosis in selected lesions; higher-risklesions, including coronary bifurcations, have not been studied. METHODS AND RESULTS: This prospective study evaluated the safety and efficacy ofsirolimus-eluting stents for treatment of coronary bifurcation lesions.

.

.

. Tags: Comparative Study; Female; Human; Male; Support, Non-U.S. Gov't Descriptors: *Coronary Restenosis--prevention and control--PC; *CoronaryStenosis--surgery--SU; *Sirolimus--therapeutic use--TU; *Stents; *Ticlopidine--analogs and derivatives--AA; Aged; Anticoagulants--therapeutic use--TU; Aspirin--therapeutic use--TU; Balloon Dilatation; Combined Modality Therapy; Comorbidity; Coronary Angiography; Coronary Restenosis--radiography--RA; Coronary Stenosis--drug therapy--DT; Coronary Thrombosis--etiology--ET; Coronary Vessels--pathology--PA; Death, Sudden; Diabetes Mellitus--epidemiology--EP; Disease-Free Survival; Drug Implants; Follow-Up Studies; Life Tables; Middle Aged; Pilot Projects; Postoperative Complications--etiology--ET; Prospective Studies; Safety; Sirolimus--administration and dosage--AD; Survival Analysis; Ticlopidine--therapeutic use--TU; Treatment Outcome CAS Registry No.: 0 (Anticoagulants); 0 (Drug Implants); 50-78-2 (Aspirin); 53123-88-9 (Sirolimus); 55142-85-3 (Ticlopidine); 90055-48-4 (clopidogrel) Record Date Created: 20040316 Record Date Completed: 20040628 Date of Electronic Publication: 20040223

? S SIROLIMUS/DE AND STENTS/DE AND CORONARY RESTENOSIS 2682 SIROLIMUS/DE 18301 STENTS/DE 1404 CORONARY RESTENOSIS S2 135 SIROLIMUS/DE AND STENTS/DE AND CORONARY RESTENOSIS? S S2 NOT S1 S3 129 S2 NOT S1

? S S3/HUMAN AND PY=2004 127 S3/HUMAN 401807 PY=2004 S4 40 S3/HUMAN AND PY=2004? T S4/6/1-5

4/6/116862577 PMID: 15057442 [Do drug-eluting stents influence the spectrum of coronary artery bypass surgery?]

Page 26

Strategy to retrieve additional references to the drug-device combination that do not cite the product’s brand name in the original source

Beeinflussen Drug-eluting Stents das Spektrum der Koronarchirurgie? 4/6/216862576 PMID: 15057441 Drug-eluting stents for in-stent restenosis and acute myocardial infarction: present data from nonrandomized studies.Mar 2004

4/6/316862575 PMID: 15057440 Classification and current treatment options of in-stent restenosis. Present status and future perspectives.Mar 2004

4/6/416862572 PMID: 15057437 Polymer-sirolimus-eluting stents in de novo lesions.Mar 2004

4/6/516862555 PMID: 15054588 Rapamycin analogs for stent-based local drug delivery. Everolimus- andtacrolimus-eluting stents.Mar 2004

Results include references to other drugs under investigation for stent delivery. How can the strategy be modified to retrieve additional bibliography on this topic? One approach….

Set Items Description S1 39 CYPHER AND STENT S2 236 STENTS/DE AND SIROLIMUS/DE AND CORONARY RESTENOSIS S3 223 S2 NOT S1 S4 131 S3/HUMAN AND PY=2004:2005

? S STENTS/DE AND CORONARY RESTENOSIS 20194 STENTS/DE 1850 CORONARY RESTENOSIS S5 1250 STENTS/DE AND CORONARY RESTENOSIS ? S S5 AND (ELUTING OR COATED) 2522 ELUTING 31152 COATED S6 400 S5 AND (ELUTING OR COATED) ? S S6 NOT S2 S7 202 S6 NOT S2

? S S7 AND (AD OR TU OR DRUG DELIVERY SYSTEMS OR DRUG IMPLANTS)/DE 449265 AD/DE 658344 TU/DE 9466 DRUG DELIVERY SYSTEMS/DE 3762 DRUG IMPLANTS/DE S8 145 S7 AND (AD OR TU OR DRUG DELIVERY SYSTEMS OR DRUG IMPLANTS)/DE

Sample titles retrieved…

Paclitaxel-eluting stents: current clinical experience.

Page 27

Note: Strategy avoids specifying word order or proximity

Optional: Use of “free-floating” subheadings and “delivery methodology” MeSH terms in an attempt to focus results on drugs.

Updated results reflect recall as of May 2005

2004

The long-term clinical results of a platelet glycoprotein IIb/IIIa receptor blocker (Abciximab: Reopro ) coated stent in patients with coronary artery disease. Dec 2004

High-dose 7-hexanoyltaxol-eluting stent with polymer sleeves for coronary revascularization: one-year results from the SCORE randomized trial. Oct 6 2004 Actinomycin-eluting stent for coronary revascularization: a randomized feasibility and safety study: the ACTION trial. Oct 6 2004

Dexamethasone-eluting stent: an anti-inflammatory approach to inhibit coronary restenosis. Sep 2004

Advanced c-myc antisense (AVI-4126)-eluting phosphorylcholine-coated stent implantation is associated with complete vascular healing and reduced neointimal formation in the porcine coronary restenosis model. Apr 2004

Methotrexate eluting stents: to modify or cure? Feb 2004 A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. Jan 15 2004 Comparison of initial efficacy and long-term follow-up of heparin-coated Jostent with conventional NIR stent. Nov 2003

Study of antirestenosis with the BiodivYsio dexamethasone-eluting stent (STRIDE): a first-in-human multicenter pilot trial.Oct 2003

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.

Page 28

File 72:EMBASE 1993-2004/Sep W2 (c) 2004 Elsevier Science B.V.

Set Items Description --- ----- -----------? S CYPHER AND STENT 136 CYPHER 20723 STENT S1 122 CYPHER AND STENT

? T S1/9/1,5


12777834 EMBASE No: 2004373942 Implantation of sirolimus-eluting stents in patients with higher risk of restenosis. One-year follow-up of 100 patients IMPLANTACJA STENTOW WYDZIELAJACYCH RAPAMYCYNE (SIROLIMUS) U CHORYCH ZEZWIEKSZONYM RYZYKIEM RESTENOZY. ROCZNA OBSERWACJA 100 PACJENTOW Lesiak M.; Rzezniczak J.; Baszko A.M.; Pyda M.A.; Grajek S.; Mularek T.;Skorupski W.; Mitkowski P.; Grygier M.; Prech M.; Cieslinski A. Dr. M. Lesiak, I Klinika Kardiologii, ul. Dl(stroke)uga 1/2, 61-848 Poznan Poland AUTHOR EMAIL: [email protected] Folia Cardiologica ( FOLIA CARDIOL. ) (Poland) 2004, 11/7 (505-511) CODEN: FCGPB ISSN: 1507-4145 DOCUMENT TYPE: Journal ; Article LANGUAGE: POLISH SUMMARY LANGUAGE: ENGLISH; POLISH NUMBER OF REFERENCES: 15

Background: In-stent restenosis is still one of the main limitations of percutaneous coronary revascularization. The novel drug-eluting stents seem to reduce the risk of restenosis substantially. We conducted this study to determine the short- and long-term results of sirolimus-eluting stent implantation in patients with higher risk of restenosis. Material and methods: Coronary angioplasty with Cypher(TM) (Cordis, Johnson & Johnson) stent

.

.

.DEVICE BRAND NAME/MANUFACTURER NAME: Cypher/Cordis Johnson and JohnsonDEVICE MANUFACTURER NAMES: Cordis Johnson and JohnsonDRUG DESCRIPTORS:*rapamycin--drug therapy--dt; *rapamycin--pharmaceutics—pr; pyridine derivative--drug therapy--dtMEDICAL DESCRIPTORS:*restenosis--complication--co; *restenosis--diagnosis--di; *restenosis--drug therapy--dt; *drug eluting stent; drug implantation; follow up; high risk patient; transluminal coronary angioplasty; stable angina pectoris--drug therapy--dt; … [remainder of record omitted here]


12754051 EMBASE No: 2004349236 Long-term effects of polymer-based, slow-release, sirolimus-eluting stents in a porcine coronary model Carter A.J.; Aggarwal M.; Kopia G.A.; Tio F.; Tsao P.S.; Kolata R.; YeungA.C.; Llanos G.; Dooley J.; Falotico R.

Page 29

“Trial search” in EMBASE

EMBASE added “drug eluting stent” to its controlled vocabulary in June 2003

A.J. Carter, Providence Heart and Vasc. Institute, Providence St. Vincent Med. Center, 9205 SW Barnes Road, 97225-5218, Portland, OR United States AUTHOR EMAIL: [email protected] Cardiovascular Research ( CARDIOVASC. RES. ) (Netherlands) 01 SEP 2004, 63/4 (617-624) CODEN: CVREA ISSN: 0008-6363 PUBLISHER ITEM IDENTIFIER: S0008636304002019 DOCUMENT TYPE: Journal ; Article LANGUAGE: ENGLISH SUMMARY LANGUAGE: ENGLISH NUMBER OF REFERENCES: 15

Background: Stent-based delivery of sirolimus (SRL) has shown reduction in neointimal hyperplasia and restenosis. The purpose of this study was to evaluate the chronic vascular response and the expression of cell cycleregulators after SRL-eluting stent implantation in a porcine coronary model.

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.

.BRAND NAME/MANUFACTURER NAME: cypher/CordisMANUFACTURER NAMES: Wyeth Ayerst/United States; CordisDEVICE BRAND NAME/MANUFACTURER NAME: BX Velocity/Cordis/United StatesDEVICE MANUFACTURER NAMES: Cordis/United StatesDRUG DESCRIPTORS:*rapamycin--drug therapy--dt; *rapamycin--pharmaceutics--pr; *rapamycin--pharmacology—pd; polymer--pharmaceutics--pr; cycline; protein p27; CD45 antigen; monocyte chemotactic protein 1; interleukin 2; interleukin 6; lymphotoxin; cyclin dependent kinase; drug carrier--pharmaceutics--prMEDICAL DESCRIPTORS:*coronary artery; long term care; drug effect; drug eluting stent; biological model; evaluation; blood vessel reactivity; implantation; swine; histology;Western blotting; thrombus; protein expression; blood vessel wall;modulation; artery intima proliferation--drug therapy--dt; artery intimaproliferation--surgery--su; cell proliferation; postoperative complication;postoperative thrombosis--complication--co; nonhuman; animal experiment;animal model; controlled study; animal tissue; article; priority journalDRUG TERMS (UNCONTROLLED): cypherCAS REGISTRY NO.: 53123-88-9 (rapamycin); 85898-30-2 (interleukin 2); 150428-23-2 (cyclin dependent kinase) [remainder of record omitted here]

? E (RAPAMYCIN)

Ref Items Type RT Index-termR1 5802 7 *RAPAMYCINR2 136528 DC=D24.440.445 (IMMUNOSUPPRESSIVE AGENT)R3 17973 B 90 IMMUNOSUPPRESSIVE AGENTR4 11 S 1 AY 22989R5 0 S 1 AY22989R6 297 S 1 RAPAMUNER7 1030 S 1 SIROLIMUSR8 5269 S 1 RN=53123-88-9

? S RAPAMYCIN/DE AND RESTENOSIS/DE AND DRUG ELUTING STENT 5480 RAPAMYCIN/DE 6233 RESTENOSIS/DE 304 DRUG ELUTING STENT S2 120 RAPAMYCIN/DE AND RESTENOSIS/DE AND DRUG ELUTING STENT

? S S2 NOT S1 S3 84 S2 NOT S1

Page 30

Verifying that RAPAMYCIN is an alternative nonproprietary name for SIROLIMUS

Strategy to retrieve references to the drug-device combination that do not cite the product’s brand name

Broader strategy to locate other drugs under investigation for stent delivery & restenosis reduction

Set Items Description S1 210 CYPHER AND STENT S2 280 RAPAMYCIN/DE AND RESTENOSIS/DE AND DRUG ELUTING STENT S3 192 S2 NOT S1 S4 157 S3/HUMAN AND PY=2004:2005

? S DRUG ELUTING STENT AND RESTENOSIS/DE 676 DRUG ELUTING STENT 6917 RESTENOSIS/DE S5 437 DRUG ELUTING STENT AND RESTENOSIS/DE


? S S6 AND (AD OR PR OR DRUG CARRIER OR DRUG IMPLANTATION OR POLYMER?)/DE 89890 AD/DE 82181 PR/DE 3591 DRUG CARRIER/DE 314 DRUG IMPLANTATION/DE 211420 POLYMER?/DE S8 44 S6 AND (AD OR PR OR DRUG CARRIER OR DRUG IMPLANTATION OR POLYMER?)/DE

Sample of citation titles retrieved…

Evaluation of a high-dose Dexamethasone-eluting stent 15 JUL 2004

Local gene transfer of phVEGF-2 plasmid by gene-eluting stents: An alternative strategy for inhibition of restenosis 06 JUL 2004

Intracoronary brachytherapy may be cost-effective for in-stent restenosis in the long term 2003

Stent-based controlled release of intravascular angiostatin to limit plaque progression and in-stent restenosis 2004

Molecular responses of vascular smooth muscle cells and phagocytes to curcumin-eluting bioresorbable stent materials 2004

First human experience with the 17-beta-estradiol-eluting stent: The estrogen and stents to eliminate restenosis (EASTER) trial 17 MAR 2004

In-Stent Restenosis Limitation with Stent-based Controlled-Release Nitric Oxide: Initial Results in Rabbits 2004

Science to Practice Why Coat a Stent with Polymer? 2004

In vitro evaluation of vascular endothelial growth factor (VEGF)-eluting stents 2003

Page 31

Updated results reflect recall as of May 2005

Example #3: Drug Combination for Hepatitis C Therapy

PEGASYS + RIBAVIRIN – Approved regimen involves separate administration, on a fixed schedule, of the antiviral drug ribavirin (COPEGUS) and an immunostimulant produced via biotechnology, pegylated (PEG) recombinant human interferon alpha-2A (PEGASYS). PEG (polyethylene glycol) modification of the interferon represents a significant advance in pharmaceutical technology. Attachment of an inert synthetic polymer to the molecule encircles the protein, effectively “disguising” it from the human metabolic system. In consequence, pegylation has enhanced clinical efficacy by lengthening the interferon’s half-life, enabling longer sustained delivery and reduction of dose frequency to once weekly (versus 3 x week for non-PEG version). When used in combination, PEGASYS and ribavirin have demonstrated dramatic improvement in long-term virological response compared to monotherapy using either agent.

MEDLINE Indexing of This TopicMEDLINE Indexing of This Topic

• Concept of pegylation is not precoordinated with interferon: two separate index terms, the 2nd of which is not consistently assigned (must be augmented with “free text” terms)– Interferon Alfa-2a– Polyethylene Glycols

• The specific interferon is sometimes incorrectly indexed (see record #7,8,10)– Also, incorrect (or missing) CAS RNs (see record #2, 9)

• “Drug Therapy, Combination” is infrequently used (assigned to only 5 out of 26 records citing PEGASYS)


Set Items Description --- ----- -----------? S PEGASYS S1 26 PEGASYS

? T S1/6/1-5

1/6/1DIALOG(R)File 154:(c) format only 2004 The Dialog Corp. All rts. reserv.

16782845 PMID: 15313671 Impact of virus genotype on interferon treatment of patients with chronic hepatitis C: a multicenter controlled study.Aug 2004


16631058 PMID: 14569259 Improved biological and transcriptional activity of monopegylated interferon-alpha-2a isomers.

Page 32


16545348 PMID: 15225169 Pegylated interferon-alpha2a kinetics during experimental haemodialysis: impact of permeability and pore size of dialysers.Jul 1 2004


16349194 PMID: 15128353 Sudden hearing loss in patients with chronic hepatitis C treated with pegylated interferon/ribavirin.May 2004


16278379 PMID: 15096276 Pegasys: software for executing and integrating analyses of biological sequences.Apr 19 2004

? T S1/9/2,4,7-10


16631058 PMID: 14569259 Improved biological and transcriptional activity of monopegylated interferon-alpha-2a isomers. Foser S; Weyer K; Huber W; Certa U Department of Pharma Technical Operations Biotechnology, F Hoffmann LaRoche Ltd, Basel, Switzerland. pharmacogenomics journal (United States) 2003, 3 (6) p312-9, ISSN1470-269X Journal Code: 101083949 Document type: Journal Article Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS The addition of polyethyleneglycol (PEG) side chains to interferon alpha-2a improves the serum stability and clinical efficacy. Current commercial PEG-INF formulations such as PEGASYS are heterogeneous and contain multiple monopegylated isomers. We have analyzed the activity of nine, purified monopegylated variants …………………………………………………………………………………………………………………………………………………. The possible clinical implications are discussed, which might guide the development of pegylated interferons with improved pharmacological properties. Tags: Comparative Study; Human

Descriptors: *Antiviral Agents--pharmacology--PD; *Interferon Alfa-2a--pharmacology--PD; *Polyethylene Glycols--pharmacology--PD; *Transcription, Genetic--drug effects--DE; Animals; Antiviral Agents--chemistry--CH; Cattle; Cell Line; Dogs; Interferon Alfa-2a--chemistry--CH; Polyethylene Glycols--chemistry--CH; Stereoisomerism; Transcription, Genetic--physiology--PH CAS Registry No.: 0 (Antiviral Agents); 0 (Polyethylene Glycols);76543-88-9 (Interferon Alfa-2a) Record Date Created: 20031211 Record Date Completed: 20040809

Page 33

Note that PEGASYS in also a brand name for computer software

Because the concept of pegylation is not precoordinated with interferon in controlled indexing, the CAS RN for only the non-PEG compound is provided.

1/9/4 DIALOG(R)File 154:MEDLINE(R) (c) format only 2004 The Dialog Corp. All rts. reserv. 16349194 PMID: 15128353 Sudden hearing loss in patients with chronic hepatitis C treated with pegylated interferon/ribavirin. Formann Elisabeth; Stauber Rudolf; Denk Doris-Maria; Jessner Wolfgang; Zollner Gernot; Munda-Steindl Petra; Gangl Alfred; Ferenci Peter Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Austria. American journal of gastroenterology (United States) May 2004, 99 (5) p873-7, ISSN 0002-9270 Journal Code: 0421030 Document type: Journal Article Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS BACKGROUND: Sudden hearing loss has been reported on standard interferon (IFN)-alpha2 therapy. This is the first report on the occurrence of suddenhearing loss in six cases of chronic hepatitis C in temporal relation totreatment with pegylated (PEG)-IFN alfa2a or b/ribavirin combination therapy. Three patients were treated in an ongoing randomized placebo-controlled trial comparing the addition of 200 mg amantadine or placebo to the combination of 180 microg PEG-IFN alpha2a (PEGASYS, Roche, Basel, CH)/wk and 1-1.2 g ribavirin/d (COPEGUS, Roche, Nutley, USA) in de novo patients infected with HCV genotype 1. Sudden hearing loss and tinnitus developed on day 1 and after 4, 23, 25, 36, and 40 wk of treatment, respectively. … Tags: Comparative Study; Female; Human; Male Descriptors: *Amantadine--adverse effects--AE; *Hearing Loss, Sudden --chemically induced--CI; *Hepatitis C, Chronic--drug therapy--DT; *Interferon Alfa-2a--adverse effects--AE; *Interferon Alfa-2b--adverse effects--AE; *Ribavirin--adverse effects--AE; Adult; Amantadine--administration and dosage--AD; Audiometry; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Hearing Loss, Sudden--diagnosis--DI; Hepatitis C, Chronic--diagnosis--DI; Interferon Alfa-2a--administration and dosage--AD; Interferon Alfa-2b--administration and dosage--AD; Middle Aged; Prognosis; RNA, Viral--analysis--AN; Ribavirin--administration and dosage--AD; Risk Assessment; Sampling Studies; Severity of Illness Index CAS Registry No.: 0 (RNA, Viral); 36791-04-5 (Ribavirin); 76543-88-9 (Interferon Alfa-2a); 768-94-5 (Amantadine); 99210-65-8 (Interferon Alfa-2b)


16144091 PMID: 15116695 Pegasys-Copegus combination treats both HIV and hepatitis C. AIDS reader (United States) Apr 2004, 14 (4) p164, ISSN 1053-0894Journal Code: 9206753 Document type: News Languages: ENGLISH Record type: Completed Subfile: AIDS/HIV Tags: Human Descriptors: *Antiviral Agents--therapeutic use--TU; *HIV Infections--drug therapy--DT; *Hepatitis C--drug therapy--DT; *Interferon Alfa-2b--therapeutic use--TU; *Ribavirin—therapeutic use--TU; Drug Combinations CAS Registry No.: 0 (Antiviral Agents); 0 (Drug Combinations); 0 (polyethylene glycol-interferon alfa-2b); 36791-04-5 (Ribavirin); 99210-65-8 (Interferon Alfa-2b)

Page 34

Pegylation may be noted in the abstract, but not be identified in indexing of MEDLINE records.

Interferon in PEGASYS is incorrectly indexed in this example. The source of the error may be imprecise identification in the primary source?


15676426 PMID: 14740531 [Treatment of chronic hepatitis C with PEG-interferon] Lecenje hronicnog hepatitisa C peg-interferonom. Fabri Milotka; Bozic Milena; Delic Dragan; Jesic Rada; Nozic Darko Klinicki centar Novi Sad, Klinika za infektivne bolesti, 21000 Novi Sad,Hajduk Veljkova 1-7. Medicinski pregled (Yugoslavia) Sep-Oct 2003, 56 (9-10) p427-30,ISSN 0025-8105 Journal Code: 2985249R Document type: Clinical Trial; Journal Article ; English Abstract Languages: SERBIAN Record type: Completed Subfile: INDEX MEDICUS INTRODUCTION: Since the discovery of the hepatitis C virus, the etiology of chronic liver diseases has been revealed in great number of patients. However, the treatment of hepatitis C viral infection still hasn't been completely resolved. Antiviral and immunomodulatory effects of interferon, and antiviral effect on the nucleoside analogs were efficient only in small number of patients. Discovery of pegylated interferon brings progress in therapeutic success rates. MATERIAL AND METHODS: Combined therapy with peginterferon alfa-2a ( Pegasys ) 180 mg once a week plus Ribavirin 800 mg a day

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.

.

Tags: Female; Human; Male Descriptors: *Antiviral Agents--administration and dosage--AD; *Hepatitis C, Chronic--drug therapy--DT; *Interferon Alfa-2b--administration and dosage--AD; Adult; Aged; Antiviral Agents--adverse effects--AE; Drug Therapy, Combination; Interferon Alfa-2b--adverse effects--AE; Middle Aged; Ribavirin--administration and dosage--AD CAS Registry No.: 0 (Antiviral Agents); 0 (polyethylene glycol-interferon alfa-2b); 36791-04-5 (Ribavirin); 99210-65-8 (Interferon Alfa-2b)


15660416 PMID: 12934164 Pegylation of interferon alfa: structural and pharmacokinetic properties. Pedder Simon C J Shearwater Corporation, a Division of Inhale Therapeutics, Charlotte,North Carolina 28227, USA. [email protected] Seminars in liver disease (United States) 2003, 23 Suppl 1 p19-22,ISSN 0272-8087 Journal Code: 8110297 Document type: Journal Article; Review; Review, Tutorial Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS The attachment of a polyethylene glycol(PEG) polymer to a protein or peptide is becoming increasingly common within the pharmaceutical industry as a way of altering the activity of the parent molecule. Significant improvements in biological activity with PEG molecules have been seen with several licensed drugs, allowing for product life cycle management, as well as with experimental compounds in development that have pharmaceutical properties making them suitable candidates for pegylation. Among the various disease states that have been targeted for the study of drugs incorporating pegylation technology, the

Page 35

Another example of incorrect indexing—despite accurate compound identification in the original source abstract. Note that pegylation may be cited in non-MeSH chemical indexing, although, in this case, it’s attributed to another form of interferon.

treatment of chronic hepatitis C with interferon-based compounds offers significant potential for clinical impact. Two separate compounds, peginterferon alfa-2a ( PEGASYS ) and peginterferon alfa-2b (PEG-Intron) are now both approved for use alone and in combination with ribavirin for the treatment of chronic hepatitis C.

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.

. Tags: Human Descriptors: *Antiviral Agents--pharmacokinetics--PK; *Interferon Alfa-2a--pharmacokinetics--PK; *Interferon Alfa-2b--pharmacokinetics--PK; *Polyethylene Glycols--pharmacokinetics--PK; Antiviral Agents--chemistry--CH; Antiviral Agents--therapeutic use--TU; Drug Carriers; Hepatitis C, Chronic--drug therapy--DT; Interferon Alfa-2a--chemistry--CH; Interferon Alfa-2a--therapeutic use--TU; Interferon Alfa-2b--chemistry--CH; Interferon Alfa-2b--therapeutic use--TU; Polyethylene Glycols--chemistry--CH; Polyethylene Glycols--therapeutic use--TU CAS Registry No.: 0 (Antiviral Agents); 0 (Drug Carriers); 0 (Polyethylene Glycols); 0 (polyethylene glycol-interferon alfa-2A); 0 (polyethylene glycol-interferon alfa-2b); 76543-88-9 (Interferon Alfa-2a); 99210-65-8 (Interferon Alfa-2b) Record Date Created: 20030822 Record Date Completed: 20040217


15631395 PMID: 12821324 Isolation, structural characterization, and antiviral activity of positional isomers of monopegylated interferon alpha-2a (PEGASYS). Foser Stefan; Schacher Alfred; Weyer Karl A; Brugger Doris; Dietel Elke;Marti Stefan; Schreitmuller Thomas Department of Pharma Technical Operations Biotechnology, Biotech Products, Biotech Development and Production, Hoffmann-La Roche Ltd., Building 066/508, Ch-4070 Basel, Switzerland. Protein expression and purification (United States) Jul 2003, 30 (1) p78-87, ISSN 1046-5928 Journal Code: 9101496 Document type: Journal Article Languages: ENGLISH Record type: Completed Subfile: INDEX MEDICUS Interferon alpha-2a plays an essential role in the treatment of chronic hepatitis C, but it is limited in its efficacy by the short in vivo half-life. To improve the half-life and efficacy, interferon alpha-2a is conjugated with a 40-kDa branched polyethylene glycol moiety (PEG-IFN, PEGASYS). From this preparation the positional PEG-IFN isomers were isolated and characterized by different analytical methods and antiviral assay.

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.

.

Descriptors: *Interferon Alfa-2b--chemistry--CH; *Interferon Alfa-2b--pharmacology--PD; Antiviral Agents--chemistry--CH; Antiviral Agents--isolation and purification--IP; Antiviral Agents--pharmacology--PD; Chromatography, High Pressure Liquid; Electrophoresis, Polyacrylamide Gel;Interferon Alfa-2b--isolation and purification--IP; Isomerism; Models,Molecular; Molecular Structure; Peptide Mapping; Protein Conformation;Spectrum Analysis, Mass CAS Registry No.: 0 (Antiviral Agents); 0 (polyethylene glycol-interferon alfa-2b); 99210-65-8 (Interferon Alfa-2b)? S INTERFERON ALFA-2A AND RIBAVIRIN

Page 36

There is, in fact, a CAS RN for this compound, although it’s omitted in indexing shown here.

Indexing error—again!

Broader strategy to retrieve references to the combined therapy that do not cite product brand names in original titles or abstracts. Note that the portion targeting PEGYLATION does not rely on MeSH indexing alone.

1973 INTERFERON ALFA-2A 3444 RIBAVIRIN S2 201 INTERFERON ALFA-2A AND RIBAVIRIN

? S HEPATITIS C! S3 21804 HEPATITIS C!

? S S2 AND S3 S4 197 S2 AND S3

? S POLYETHYLENE GLYCOLS! OR PEG OR PEGYLATED OR PEGIFN OR PEGINTERFERON 15819 POLYETHYLENE GLYCOLS! 7445 PEG 1032 PEGYLATED 5 PEGIFN 157 PEGINTERFERON S5 20565 POLYETHYLENE GLYCOLS! OR PEG OR PEGYLATED OR PEGIFN OR PEGINTERFERON? S S4 AND S5 S6 140 S4 AND S5

? S DRUG THERAPY, COMBINATION OR DRUG COMBINATIONS 57299 DRUG THERAPY, COMBINATION 26418 DRUG COMBINATIONS S7 82800 DRUG THERAPY, COMBINATION OR DRUG COMBINATIONS? S S6 AND S7 S8 101 S6 AND S7


Sample of titles retrieved…

Use of PEG-interferon alfa-2a plus ribavirin as treatment for chronic HCV hepatitis in a child cured of ALL.Aug 2004

Pilot study of pegylated interferon alfa-2b and ribavirin for recurrent hepatitis C after liver transplantation.Dec 2003

Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.Jul 29 2004

Cost effectiveness of peginterferon alpha-2a plus ribavirin versus interferon alpha-2b plus ribavirin as initial therapy for treatment-naive chronic hepatitis C.

Peginterferon alfa-2a plus ribavirin for treating chronic hepatitis C virus infection: analysis of Mexican patients included in a multicenter international clinical trial.Jul-Sep 2003

Page 37

A Closer Look at “Drug Combination” Indexing in MEDLINE & EMBASE

As Example #3 illustrated, this heading is assigned for drug-biologic, as well as drug-drug, combinations (e.g, PEGASYS).

According to the MeSH Scope note, DRUG COMBINATIONS would not be applicable when the therapeutic agents are not integrated into a single, integrated dosage form. However, this term was, in fact, used in indexing selected citations to PEGASYS.

This MeSH heading could be applicable to products like GLIADEL or BEXXAR.

In EMBASE, the subheading DRUG COMBINATION (CB) is “Used with drugs that are given in combination, when this is a significant aspect of the article.” This could apply to both drug mixtures incorporated into a single dosage form and to drugs administered separately—consecutively or concurrently—in treatment of a given condition. Advantage: broader-based applicability, plus the ability to LINK it directly to specific drug descriptors: S drug name(L)CB.

Page 38

MeSH scope note from DataStarWeb

File 72:EMBASE 1993-2004/Sep W2 (c) 2004 Elsevier Science B.V. Set Items Description --- ----- -----------? S PEGASYS S1 230 PEGASYS

? RANK DE CONTPress ENTER to view the TOP 50 terms or enter a number N to view the top N terms or >N to view terms with more than N items or enter ALL to view all terms? 30Enter title for continuous output or press ENTER for current title option? TOP 30 DESCRIPTORS ASSIGNED TO EMBASE RECORDS FOR PEGASYS Adding title to results...TOP 30 DESCRIPTORS ASSIGNED TO EMBASE RECORDS FOR PEGASYS---------------------------------------------------------RANK: S1/1-230 Field: /DE File(s): 72(Rank fields found in 230 records -- 5212 unique terms) RANK No. Items Term-------- ----- ---- 1 213 HUMAN 2 202 DRUG THERAPY 3 202 DT 4 182 PEGINTERFERON ALPHA2A 5 172 HEPATITIS C 6 168 HEPATITIS C --DRUG THERAPY --DT 7 151 CB 8 151 DRUG COMBINATION 9 139 RIBAVIRIN 10 137 PEGINTERFERON ALPHA2A --DRUG THERAPY --DT 11 129 RIBAVIRIN --DRUG THERAPY --DT 12 128 ADVERSE DRUG REACTION 13 128 AE 14 128 SI 15 128 SIDE EFFECT 16 123 CLINICAL TRIAL 17 121 RIBAVIRIN --DRUG COMBINATION --CB 18 116 CT 19 106 PD 20 106 PHARMACOLOGY 21 101 DRUG EFFICACY 22 91 PEGINTERFERON ALPHA2B 23 89 CM 24 89 DRUG COMPARISON 25 89 SC 26 89 SUBCUTANEOUS DRUG ADMINISTRATION 27 87 DO 28 87 DRUG DOSE 29 86 PEGINTERFERON ALPHA2A --DRUG COMBINATION --CB 30 85 HEPATITIS C VIRUS ---end of results---

? EXIT;YExiting rank... (no terms were saved)

Page 39

EMBASE provides a specific descriptor for the immunomodulator, incorporating the concept of pegylation.

DRUG COMBINATION is also available as a subheading for direct LINKing to specific

drug descriptors

? S PEGINTERFERON ALPHA2A(L)CB 451 PEGINTERFERON ALPHA2A/DE 214503 CB/DE S2 261 PEGINTERFERON ALPHA2A(L)CB

? S RIBAVIRIN(L)CB 4852 RIBAVIRIN/DE 214503 CB/DE S3 2399 RIBAVIRIN(L)CB


? S S4 AND HEPATITIS C 18185 HEPATITIS C S5 235 S4 AND HEPATITIS C



Combination pegylated interferon and ribavirin therapy precipitating acute failure and exacerbating IgA nephropathy [2]

Platelet sparing effect of COX II inhibition used with pegylated interferon alfa-2a for the treatment of chronic hepatitis C: A short term pilot study

Liver fibrosis stage predicts early treatment outcomes with peginterferon plus ribavirin in HIV/hepatitis C virus co-infected patients

Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons

Page 40

Extending the strategy for retrieval of references to the combined therapy that do not cite product brand names

Observations?

Brand/manufacturer name indexing is particularly helpful when searching for information on new drug/device combination products or “hybrid” drug delivery technology.

–EMBASE adds brand/company names to online records whenever they are cited in theoriginal source—whether or not they appear in the title and abstract.

–Other biomedical files with (more selective and less consistent) brand name indexing: Derwent Drug File, International Phamaceutical Abstracts

Policies regarding new drug/device identification in indexing differ.

MEDLINE is slow to add new terms to its highly controlled MeSH indexing vocabulary. Hence, searches on recent technology break-throughs require use of “free text” keywords for retrieval from titles and abstracts, in conjunction with broad category descriptors typically assigned by indexers.

In contrast, EMBASE is quick to adopt new terminology for easier, precordinated retrieval of bibliography on topics such as “drug eluting stents,” “recombinant bone morphogenetic protein 2,” or “peginterferon alpha2.”

Another pertinent example:

– BEXXAR, the 2nd of 2 immunoconjugates approved for use as antineoplastic agents,combines the action of a monoclonal antibody with a radioisotope for delivery of low-doseradiation.

– MEDLINE indexes references to BEXXAR under broad category terms: antibodies, monoclonal AND (iodine radioisotopes OR immunoconjugates). Retrieval must then be narrowed down by adding “free text” keywords: (i131 OR i()131 OR iodine()131)(n)tositumomab.

– EMBASE already includes a specific descriptor for Bexxar: tositumomab I 131.

Drug nonproprietary (generic) names may vary from file to file.

CAS Registry Numbers cannot be relied upon to retrieve all pertinent references in biomedical databases – especially in MEDLINE.

The drug delivery mechanism is not always indexed -- specifically, its major chemical components: e.g., collagen (INFUSE Bone Graft), polymers (GLIADEL).

– When searching for references in clinical bibliographic databases, it’s often necessary to use a group of descriptors that imply discussion of drug delivery technology, such as “biocompatible materials,” “drug implants,” “drug carriers,” “pharmaceutics,” etc.—supplemented with “free text” keywords.

Anticipate inconsistency– Invest time in careful scans of output to locate additional terms, then incorporate them into subsequent, follow-up strategies.– Take advantage of RANKed analysis of indexing (free in most Dialog files) to assist in this process.

Page 41

– Iterative techniques yield the best results.

Page 42

Extending Your ReachExtending Your Reach: Other Biomedical Files: Other Biomedical Files

• Adis Clinical Trials Insight – Good source for details about prospective, as well as ongoing, trials due to coverage of company media releases and detailed indexing of conference papers or poster presentations– Organizes trial data into a structured record with a

standardized, predictable format– Includes details of study designSTUDY DESIGN: multicentre; randomised; double-

blind; parallelSTUDY CONTROLS: drug combination comparisonSTUDY PHASE: Phase IIISTUDY END POINTS: Objective clinical response rate;

Progression-free survivalduration; Progression-free

survival rate;…

DIALOG(R)File 173:Adis Clinical Trials Insight(c) 2004 ADI BV. All rts. reserv.

00049236 809032090 ORIGINAL TITLE: NeoPharm Enrolls First Patient In IL13-PE38QQR ``Precise'' Trial; www.PRECISETrial.com Available for More Study Information.ADIS TITLE: Interleukin-13-PE38QQR vs carmustine polifeprosan-20 wafer: therapeutic use. Glioblastoma Phase III trial initiated.AUTHOR: NeoPharm IncCORPORATE SOURCE: NeoPharm Inc., Lake Forest, Illinois, USA.JOURNAL NAME: Media Release( 0 ) : p.8 Mar 2004. Available from: p.URL: p.http://www.neophrm.comPUBLICATION DATE: 8 March 2004 (20040308)DOCUMENT TYPE: StudyLANGUAGE: EnglishRECORD TYPE: SUMMARYTHERAPEUTIC AREA: Oncology

STUDY MESSAGES: Other: A pivotal trial (PRECISE) comparing the efficacy and tolerability of interleukin-13-PE38QQR and carmustine polifeprosan-20 wafer in patients with recurrent glioblastoma multiforme has been initiated.RESULTS HIGHLIGHTS: Efficacy: A pivotal trial (PRECISE) comparing the efficacy and tolerability of interleukin-13-PE38QQR and carmustine polifeprosan-20 wafer in patients with recurrent glioblastoma multiforme has been initiated. The primary endpoint is survival, with quality of life as a secondary endpoint.COMMENT: Adis Comment: NeoPharm has signed an exclusive worldwide agreement with the US National Institutes of Health and the FDA to develop and commercialise IL13-PE38QQR, which has European and US orphan drug designation for malignant glioma, as well as fast track status in the US for this indication. Some trial details were taken from the trial website (http:// www.precisetrial.com).STUDY PURPOSE: Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumour, with a median survival of <1 year

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from diagnosis. Following surgery, tumour recurrence typically occurs close to the resection cavity. Carmustine polifeprosan-20 wafer (Gliadel (R)) is approved in the US for the treatment of recurrent and newly diagnosed GBM. Interleukin (IL)-13-PE38QQR is a recombinant protein composed of IL-13 and a truncated form of Pseudomonas exotoxin. IL-13 binds to receptors on brain tumour cells, resulting in internalisation of the agent followed by toxin-induced cell death. The pivotal PRECISE (Phase III Randomized Evaluation of Convection Enhanced Delivery of IL13-PE38QQR with Survival Endpoint) trial will compare the efficacy and tolerability of IL13-PE38QQR (NeoPharm) and Gliadel (R) (Guilford Pharmaceuticals) in patients with recurrent GBM. Enrolment in this trial has now begun.AUTHOR COMMENT: According to Sandeep Kunwar (Brain Tumor Research Center at the University of California-San Francisco), "The selective molecular targeting of IL13-PE38QQR, when coupled with positive-pressure Convection Enhanced Delivery, is among the most promising therapies we have observed in controlling aggressive and recurrent brain tumors. We are excited to embark on this Phase III Trial to hopefully validate the potential of this new approach to prolonging survival and improving quality of life in this group of patients."STUDY DETAILS: Design: multicentre, randomised Control: drug comparison Phase: Phase III Methodology: Patients will be randomised 2:1 to receive IL13-PE38QQR or Gliadel (R). EndPoints: Quality of life, Survival Name: PRECISE Companies: NeoPharm IncSUBJECT DETAILS: Type: patients No: 300 Age: >= 18 years Sex: not stated Location: Canada,Germany,Israel,Netherlands,United-Kingdom,USA Disease: Glioblastoma Characteristics: patients will have GBM in first recurrence after tumour resection/biopsy and radiotherapy completed >=4 weeks prior to study entry. Prior chemotherapy is permitted.

TREATMENTS: Interleukin-13-PE38QQR IL3-PE38QQR will be delivered via convection-enhanced delivery (CED) using 2-4 catheters placed in the brain surrounding the resection cavity. CED is designed to deliver the drug as a slow infusion over several days. -------------------------------------------------------------------- Drug/Treatment -------------------------------------------------------------------- Interleukin-13-PE38QQR - NeoPharm Inc --------------------------------------------------------------------Carmustine polifeprosan-20 wafer Up to eight Gliadel (R) wafers will be placed in the tumour resection cavity at the time of surgery. The wafers dissolve over 2-3 weeks, releasing carmustine. -------------------------------------------------------------------- Drug/Treatment -------------------------------------------------------------------- Carmustine polifeprosan-20 wafer - Guilford Pharmaceuticals (Gliadel(R)) --------------------------------------------------------------------

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Drugs: interleukin-13-PE38QQR, carmustine polifeprosan-20 wafer (Gliadel (R)). IL3-PE38QQR will be delivered via convection-enhanced delivery (CED) using 2-4 catheters placed in the brain surrounding the resection cavity. CED is designed to deliver the drug as a slow infusion over several days. Up to eight Gliadel (R) wafers will be placed in the tumour resection cavity at the time of surgery. The wafers dissolve over 2-3 weeks, releasing carmustine.

RESULTS: The primary endpoint is survival, with secondary endpoints including safety and quality of life. Enrolment is expected to take 18 months. Most patients will be treated in the US, with additional centres to be added during the trial.

STUDY DESIGN: multicentre; randomised

STUDY CONTROLS: drug comparison

STUDY PHASE: Phase III

STUDY END POINTS: Quality of life; Survival; Health economics; Pharmacoeconomics

PATIENT AGE: adult

NO. OF PATIENTS: 300

DESCRIPTORS: Carmustine polifeprosan 20 wafer therapeutic use; Alkylating agents therapeutic use; Antineoplastics therapeutic use; DNA antagonists therapeutic use; DNA synthesis inhibitors therapeutic use; Nitrosoureas therapeutic use; Interleukin 13 PE38QQR therapeutic use; Research drug therapeutic use; Glioblastoma treatment; Astrocytoma treatment; Benign tumours treatment; Brain cancer treatment; Brain disorders treatment; Cancer treatment; CNS cancer treatment; CNS disorders treatment; Glioma treatment; Neurological disorders treatment; Tumours treatment; Development status; Media release types; NeoPharm Inc; Companies; Orphan drugs; Research and development; Trial enrolment

Adis CTI is also a source for previewing results of clinical trials and other studies (e.g., pharmacoeconomics) disclosed at clinical conferences as contributed papers or poster presentations.

Adis Clinical Trials Insight

• Primary sources include meeting abstracts published in journal supplements or in separately issued proceedings– Adis often adds data obtained from the actual oral or

poster presentation• Separate records provided for each conference

presentation covered– Can limit retrieval to specific phases (PS= ) and/or study design

keywords

• Records typically include far more detail than found in original author’s abstract

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DIALOG(R)File 173:Adis Clinical Trials Insight(c) 2004 ADI BV. All rts. reserv.

00035199 800928568ORIGINAL TITLE: Sirolimus-eluting stents for bifurcation lesions: comparison to standard bare stents using the T-stenting technique.ADIS TITLE: Sirolimus: therapeutic use. Prevention of coronary artery restenosis Drug-eluting stents in patients with bifurcation lesions.AUTHOR: Weisz G; Dangas G D; Colombo A; Moussa I; Collins M; et alCORPORATE SOURCE: Lenox Hill Heart and Vascular Institute and Cardiovascular Research Foundation, New York, New York, USA.JOURNAL NAME: Circulation( Circulation )106 (Suppl.) : p.519 (plus oral presentation) 5 Nov 2002 PUBLICATION DATE: 5 November 2002 (20021105)DOCUMENT TYPE: StudyLANGUAGE: EnglishRECORD TYPE: SUMMARYTHERAPEUTIC AREA: Ischaemic Heart Disease; Antithrombotics

OUTCOME: Efficacy: sirolimus-eluting stent > bare stent.STUDY MESSAGES: Efficacy: Sirolimus-eluting stents are more effective than bare stents for the prevention of coronary artery restenosis in patients with de novo bifurcation lesions.CLINICAL RELEVANCE: BRESULTS HIGHLIGHTS: Efficacy: Sirolimus-eluting stents were more effective than bare stents for the prevention of coronary artery restenosis in patients with de novo bifurcation lesions. The rate of angiographic restenosis at 6 months was lower in sirolimus-eluting stent recipients compared with bare stent recipients (29 vs 69%).COMMENT: Adis Comment: This study was published as an abstract in the proceedings of the 75th Scientific Sessions of the American Heart Association (AHA), held in Chicago, Illinois, USA in November 2002. Additional information used in this assessment was presented orally at the conference.

STUDY PURPOSE: The restenosis rate is greater in patients with bifurcation lesions undergoing coronary interventions. Sirolimus-eluting stents have ben shown to be effective for the prevention of coronary artery restenosis in patients with simple lesions but their efficacy in patients with complex lesions is unknown. This study compared the efficacy of sirolimus-eluting CYPHER(TM) stents with that of bare stents for the prevention of coronary artery restenosis in patients with de novo bifurcation lesions.

AUTHOR COMMENT: "Implantation of SES (sirolimus-eluting stents) in both branches of bifurcation lesions is safe and feasible."

STUDY DETAILS: Design: multicentre, prospective Control: drug + nondrug vs nondrug comparison Phase: Phase II EndPoints: Coronary revascularisation event rate, Late loss, Lumen parameters, Minimal lumen diameter, Restenosis, Stenosis, Thrombolysis in myocardial infarction patency

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SUBJECT DETAILS: Type: patients No: 44 Age: mean 66 years Sex: not stated Location: not-stated Disease: Coronary-artery-restenosis, Coronary-disorders Characteristics: the target lesion was a left anterior descending/diagonal bifurcation lesion in 80-92% of patients across treatment groups. Reference vessel diameter was 2.5-3.5mm.

TREATMENTS: Bare stent Controls received bare stents. -------------------------------------------------------------------- Drug/Treatment -------------------------------------------------------------------- Coronary-stenting --------------------------------------------------------------------Sirolimus-eluting stent -------------------------------------------------------------------- Drug/Treatment -------------------------------------------------------------------- Sirolimus Coronary stenting --------------------------------------------------------------------Drug: sirolimus. Treatment: coronary stenting. Patients received sirolimus-eluting CYPHER(TM) stents using the T-stenting technique. Controls received bare stents.

RESULTS: -------------------------------------------------------------------- Angiographic Bare stent Sirolimus-eluting stent outcomes ------------------------ ----------------------- main branch side branch main branch side branch -------------------------------------------------------------------- Lesion length (mm) 13.4 10.7 11.4 10.2 Reference diameter 2.8 2.2 2.8 2.4 (mm) Minimal lumen diameter (mm): preprocedure 0.79 0.77 0.93 0.75 postprocedure 2.69 1.98 2.97 2.19 Diameter stenosis (%): preprocedure 70.1 68.4 66.4 68.8 postprocedure 12.4 20.8 9.9 18.6 TIMI grade 3 flow 100 100 100 100 at 6 months (% patients) Restenosis at 6 9/13 9/13 1/17 5/17 months (patients) --------------------------------------------------------------------

TIMI = Thrombolysis In Myocardial Infarction.

Six-month outcomes Overall, the angiographic restenosis rate at 6 months was lower in sirolimus- eluting stent recipients compared with controls (29 vs 69% of patients). In sirolimus-eluting stent recipients, there was almost no change in minimal lumen diameter or diameter stenosis in the main branch, while there was a slight increase in minimal lumen diameter and diameter stenosis in the side branch. Late loss was 0 in the main branch, but

Page 47

somewhat higher in the side branch in sirolimus-eluting stent recipients. The incidence of target lesion revascularisation was 15% in sirolimus-eluting stent recipients and 38% in controls. The pattern of restenosis was mainly diffuse in controls and focal in sirolimus-eluting stent recipients.

STUDY DESIGN: multicentre; prospective

STUDY CONTROLS: drug + nondrug vs nondrug comparison

STUDY PHASE: Phase II

STUDY END POINTS: Coronary revascularisation event rate; Late loss; Lumen parameters; Minimal lumen diameter; Restenosis; Stenosis; Thrombolysis in myocardial infarction patency; Cardiac parameters; Cardiovascular disorders; Cardiovascular event rates; Cardiovascular function parameters; Heart disorders; Valvular heart disorders

NO. OF PATIENTS: 44

DESCRIPTORS: Sirolimus therapeutic use; Enzyme inhibitors therapeutic use; Immunomodulators therapeutic use; Immunosuppressants therapeutic use; Kinase inhibitors therapeutic use; Macrolides therapeutic use; mTOR inhibitors therapeutic use; Protein kinase inhibitors therapeutic use; Coronary artery restenosis prevention; Cardiovascular disorders prevention; Coronary disorders prevention; Heart disorders prevention; Vascular disorders prevention; Vascular restenosis prevention; Coronary stenting; Coronary interventions; Heart surgery; Stent placement; Surgery

Adis Clinical Trials Insight

• To retrieve records for presentations at specific meetings, search the conference title (no need to worry about where & when to truncate—usually spelled out in full) and its abbreviation– Search without field qualifiers– This “free text” technique will enable you to locate

conference paper entries originating either from journal supplements or from separately published proceedings

– AND with publication date – when meeting was held (if known)

– Add other factors as needed (e.g., product name)

Page 48

BIOSIS Previews

Cross-file search strategies that include BIOSIS Previews, in addition to MEDLINE & EMBASE, invariably uncover references not indexed elsewhere.

Extending Your ReachExtending Your Reach: Other Biomedical Files: Other Biomedical Files

• BIOSIS Previews – Scope extends beyond clinical literature to include more “basic science” sources– Emphasis on research, rather than routine clinical practice or

established procedures, making it a good source for searching medical technologies under development & preclinical literature

– Provides access to additional resources not found in other “Big 4” files

• Books, theses, reports, U.S. patents, proceedings of scientific symposia, conference papers & poster presentations at scientific meetings

– Unfortunately, BIOSIS records for individual presentations at scientific conferences (other than FASEB) usually do notinclude abstracts online

Isolating References to Conference Papers Isolating References to Conference Papers in BIOSIS Previewsin BIOSIS Previews

• Use Document (Publication) Type indexing– DT=MEETING ABSTRACT– DT=MEETING PAPER– DT=MEETING POSTER

• Searching keywords from the conference titleis another option– S CT=(international()conference(1w)antiviral()research)

• Conference location, year, and/or sponsor are also directly searchable– S CL=Tucson– S CL=(providence()(rhode()island or RI))– S CY=2004– S SP=(european()society(1w)investigative()dermatology)

Note, also the Concept Code CC=00520 on p. 49

Page 49

DIALOG(R)File 55:Biosis Previews(R)(c) 2004 BIOSIS. All rts. reserv.

0013071381 BIOSIS NO.: 200100243220 Direct immobilization of bone morphogenetic protein 2 (BMP-2) on metal implants for enhanced osseointegrationAUTHOR: Jennissen Herbert P (Reprint); Chatzinikolaidou Maria (Reprint); Rumpf Heike M (Reprint)AUTHOR ADDRESS: Universitaet Essen, Hufelandstr 55, D-45122, Essen, Germany **GermanyJOURNAL: FASEB Journal 15 (4): pA68 March 7, 2001 2001MEDIUM: printCONFERENCE/MEETING: Annual Meeting of the Federation of American Societiesfor Experimental Biology on Experimental Biology 2001 Orlando, Florida,USA March 31-April 04, 2001; 20010331ISSN: 0892-6638DOCUMENT TYPE: Meeting; Meeting AbstractRECORD TYPE: AbstractLANGUAGE: English

ABSTRACT: Biologically active recombinant human BMP-2 (rhBMP-2) was prepared in an E. coli system (1). Flat electropolished titanium (size 0.8 X 10 X 15 mm) plates (1) and porous-titanium-alloy plasma spray coated titanium-alloy implants (10 mm in length) (2) were surface-enhanced by a novel procedure with chromosulfuric acid (CSA) (1). Characteristically the treatment of metals with chromosulfuric acid (1) leads to ultrahydrophilic (3) bioadhesive surfaces. rhBMP-2 was immobilized by covalent and non-covalent methods (1,2) on these CSA-treated surfaces, which showed 5-6-fold higher protein binding capacities than Ti-controls. The amount of rhBMP-2 immobilized ranged from 1-200 ng/cm2. Biocoated surfaces of this type may function as chemotactic as well as juxtacrine interfaces in stimulating tissue growth and implant integration (1). Direct immobilization of BMP-2 on the implant surface thus eliminates the need for a separate BMP-2 carrier- or delivery system such as collagen, as is widely employed by others. Such surface-immobilized protein layers can be further studied by pertinent methods (4). Employing an in vivo healing model in sheep (2) it can be shown that the rhBMP-2 coated implants displayed a greatly improved osseointegration with a minimal residual gap within 28 days.

DESCRIPTORS: MAJOR CONCEPTS: Biomedical Engineering--Allied Medical Sciences; Equipment, Apparatus, Devices and Instrumentation; Skeletal System-- Movement and Support BIOSYSTEMATIC NAMES: Bovidae--Artiodactyla, Mammalia, Vertebrata, Chordata, Animalia ORGANISMS: sheep (Bovidae) ORGANISMS: PARTS ETC: bone--skeletal system COMMON TAXONOMIC TERMS: Animals; Artiodactyls; Chordates; Mammals; Nonhuman Vertebrates; Nonhuman Mammals; Vertebrates CHEMICALS & BIOCHEMICALS: chromosulfuric acid; recombinant human bone morphogenetic protein 2--osseointegration METHODS & EQUIPMENT: direct immobilization--cytological method; metal implant--bone morphogenetic protein 2 coated, prosthetic MISCELLANEOUS TERMS: Meeting Abstract; Meeting AbstractCONCEPT CODES: 10511 Biophysics - Bioengineering 00520 General biology - Symposia, transactions and proceedings 18004 Bones, joints, fasciae, connective and adipose tissue - Physiology and biochemistryBIOSYSTEMATIC CODES: 85715 Bovidae

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Indexing of conference proceedings

Complementary ResourcesComplementary Resources

• Derwent Drug File– Another source of conference paper indexing– Includes citations to journal supplements where meeting

abstracts typically appear• MEDLINE & EMBASE do not provide thorough or timely

indexing of journal supplements– Derwent records DO include abstracts for individual

presentations• To isolate references to conference papers, search the

phrase “conference abstract” in the record text• Conference title, location, and date are also directly

searchable as keywords in record text

– Remember, also, that DDF is one of the few bibliographic databases that includes product brand name indexing

DIALOG(R)File 377:Derwent Drug File(c) 2004 Thomson Derwent. All rts. reserv.

01073020 DERWENT ACCESSION NUMBER: 2004-14790 Sirolimus-eluting stents in unprotected left main coronary arteries.Chieffo A; Michev I; Stankovic G; Airoldi F; Montorfano M; Orlic D; Rogacka R; Colombo A(Milan, It.)Eur.Heart J. 24, Abstr.Suppl., 431, 2003CODEN: EHJODF ISSN: 0195-668X LANGUAGE: English RECORD TYPE: AbstractREPRINT ADDRESS: San Raffaele, Emodinamica, Milan, Italy.

ABSTRACT:The safety and efficacy of Cypher sirolimus-eluting stents (Cordis) wasinvestigated in 14 patients (12 male; mean age 59.3 yr) with unprotectedleft main coronary artery stenosis. Minimal lumen diameter increased from1.23 at baseline to 3.7 mm after the procedure, whereas mean diameterstenosis decreased from 61.8% to 10.23%. Acute gain was 2.1 mm. At 30 daysclinical follow-up, no patient suffered from death, MI, repeatedrevascularization or thrombotic event. Results demonstrate the safety andfeasibility of Cypher sirolimus-eluting stents. (conference abstract:European Society of Cardiology Congress, 30th August-3rd September 2003,Vienna, Austria). (No EX). LINK TERMS:*01*; SIROLIMUS --TR; CYPHER --TR; CORDIS --FT; STENOSIS --TR; RAPAMYCIN --RN; IN-VIVO --FT; CASES --FT; RESTENOSIS-INHIBITOR --FT; STENT --FT; ANTIBIOTICS --FT; IMMUNOSUPPRESSIVES --FT; TR --FT;*01*; 53123-88-9

CAS(R) REGISTRY NUMBERS: *01* 53123-88-9SECTION HEADINGS: Vasoactive (58)THEMATIC GROUPS: T (Therapeutics)

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International Pharmaceutical Abstracts

Contributes references to specialty journals in the pharmaceutics & pharmaceutical technology subject area.

Also includes product brand name indexing (when proprietary names are cited in primary sources) and LINK terms for coordinating concepts such as “stents,” “carriers,” “coatings,” “implants,” or “combined therapy” with specific drug or other chemical substance descriptors.

CHEMICAL/BRAND NAMES: Pegasys; RebetolDESCRIPTORS: Antivirals -- ribavirin; Combined therapy -- peginterferon alfa-2a and ribavirin; Combined therapy -- ribavirin and peginterferon alfa-2a; Immunotherapy -- peginterferon alfa-2a; Hepatitis C -- ribavirin ; Hepatitis C -- peginterferon alfa-2a

CHEMICAL/BRAND NAMES: GliadelDESCRIPTORS: Implants -- carmustine; Release -- carmustine; Metabolism -- carmustine; Drugs, body distribution -- carmustine; Pharmacokinetics -- carmustine; Urine levels -- carmustine; Antineoplastic agents -- carmustine

DIALOG(R)File 74:Int.Pharm.Abs(c) 2004 Amer.Soc.of Health-Sys.Pharm. All rts. reserv.

00386564 41-12250CONTROLLED RELEASE OF RHBMP-2 FROM COLLAGEN MINIPELLET AND THE RELATIONSHIPBETWEEN RELEASE PROFILE AND ECTOPIC BONE FORMATIONMaeda, H; Sano, A; Fujioka, KSumitomo Pharmaceut Co Ltd, Formulat Res Labs, 3-45 Kurakakiuchi 1-Chome, Ibaraki, Osaka 5670878, Japan [email protected] Journal of Pharmaceutics (Netherlands), V275, (1-2), p109-122, 2004CODEN: IJPHDE ISSN: 0378-5173 LANGUAGE: English RECORD TYPE: Abstract

The purpose of this study was to examine the effects of various additives on the profiles of rhBMP-2 release from minipellet, which is a sustained release formulation for protein drugs using collagen as a carrier, and to examine the influence of varying release profiles on ectopic bone formation. When the amount of rhBMP-2 remaining in the preparation after subcutaneous implantation to mice was examined, it was found that the addition of sucrose, glucose, PEG4000, alanine (Ala) or acacia in a concentration of 20% (w/w) to the minipellet with 5% (w/w) of rhBMP-2 did not accelerate the drug release in a noticeable manner, while the addition of sodium chondroitin sulfate, glutamic acid (Glu) or citric acid accelerated the release of rhBMP-2 markedly. When two types of minipellets (a fast release type added with 20% Glu and 20% Ala and a slow release type without additives) containing varying amounts of rhBMP-2 were implanted subcutaneously to mice, the soft X-ray observation, histological examination and measurement of calcium formation 3 weeks after implantation revealed extensive ectopic bone formation in mice implanted with the fast release type preparation. Ectopic bone formation was dose-dependent. The result of this study exhibited that the effects of controlled release formulation of rhBMP-2 on bone formation vary depending on their release profiles, and suggested that combination of initial burst and sustained release was effective for bone formation. It was also shown that minipellet is useful as a controlled release formulation which can release rhBMP-2 to areas around the implanted site with various release profiles. (31 references)

CAS REGISTRY NUMBERS: 246539-15-1 (Dibotermin alfa); 9007-34-5 (Collagen); 5996-10-1 (Dextrose); 57-50-1 (Sucrose); 25322-68-3 (Polyethylene glycol 4000); 56-41-7 (Alanine); 9000-01-5 (Acacia); 9082-07-9 (Chondroitin sodium sulfate); 56-86-0 (Glutamic acid); 77-92-9 (Citric acid)CHEMICAL/BRAND NAMES: rhBMP-2; Bone morphogenetic protein-2; Glucose; PEG 4000DESCRIPTORS: Release -- dibotermin alfa; Proteins -- dibotermin alfa; Sustained action medications -- dibotermin alfa; Pharmacodynamics --

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dibotermin alfa; Formulations -- dibotermin alfa; Carriers -- collagen; Pellets -- collagen; Excipients -- dextrose; Excipients -- sucrose; Excipients -- polyethylene glycol 4000; Excipients -- alanine; Excipients -- acacia; Excipients -- chondroitin sodium sulfate; Excipients -- glutamic acid; Excipients -- citric acid; Concentration -- excipientsSECTION HEADINGS: Biopharmaceutics (08); Pharmaceutics (09); Pharmacology (11)

DIALOG(R)File 74:Int.Pharm.Abs(c) 2004 Amer.Soc.of Health-Sys.Pharm. All rts. reserv.

00316631 37-11948BONE REGENERATION WITH RECOMBINANT HUMAN BONE MORPHOGENETIC PROTEIN-2(RHBMP-2) USING ABSORBABLE COLLAGEN SPONGES (ACS): INFLUENCE OF PROCESSINGON ACS CHARACTERISTICS AND FORMULATIONFriess, W.; Uludag, H.; Foskett, S.; Biron, R.Dept. of Pharm. Tech., Friedrich-Alexander Univ., Cauerstr. 4, 91058 Erlangen, Germany Internet: [email protected] Development and Technology (USA), V4, (3), p387-396, 1999CODEN: PDTEFS ISSN: 1083-7450 LANGUAGE: English RECORD TYPE: Abstract

Three implantable collagen sponges were soaked with bone morphogeneticprotein-2 (recombinant human bone morphogenetic protein 2), and the effectsof sponge mass, crosslinking, and sterilization were studied.

.

.

.CAS REGISTRY NUMBERS: 156860-51-4 (Bone morphogenetic protein-2); 9007-34-5 (Collagen)CHEMICAL/BRAND NAMES: Recombinant human bone morphogenetic protein 2DESCRIPTORS: Proteins -- bone morphogenetic protein-2, sponges; Carriers -- collagen, bone morphogenetic protein-2; Sponges -- collagen, bone morphogenetic protein-2; Sterilization -- bone morphogenetic protein-2, sponges; Stability -- bone morphogenetic protein-2, sponges; Precipitation -- bone morphogenetic protein-2, sponges; Hydrogen ion concentration -- bone morphogenetic protein-2, sponges; Temperature -- bone morphogenetic protein-2, sponges; Weight -- sponges, bone morphogenetic protein-2; Salts -- effects, bone morphogenetic protein-2; Concentration -- salts, bone morphogenetic protein-2SECTION HEADINGS: Pharmaceutics (09); Drug stability (10)

Complementary ResourcesComplementary Resources

• SciSearch– Multi-disciplinary in scope, with coverage of 5,200 journals, provides access to

a cross-section of literature that includes not only biomedical journals, but also engineering, mathematics, biophysics, and pharmaceutical technology resources

– Cover-to-cover indexing not found elsewhere– Extremely timely; very short lag time– Natural language indexing reflects terminology changes, new concept

vocabulary – Cited reference search capabilities

• CA Search– Another source for pharmaceutics-oriented literature. Also indexes conference

proceedings & provides a selective gateway to the patent literature

• JICST– Coverage of literature published in Japan, encompassing all fields of science,

technology, and medicine. Indexing of 6,000 journals + conference papers, technical reports

• PASCAL– Often yields additional references to scientific & technical literature, including

conference papers

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Extending Your Reach: Engineering Literature Resources

File 8:Ei Compendex(R) 1970-2004/Sep W1 (c) 2004 Elsevier Eng. Info. Inc.

Set Items Description --- ----- -----------? S CYPHER S1 20 CYPHER

? T S1/6/1-7

1/6/106838224 Title: pH-Sensitive Cyanine Dyes for Biological Applications

1/6/206749894 Title: A Cypher/ZASP Mutation Associated with Dilated Cardiomyopathy Alters the Binding Affinity to Protein Kinase C

1/6/306450598 Title: Characterization and in vivo functional analysis of splice variants of cypher

1/6/406129525 Title: Man-portable networked sensor system Conference Title: Sensor Technology for Soldier Systems Publication Year: 1998

1/6/505951361 Title: An improved lower bound for the time complexity of mutual exclusion Conference Title: 20th Annual ACM Symposium on Principles of DistributedComputing

1/6/604515790 Title: Sikorsky aircraft's unmanned aerial vehicle, cypher: system description and program accomplishments Conference Title: Proceedings of the 1995 51st Annual Forum. Part 1 (of 3)

1/6/704366717 Title: Chaotic bit sequences for stream cipher cryptography and their correlation functions Conference Title: Chaotic Circuits for Communication

? S SIROLIMUS AND STENT? 7 SIROLIMUS 675 STENT? S2 0 SIROLIMUS AND STENT?

? S DRUG()(ELUTING OR COATED)()STENT? 22428 DRUG 475 ELUTING 46185 COATED 675 STENT? S3 7 DRUG()(ELUTING OR COATED)()STENT?

Page 54

Beware of the ambiguity of brand names when searched without qualifying keywords to indicate desired applications!

When searching for specific medical applications in engineering databases, it may be necessary to use a broad, “free text” approach.

? S DRUG()DELIVERY 22428 DRUG 25548 DELIVERY S4 3387 DRUG()DELIVERY


Title: Application of fluorescence correlation spectroscopy for drug delivery to tumor tissue Conference Title: Laser Microscopy

Title: Geometrical effects in mechanical characterizing of microneedle for biomedical applications

Title: Surface stress, kinetics, and structure of alkanethiol self-assembled monolayers

Title: Supramolecular assemblies based on copolymers of PEG600 and functionalized aromatic diesters for drug delivery applications

Title: PH-Gated porosity transitions of polyelectrolyte multilayers in confined geometries and their application as tunable Bragg reflectors

Title: Three-month, zero-order piroxicam release from monodispersed double-walled microspheres of controlled shell thickness

Title: Influence of nitinol wire surface preparation procedures, on cell surface interactions and polymer coating adherence Conference Title: Medical Device Materials - Proceedings of the Materialsand Processes for Medical Devices Conference 2003

Title: Intravascular brachytherapy with radioactive stents produced by ion implantation Conference Title: 13th International conference on Ion beam modificationof Materials

In the engineering literature, topical emphasis shifts to durability testing, mathematical analysis, and materials preparation, manufacturing, and characterization.

DIALOG(R)File 8:Ei Compendex(R)(c) 2004 Elsevier Eng. Info. Inc. All rts. reserv.

06897932 E.I. No: EIP04258217698 Title: Influence of nitinol wire surface preparation procedures, on cell surface interactions and polymer coating adherence Author: Carroll, W.M.; Rochev, Y.; Clarke, B.; Burke, M.; Bradley, D.J.;Plumley, D.L.; Proft, J. Corporate Source: Natl. Ctr. for Biomed. Eng. Science National Universityof Ireland, Galway, Ireland Conference Title: Medical Device Materials - Proceedings of the Materialsand Processes for Medical Devices Conference 2003 Conference Location: Anaheim, CA., United States Conference Date:20030908-20030910 Sponsor: ASM International Source: Medical Device Materials - Proceedings of the Materials and Processes for Medical Devices Conference 2003 Medical Device Materials -Proceedings of the Materials and Processes for Medical Devices Conference 2003 Publication Year: 2003 ISBN: 0871707985

Page 55

Coverage of conference proceedings could complement retrieval from biomedical databases.

Although DRUG DELIVERY is not a controlled vocabulary Descriptor in Compendex, the phrase frequently occurs in record titles and abstract text.

Language: English Document Type: CA; (Conference Article) Treatment: X; (Experimental) Journal Announcement: 0406W4 Abstract: As the use of nitinol continues to grow in medical applications, so also does the need to acquire additional fundamental information regarding the stability of the material, in specific areas of deployment in the body. For devices fabricated from wires, data relating to the influence of wire surface state is an important consideration In the present study a range of wires, all in the shape set condition, but with subtle variations in surface preparation procedures are characterized in terms of surface roughness, cell surface interactions and polymer coating adhesion. Pickling of the wire leads to the roughest surface state while mechanical polishing after etching and pickling considerably reduces the surface roughness. Cell growth on all the different wire surfaces is good with the smoothest surface leading to the lowest degree of cell spreading. Quantitative procedures for measuring the adherence of polymer coatings on stents has become a very important experimental necessity as drug eluting stents become more widely used. This work reports on thefirst data measured for polymer coatings on nitinol wire substrates. Themeasured values of adhesion energy clearly show that adhesion is best whenthe wire surface state is at its roughest. 11 Refs. Descriptors: *Biomedical engineering; Cells; Polymers; Oxides; Coatings;Wire; Body fluids; Medical applications; Poisson ratio; Biocompatibility;Surface roughness; Corrosion resistance; Fracture toughness Identifiers: Surface preparation procedures; Adhesion energy; Cellsurface interactions; Gene expressions Classification Codes: 461.9.1 (Immunology); 539.2.1 (Protection Methods) 461.1 (Biomedical Engineering); 461.2 (Biological Materials); 815.1(Polymeric Materials); 813.2 (Coating Materials); 535.2 (Metal Forming);408.1 (Structural Design, General); 461.9 (Biology); 931.2 (PhysicalProperties of Gases, Liquids & Solids); 539.1 (Metals Corrosion); 422.2(Test Methods); 539.2 (Corrosion Protection) 461 (Bioengineering); 815 (Polymers & Polymer Science); 804 (ChemicalProducts Generally); 813 (Coatings & Finishes); 535 (Rolling, Forging &Forming); 408 (Structural Design); 931 (Applied Physics Generally); 539(Metals Corrosion & Protection; Metal Plating); 422 (Strength of BuildingMaterials; Test Equipment & Methods) 46 (BIOENGINEERING); 81 (CHEMICAL ENGINEERING, PROCESS INDUSTRIES); 80 (CHEMICAL ENGINEERING, GENERAL); 53 (METALLURGICAL ENGINEERING, GENERAL);40 (CIVIL ENGINEERING, GENERAL); 93 (ENGINEERING PHYSICS); 42 (BUILDINGMATERIALS PROPERTIES & TESTING)

Selected Ei COMPENDEX Classification Codes

CC=46 (BIOENGINEERING)CC=461.1 (BIOMEDICAL ENGINEERING)CC=461.2 (BIOLOGICAL MATERIALS)CC=461.3 (BIOMECHANICS)CC=461.4 (HUMAN ENGINEERING)CC=461.5 (HUMAN REHABILITATION ENGINEERING)CC=461.6 (MEDICINE)CC=461.7 (HEALTH CARE)CC=461.8 (BIOTECHNOLOGY)CC=461.8.1 (GENETIC ENGINEERING)CC=461.9 (BIOLOGY)CC=461.9.1 (IMMUNOLOGY)CC=462 (MEDICAL ENGINEERING & EQUIPMENT)CC=462.1 (BIOMEDICAL EQUIPMENT, GENERAL)CC=462.2 (HOSPITALS, EQUIPMENT & SUPPLIES)CC=462.3 (DENTAL EQUIPMENT & SUPPLIES)CC=462.4 (PROSTHETICS)CC=462.5 (BIOMATERIALS)

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File 4:INSPEC 1983-2004/Sep W1 (c) 2004 Institution of Electrical Engineers

Set Items Description --- ----- -----------? S DRUG()DELIVERY 5631 DRUG 26266 DELIVERY S1 1067 DRUG()DELIVERY

? T S1/6/1-9

1/6/18097010 INSPEC Abstract Number: A2004-20-8770G-022 Title: The effects of drugs on Pluronic F127 structure Publication Date: 2004

1/6/28096989 INSPEC Abstract Number: A2004-20-8770J-034 Title: Applications of electrospinning: tissue engineering scaffolds and drug delivery system Publication Date: 2004

1/6/38095179 INSPEC Abstract Number: A2004-20-8120T-031 Title: Development of porous polymer-ceramic composites as bone grafts Publication Date: 2002

1/6/48089300 INSPEC Abstract Number: A2004-20-8120S-023 Title: Enzymatically degradable and pH-sensitive hydrogels for colon-targeted oral drug delivery. I. synthesis and characterization Publication Date: 15 June 2004

1/6/58087059 INSPEC Abstract Number: A2004-20-6185-002, B2004-10-0580-006 Title: Coarse-grained simulation of polymer translocation through an artificial nanopore Publication Date: 27 April 2004

1/6/68085145 INSPEC Abstract Number: A2004-20-8728-005, B2004-10-7510D-054 Title: Role of transdermal potential difference during iontophoretic drug delivery Publication Date: Sept. 2004

1/6/78081773 INSPEC Abstract Number: B2004-10-8360-169 Title: Quasiresonant flyback converter for transdermal drug delivery applications Publication Date: 2004

1/6/88081675 INSPEC Abstract Number: B2004-10-7520-010 Title: Applications of soft-switching full-bridge converter and rotational electric field to transdermal drug delivery Publication Date: 2004

1/6/98076244 INSPEC Abstract Number: A2004-20-8760M-007, B2004-10-7530B-010 Title: Finger doses received during /sup 18/FDG injections calculated with Monte Carlo Simulations Publication Date: Aug. 2004

Page 57

? T S1/9/2

1/9/2DIALOG(R)File 4:INSPEC(c) 2004 Institution of Electrical Engineers. All rts. reserv.

8096989 INSPEC Abstract Number: A2004-20-8770J-034 Title: Applications of electrospinning: tissue engineering scaffolds and drug delivery system Author(s): Shanmugasundaram, S.; Griswold, K.A.; Prestigiacomo, C.J.;Arinzeh, T.; Jaffe, M. Author Affiliation: Dept. of Biomed. Eng., New Jersey Inst. of Technol.,Newark, NJ, USA Conference Title: Proceedings of the IEEE 30th Annual Northeast Bioengineering Conference (IEEE Cat. No.04CH37524) p.140-1 Editor(s): Schreiner, S.; Cezeaux, J.L.; Muratore, D.M. Publisher: IEEE, Piscataway, NJ, USA Publication Date: 2004 Country of Publication: USA xxiii+262 pp. ISBN: 0 7803 8285 4 Material Identity Number: XX-2004-00999 U.S. Copyright Clearance Center Code: 7803-8285/04/$20.00 Conference Sponsor: BEACON; Tyco Healthcare; Reebok; BEI; The Whitaker Found Conference Date: 17-18 April 2004 Conference Location: Springfield, MA, USA Language: English Document Type: Conference Paper (PA) Treatment: Practical (P); Experimental (X) Abstract: The potential importance of electrospun nanofibers on the performance of fiber-based medical devices is under assessment. Initial work has focused on the behavior of tissue engineering scaffolds comprised of polylactide nanofibers and the utility of such nanofibers as a package for drug delivery. Electrospinning was utilized to fabricate poly-L-lactide (PLLA) non-woven mats of two distinctly different fiber diameters (13 micron and about 130 nanometers). The potential of these non-woven mats as tissue engineering scaffolds was assessed by cell proliferation studies of human mesenchymal stem cells (hMSCs). Electrospun fiber mats were characterized for fiber diameter, porosity, pore size and pore size distribution. The electrospun scaffolds achieved a high surface area and porosity. MSCs were seeded on to the PLLA scaffolds and the cell-polymer constructs were cultured under static culture conditions. Cell proliferation studies was performed, with the results showing that hMSCs tend to proliferate more on nanofiber scaffolds than on the conventional diameter microfiber scaffolds. For the development of the drug delivery system, targeted for catheter delivery through small diameter bloodvessels, poly (D,L-lactide-coglycolide) (DLPLGA) nanofibers were electrospun from a tetrahydrofuran solvent. Three different concentration ratios of DLPLGA, 85/15, 80/20, and 75/25 were analyzed as the base polymer for drug release studies. A highly researched chemotherapy compound was chosen as a model compound for release studies. A homogeneous solution of polymer and drug was electronspun and the resulting nanofibers were analysed for drug incorporation and retention of drug chemistry. (2 Refs) Subfile: A Descriptors: biomedical materials; blood vessels; catheters; cellularbiophysics; drug delivery systems; materials preparation; nanostructuredmaterials; polymer fibres; porosity; tissue engineering Identifiers: electrospinning; tissue engineering scaffolds; drug deliverysystem; electrospun nanofibers; fiber-based medical devices; polylactidenanofibers; poly-L-lactide nonwoven mats; human mesenchymal stem cells;fiber diameter; porosity; pore size; pore size distribution; high surfacearea; cell-polymer constructs; static culture conditions; catheter delivery; small diameter blood vessels; tetrahydrofuran solvent; chemotherapycompound Class Codes: A8770J (Prosthetics and other practical applications);A8770G (Patient care and treatment); A8725 (Cellular biophysics); A8120S (Preparation of polymers and plastics) Copyright 2004, IEE

Page 58

Controlled DE is available in INSPEC

? S DRUG()DELIVERY()SYSTEMS 5631 DRUG 26266 DELIVERY 1200342 SYSTEMS S2 757 DRUG()DELIVERY()SYSTEMS? S S2/DE S3 665 S8/DE

A Selection of INSPEC Device-Related Class Codes

CC=A8700 Biophysics, medical physics, & biomedical engineeringCC=A8716 BiothermicsCC=A8725 Cellular biophysicsCC=A8728 BioelectricityCC=A8730C Electrical activity in neurophysiological processesCC=A8730E External and internal data communications, nerve conduction and

synaptic transmissionCC=A8740 Biomagnetism)CC=A8745 Biomechanics, biorheology, biological fluid dynamicsCC=A8745B Mechanical properties of tissues & organsCC=A8745D Physics of body movementsCC=A8745F Rheology of body fluidsCC=A8745H Haemodynamics, pneumodynamicsCC=A8750 Biological effects of radiationsCC=A8750C Bioacoustics (sonic and ultrasonic effects on living matter)CC=A8750G Biological effects of ionizing radiations (UV, X-RAYS)CC=A8760 Medical & biomedical uses of fields, radiationsCC=A8760B Sonic and ultrasonic radiation (medical uses)CC=A8760D Electric & magnetic fields (medical uses)CC=A8760F Laser applications in medicineCC=A8760G Laser beams, microwaves & other electromagnetic waves (medical uses)CC=A8760I Medical magnetic resonance imaging & spectroscopyCC=A8760J X-rays & particle beams (medical uses)CC=A8760K Nuclear medicine, emission tomographyCC=A8760L Preparation of radioactive materials for medical usesCC=A8760M Radiation dosimetryCC=A8760P Radiation protectionCC=A8760R Radioactive pollution & natural radioactivity: health effectsCC=A8765 Aerospace biophysics & medical physics CC=A8770 Biomedical engineeringCC=A8770E Patient diagnostic methods & instrumentationCC=A8770F ElectrodiagnosticsCC=A8770G Patient care and treatmentCC=A8770H Radiation therapyCC=A8770J Prosthetics & other practical applicationsCC=A8780 Biophysical instrumentation & techniquesCC=A8780B BiosensorsCC=A8790 Other topics in biophysics, medical physicsCC=B7500 Medical physics & biomedical engineeringCC=B7510 Biomedical measurement & imagingCC=B7510B Radiation & radioactivity applications in biomedicineCC=B7510D Bioelectric signalsCC=B7520 Patient care & treatmentCC=B7520C Radiation therapyCC=B7520E Prosthetics & orthoticsCC=B7520H Aids for the handicappedCC=B7530 Health PhysicsCC=B7530B Radiation protection & dosimetryCC=B7540 Hospital EngineeringCC=C1290L Systems theory applications in biology & medicineCC=C3385 Biological & medical control systemsCC=C3385C Prosthetic & orthotic control systemsCC=C7140 Medical administrationCC=C7330 Biology and medical computingCC=D2060 Health care applications

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Caution: Many drug delivery systems will be indexed under more specific materials + applications terms/classification codes, rather than the general Descriptor.

A Pertinent Dialindex / OneSearch Category on Dialog

MEDDEV: Medical Devices

Files Included: 2 INSPEC (1969-present) 5 BIOSIS Previews(R) (1969-present) 6 NTIS - National Technical Information Service 8 Ei Compendex(R) 34 SciSearch(R) - a Cited Reference Science Database - 1990- 35 Dissertation Abstracts Online 65 Inside Conferences 73 EMBASE(R) (1974-present) 74 International Pharmaceutical Abstracts 92 IHS International Standards and Specifications 94 JICST-EPlus - Japanese Science & Technology 144 PASCAL 155 MEDLINE(R) (1966-present) 158 DIOGENES(R) FDA Regulatory Updates 172 EMBASE(R) Alert 182 FDA News 188 Health Devices Sourcebook(R) 198 Health Devices Alerts(R) 399 CA SEARCH(R) - Chemical Abstracts(R) (1967- present) 434 SciSearch(R) - a Cited Reference Science Database - 1974-1989 441 ESPICOM Pharmaceutical & Medical Device News 444 New England Journal of Medicine

Also - MEDITEC: Biomedical EngineeringBMED on DataStar, 1986 - present, updated weekly

Compiled by FIZ Technik, the MEDITEC database contains citations, with abstracts, to the international literature on biomedical engineering. Information is compiled from journals, conference papers, books, technical reports, and dissertations. The primary language of the database is German, but many search terms and abstracts are also in English.

Topics covered include:

Biomedical measurements (recording, plotting, processing, and evaluation of physiological parameters) Medical imaging (e.g., computed tomography, magnetic resonance imaging) Data processing in medicine Biomaterials and materials for medical instrumentation Medical instruments for diagnostic and therapeutic applications Prostheses and rehabilitation engineering Clinical laboratory technology Optometry and ophthalmological instruments Dental technology Clinical engineering, hospital management

Page 60

Drug Pipeline Databases: Will They Help in Identifying Products That Incorporate New Drug Delivery Technology? YES!

Pipeline File CharacteristicsPipeline File Characteristics

• Typically provide useful details about company relationships/contributions in formulations involving advanced delivery mechanisms

– “Guilford has developed Gliadel, a biodegradable polyanhydridepolymer (polifeprosan 20) formulation of carmustine, using a Biodel delivery system acquired from Scios (now Johnson and

Johnson), for primary brain cancer…”

– “Bioxel Pharma is collaborating with PolyGene, Israel, in the development of a paclitaxel-loaded polymer implant for the treatment of solid tumours. The implant will use Bioxel'spaclitaxel and PolyGene's proprietary biodegradable polymer technology…”


• Compile alternative names for products that can assist in constructing natural language strategiesfor retrieval of pertinent references from bibliographic databases

DRUG NAME: dibotermin alfaORIGINATOR: Wyeth (USA) [Launched]LICENSEE: Yamanouchi (Japan) [Launched]

Medtronic (USA) [Launched]SYNONYMS: BMP, Wyeth

BMP-2, CollagenesisBMP-2, Yamanouchibone inducing proteins, WyethrhBMP-2, WyethInduxYM-484BMP-2, WyethrhBMP-2/ACSrhBMP-12BMP-12, WyethINFUSE Bone GraftInductOs

CAS REG NO: 246539-15-1


• Systematically classify products by – therapeutic category – pharmacological mechanism of action– proposed indications

Pharmacological Action: radiotherapeutic; oligonucleotide; biotechnology Therapeutic Class Code: C1D (Coronary Therapy);

V3C (Radiopharmaceuticals); L1X9 (All Other Antineoplastics)

Clinical Indications: restenosis; cancer

• Identify regulatory status and coordinate with targetmarket(s) (countries)

DEVELOPMENT STATUS: Phase III, USA, Diabetic macular oedemaPhase III, Singapore, UveitisPhase III, USA, UveitisPhase II, USA, Age-related macular degenerationPhase II, USA, Choroidal neovascularisation

Page 61

PharmaprojectsPharmaprojects• Only pipeline file to enhance the EPhMRA therapeutic

classification scheme with an entire category designed to improve indexing of formulations

• Only file to provide hierarchical indexing for routes of administration, as well

• “Novelty” rating will help identify products involving new formulations

THER. CLASS: F9A (Formulation, implant)K1B (Anticancer, alkylating)

ORIGIN: CH-SY (Chemical, synthetic)RTE OF ADMIN:T-IL (Topical, intralesional)INDICATIONS: Cancer, brain L Launched

Surgery adjunct L Launched...

RATING: NOVELTY: 3 (New Formulation)

? E FORMULATION/DE

Ref Items Index-termE1 1 FORMULATION SYSTEME2 557 FORMULATION TECHNOLOGY)E3 0 *FORMULATION/DEE4 10 FORMULATION, CONJUGATE, CARBOHYDRATE)E5 79 FORMULATION, CONJUGATE, PEGYLATED)E6 143 FORMULATION, DERMAL, TOPICAL)E7 293 FORMULATION, FIXED-DOSE COMBINATIONS)E8 85 FORMULATION, IMPLANT)E9 46 FORMULATION, INHALABLE, DRY POWDER)E10 33 FORMULATION, INHALABLE, OTHER)E11 30 FORMULATION, INHALABLE, SOLUTION)E12 42 FORMULATION, INHALABLE, SYSTEMIC)E13 60 FORMULATION, INHALABLE, TOPICAL)E14 206 FORMULATION, MODIFIED-RELEASE, <=24HR)E15 92 FORMULATION, MODIFIED-RELEASE, >24HR)E16 54 FORMULATION, MODIFIED-RELEASE, IMMEDIATE)E17 37 FORMULATION, MODIFIED-RELEASE, MULTI)E18 333 FORMULATION, MODIFIED-RELEASE, OTHER)E19 105 FORMULATION, MUCOSAL, TOPICAL)E20 11 FORMULATION, OPTIMIZED, DRUG-LOADED)E21 146 FORMULATION, OPTIMIZED, LIPOSOMES)E22 33 FORMULATION, OPTIMIZED, MICROEMULSION)E23 72 FORMULATION, OPTIMIZED, MICROENCAPSULATE)E24 79 FORMULATION, OPTIMIZED, MICROPARTICLES)E25 35 FORMULATION, OPTIMIZED, NANOPARTICLES)E26 39 FORMULATION, ORAL, ENTERIC-COATED)E27 41 FORMULATION, ORAL, ORALLY-DISINTEGRATING)E28 261 FORMULATION, ORAL, OTHER)E29 37 FORMULATION, ORAL, SOLUBILITY-ENHANCED)E30 20 FORMULATION, ORAL, TARGETED)E31 284 FORMULATION, OTHER)E32 22 FORMULATION, PARENTERAL, NEEDLE-FREE)E33 95 FORMULATION, PARENTERAL, OTHER)E34 64 FORMULATION, PARENTERAL, TARGETED)E35 23 FORMULATION, TRANSDERMAL, ENHANCED)E36 47 FORMULATION, TRANSDERMAL, OTHER)E37 195 FORMULATION, TRANSDERMAL, PATCH)E38 147 FORMULATION, TRANSDERMAL, SYSTEMIC)E39 98 FORMULATION, TRANSMUCOSAL, NASAL)E40 82 FORMULATION, TRANSMUCOSAL, SYSTEMIC)

Page 62

Route of Administration Indexing in Pharmaprojects

Searchable as keywords (/RO) or accessible through a two-part, hierarchical coding scheme (RO=) with four main categories:

• A (Alimentary)• P (Parenteral)• R (Respiratory)• T (Topical)

Use extended codes for more precise retrieval, e.g.,

S RO=P-IA for Parenteral, Intra-arterial

A-BC (Alimentary, buccal)A-CO (Alimentary, intracolonic)A-DU (Alimentary, intraduodenal)A-GA (Alimentary, gastric)A-OM (Alimentary, oral mucosal)A-PO (Alimentary, po)A-RC (Alimentary, intrarectal)A-SL (Alimentary, sublingual)A-UN (Alimentary, general)

R-IB (Respiratory, inhaled bronchial)R-IG (Respiratory, inhaled general)R-IP (Respiratory, inhaled pulmonary)R-IT (Respiratory, inhaled tracheal)R-NA (Respiratory, transnasal)R-UN (Respiratory, general)

P-AB (Parenteral, intra-abdominal)P-AC (Parenteral, intra-articular)P-BC (Parenteral, buccal)P-CA (Parenteral, intracavity)P-CL (Parenteral, intracranial)P-CN (Parenteral, intracavernosal)P-CR (Parenteral, intracerebral)P-CV (Parenteral, intracervical)P-DM (Parenteral, intradermal)P-HP (Parenteral, intrahepatic)P-IA (Parenteral, intra-arterial)P-IC (Parenteral, intracardiac)P-ID (Parenteral, intraduodenal)P-IL (Parenteral, intraileal)P-IM (Parenteral, intramuscular)P-IP (Parenteral, intraperitoneal)P-IT (Parenteral, intratracheal)P-IV (Parenteral, intravenous)P-JE (Parenteral, intrajejunal)P-LM (Parenteral, intralymphatic)P-OM (Parenteral, oral mucosal)P-OR (Parenteral, intraocular)P-PL (Parenteral, intrapleural)P-PS (Parenteral, intraprostatic)P-SC (Parenteral, subcutaneous)P-SP (Parenteral, intraspinal)P-TH (Parenteral, intrathoracic)P-TU (Parenteral, intratumoural)P-UN (Parenteral, general)P-UT (Parenteral, intrauterine)P-VA (Parenteral, intravascular)P-VE (Parenteral, intravesical)

T-BC (Topical, buccal)T-CR (Topical, cream)T-DM (Topical, skin)T-EA (Topical, ears)T-EY (Topical, eyes)T-FI (Topical, film)T-GL (Topical, gel)T-IL (Topical, intralesional)T-MO (Topical, mousse)T-NS (Topical, nose)T-ON (Topical, ointment)T-PA (Topical, patch)T-PE (Topical, pellet)T-PN (Topical, penile)T-PO (Topical, powder)T-PS (Topical, paste)T-SG (Topical, subgingival)T-SO (Topical, solution)D-TR (Transdermal)T-SP (Topical, spray)T-UN (Topical, general)T-UT (Topical, intrauterine)T-VG (Topical, vaginal)

UN (Unknown)NA (Not applicable)

Page 63

File 128:PHARMAPROJECTS 1980-2004/Sep W2 (c) 2004 PJB Publications,Ltd.

Set Items Description --- ----- -----------? S TC=F9A S1 85 TC=F9A

? E NR=

Ref Items Index-termE1 1 NA=99MTC-ECDE2 1 NA=99MTC-5T4 MABE3 0 *NR=E4 1495 NR=0 (NOT AVAILABLE)E5 1349 NR=1 (ALL PRECLINICAL)E6 1657 NR=2 (ESTABLISHED STRATEGY)E7 1390 NR=3 (NEW FORMULATION)E8 433 NR=4 (LOW NOVELTY)E9 851 NR=5 (2ND, 3RD OR 4TH COMPOUND)E10 1743 NR=6 (LEADING COMPOUND)E11 5294 OM=BIE12 212 OM=BI-B

Enter P or PAGE for more? S E7 S2 1390 NR='3' (NEW FORMULATION)


? S S3 AND TC=K 6649 TC=K S4 11 S3 AND TC=K

? T S4/9/1-2

4/9/1DIALOG(R)File 128:PHARMAPROJECTS(c) 2004 PJB Publications,Ltd. All rts. reserv.

0033870DRUG NAME: paclitaxel implant, BioxelORIGINATOR: Bioxel (Canada) [Preclinical]

TEXT: Bioxel Pharma is collaborating with PolyGene, Israel, in thedevelopment of a paclitaxel-loaded polymer implant for the treatment ofsolid tumours. The implant will use Bioxel's paclitaxel and PolyGene'sproprietary biodegradable polymer technology.

.

.

.THER. CLASS: F9A (Formulation, implant) K2 (Anticancer, hormonal)ORIGIN: NP-P (Natural product, plant)RTE OF ADMIN:P-UN (Parenteral, general)INDICATIONS: Cancer, general P PreclinicalPHARM. CODE: TUBE-B-AN, Beta tubulin antagonist, Physiological, Biochemical , Beta tubulin antagonist, Beta tubulin binding agent , P-B-TUBE-B-AN Therapy Pharmacology StatusLINKING: F9A NA Preclinical K2 TUBE-B-AN Preclinical

Page 64

F9A represents FORMULATION, IMPLANT

EXPAND for Novelty Rating options

Focusing on anticancer products (K category)

RATING: NOVELTY: 3 (New Formulation) DEVELOPMENT SPEED: 1 (Speed Rating - Development not started) MARKET SIZE: 3 (Market Rating - US$ 2001-5000 million) TOTAL RATING: 7 (Total Rating)LATEST UPD: 20030520 (AG) Expected timing of preclinical studies reportedUPDATED: 20020321 (Act) New ProductREVISED: 20030530; 2003


0031548DRUG NAME: 5-FU microspheres, EthypharmORIGINATOR: Ethypharm (France) [Phase III Clinical Trial]LICENSEE: Biovail (Canada) [Phase III Clinical Trial]

TEXT: Ethypharm is developing a radiosensitizing biodegradableimplantable microsphere formulation of 5-fluorouracil (5-FU) for theprevention of glioblastoma recurrence following surgical resection (CompanyWeb Page, Ethypharm, 10 Nov 2000).

.

.

.STATUS: (Active) World Phase III Clinical Trial China Preclinical France Phase III Clinical Trial

THER. CLASS: F3C1 (Formulation, optimized, microencapsulate) F9A (Formulation, implant) K1C (Anticancer, antimetabolite) K5A (Radio-chemosensitizer)ORIGIN: CH-SY (Chemical, synthetic)RTE OF ADMIN:P-CA (Parenteral, intracavity)INDICATIONS: Cancer, brain C3 Phase III Clinical TrialPHARM. CODE: SY-TH-AN, Thymidylate synthase inhibitor, Enzyme, Transferase, Thymidylate synthase inhibitor, Antineoplastic e.g. 5 fluorouracil, floxuridine, E-TR-SY-TH-AN, 2.1.1.45 RNA-SYN-AN, RNA synthesis inhibitor, Physiological, Biochemical, RNA synthesis inhibitor, Antineoplastic e.g. daunorubicin, dactinomycin, Antineoplastic e.g. anthracyclines , anthracenediones, Antineoplastic e.g. plicamycin, P-B-RNA-SYN-AN Therapy Pharmacology StatusLINKING: F3C1 NA Phase III Clinical Trial F9A NA Phase III Clinical Trial K1C SY-TH-AN RNA-SYN-AN Phase III Clinical Trial K5A SY-TH-AN RNA-SYN-AN Phase III Clinical TrialRATING: NOVELTY: 3 (New Formulation) DEVELOPMENT SPEED: 2 (Speed Rating - Slower than Average) MARKET SIZE: 2 (Market Rating - US$ 501-2000 million) TOTAL RATING: 7 (Total Rating)LATEST UPD: 20030522 (JB) Plans for clinical trials in China reportedUPDATED: 20020828 (Est) Status changed (Phase III Clinical Trial) 20020415 (Act) New Licensee (Biovail) 20001123 (Act) New ProductREVISED: 20040227; 2004

Page 65

? S INFUSE/NA S5 1 INFUSE/NA? T S5/9


0010425DRUG NAME: dibotermin alfaORIGINATOR: Wyeth (USA) [Launched]LICENSEE: Yamanouchi (Japan) [Launched] Medtronic (USA) [Launched]SYNONYMS: BMP, Wyeth BMP-2, Collagenesis BMP-2, Yamanouchi bone inducing proteins, Wyeth rhBMP-2, Wyeth Indux YM-484 BMP-2, Wyeth rhBMP-2/ACS rhBMP-12 BMP-12, Wyeth INFUSE Bone Graft InductOsCAS REG NO: 246539-15-1PATENT: 4,877,864 [US 4877864] United States of AmericaPRIORITY: March 26, 1987, United States of America (US)

TEXT: Dibotermin alfa is a recombinant bone morphogenetic protein-2(BMP-2) developed by Genetics Institute (GI; now Wyeth) and Wyeth Pharmaceuticals (Wyeth) (formerly Wyeth-Ayerst (American Home Products)) asan osteoinductive agent for use as an adjunct to standard care or as areplacement for autogenous bone graft in surgery. It recruits and activatescells that form and remodel cartilage and bone tissue (Ann Rep, GI, 1991;Company communications, GI, Feb 1995 and Feb 1996).

Marketing

It is launched in the US (2003) in conjunction with MedtronicSofamor Danek's (MSD) LT-CAGE Lumbar Tapered Fusion Device to treat lumbarinterbody spinal fusion (Press release, Integra, 15 Jul 2002; Company WebPage, Wyeth, 4 Aug 2003), and is approved as an absorbable collagen spongematrix in the US (rhBMP-2/ACS; INFUSE Bone Graft) for use in acutelong-bone fractures requiring open surgical management.

.

.

.THER. CLASS: T2A3 (Recombinant growth factor) M5Z (Musculoskeletal)ORIGIN: BI-P-R (Biological, protein, recombinant)RTE OF ADMIN:P-SC (Parenteral, subcutaneous)INDICATIONS: Regeneration, bone L Launched Regeneration, cartilage L LaunchedPHARM. CODE: BONE-BM-AG, Bone stimulating morphogenic protein factor stimulant, Physiological, Hormonal, Bone stimulating morphogenic protein factor stimulant, Morphogenetic protein bone stimulating factor stimulant, BMP bone factor stimulant, P-H-BONE-BM-AG

[remainder of record omitted here]

Page 66

Both the Therapeutic Class & Substance Origin fields can be helpful in identifying biologics &

biotech drugs in Pharmaprojects

Substance Origin Indexing in Pharmaprojects

Three basic options: Biological, Chemical Synthesis, or Natural Product

Searchable as keywords in /OM field (use proximity operators for phrases)

Hierarchical, pre-cascaded (pre-Exploded, no need to truncate codes) classification scheme for retrieving specific categories of origin in OM= field, e.g.,

S OM=B to locate biologicsS OM=BI-P to retrieve biological proteinsS OM=BI-P-R to isolate biological recombinant proteins

BI-B (Biological, bacterial cells)BI-C-A (Biological, cellular, autologous)BI-C-H (Biological, cellular, heterologous)BI-C-X (Biological, cellular, xenogeneic)BI-N (Biological, nucleic acid)BI-N-NV (Biological, nucleic acid, non-viral vector)BI-N-VV (Biological, nucleic acid, viral vector)BI-O (Biological, other)BI-P-A (Biological, protein, antibody)BI-P-R (Biological, protein, recombinant)BI-PT (Biological, peptide)BI-PT-R (Biological, peptide, recombinant)BI-V (Biological, virus particles)

CH-SE (Chemical, semisynthetic)CH-SY (Chemical, synthetic)CH-SY-I (Chemical, synthetic, isomeric)CH-SY-N (Chemical, synthetic, nucleic acid)CH-SY-P (Chemical, synthetic, peptide)

NP-A (Natural product, animal)NP-B (Natural product, bacterial)NP-F (Natural product, fungal)NP-O (Natural product, other)NP-P (Natural product, plant)

Therapeutic Category T Codes in Pharmaprojects (S TC= )

T2A1 (Recombinant interferon)T2A2 (Recombinant interleukin)T2A3 (Recombinant growth factor)T2B (Recombinant vaccine)T2C (Recombinant hormone)T2D (Lytic virus)T2Z (Recombinant, other)T3A2 (Monoclonal antibody, human)T3A2 (Monoclonal antibody, human)T3A1 (Monoclonal antibody, murine)T3A2 (Monoclonal antibody, human)T3A4 (Monoclonal antibody, chimaeric)T3A5 (Monoclonal antibody, humanized)T3A9 (Monoclonal antibody, other)T3B1 (Immunotoxin)T3B9 (Immunoconjugate, other)T4A (Gene therapy)T4B (Antisense therapy)T4C (Genomics-based drug discovery)T4D (Gene delivery vector)T4E (Non-antisense oligonucleotide)T5Z (Biotechnology, other)

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IMS R&D Focus: Indexing of Drug-Eluting Stents

DIALOG(R)File 445:IMS R&D Focus(c) 2004 IMS Health & Affiliates. All rts. reserv.

02019222 Drug Name: drug delivery system, vascular stent sirolimus; sirolimus vascular stentBrand Name: CYPHER; CYPHER SELECTR&D Focus - April 12, 2004 (20040412)

COMPANY INFORMATION: Originator: Cordis; (USA); Johnson & Johnson; licensor; NA Licensee/Licensor: Guidant; (USA); NA; licensee; USA

DRUG INFORMATION: Pharmacological Action: antiproliferative agent; stent Therapeutic Class Code: C1D (Coronary Therapy); V7A (All Other Non-Therapeutic Products) Clinical Indications: restenosis Molecular Code: 7133780000

LATEST INFORMATION: 12 April 2004: The Japanese Ministry of Health, Labor and Welfare hasapproved the use of Cordis' sirolimus-eluting coronary stent (CYPHER) inJapan for the treatment of restenosis, it was announced on 31 March 2004.Cordis anticipates launching the product in Japan mid-2004. The product hasbeen made available in the USA and throughout 80 countries in Europe, theMiddle East, Canada, Asia-Pacific and Latin America.

CURRENT DEVELOPMENT STATUS: Highest Phase: Marketed (80) Development Phase/ Country/Indication: Marketed--USA--restenosis Registered--EU--restenosis Registered--Switzerland--restenosis Registered--Japan--restenosis Phase III--Latin America--restenosis Phase III--Asia--restenosisDEVELOPMENT HISTORY: MAR 2004: Recommended and Registered, Japan (restenosis). FEB 2004: Agreement between Cordis and Guidant. APR 2003: Registered and marketed, USA (restenosis) APR 2002: Registered, Europe. 2001: Phase III, USA. 2000: Phase III, Europe, Latin America.

COMMERCIAL SUMMARY: Cordis is developing a stent coated with sirolimus for the treatment ofrestenosis (Cordis, SEP 2002). This sirolimus-eluting stent uses SurModics'patented drug-eluting coating. The product has been approved and launched in the USA as a treatment for restenosis… [remainder of record omitted here]

However, for stents still in early stage of development, keyword could appear in record text (see examples on next page).

– Recommendation: search “stent” [truncated] without qualification to a specific field

Page 68

STENT may appear in the drug name or in the pharmacological action field.

DIALOG(R)File 445:IMS R&D Focus (c) 2004 IMS Health & Affiliates. All rts. reserv. 02023117 Drug Name: restenosis therapy, Biotica R&D Focus - September 06, 2004 (20040906) COMPANY INFORMATION: Originator: Biotica; (UK); NA; NA; NA DRUG INFORMATION: Pharmacological Action: antiproliferative agent Therapeutic Class Code: C1D (Coronary Therapy) Clinical Indications: restenosis Drug Status: New Drug Molecular Code: 7168080000 LATEST INFORMATION: 6 September 2004: Utilizing its polyketide biosynthesis technology, Biotica is developing rapamycin analogues for use in a drug-eluting stent. The company expects that the analogues will inhibit smooth muscle proliferation thereby preventing restenosis. Lead optimization is under way in the UK, and the company anticipates selecting a clinical candidate second half 2005.

CURRENT DEVELOPMENT STATUS: Highest Phase: Preclinical (20)

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. 5/9/2 DIALOG(R)File 445:IMS R&D Focus (c) 2004 IMS Health & Affiliates. All rts. reserv. 02021330 R&D Focus - December 01, 2003 (20031201) COMPANY INFORMATION: Originator: AVONTEC; (Germany); NA; NA; NA Licensee/Licensor: BIOTRONIK; (Germany); NA; other; NA DRUG INFORMATION: Laboratory Code: AVT 003 Pharmacological Action: biotechnology; oligonucleotide Therapeutic Class Code: C1D (Coronary Therapy); V7A (All Other Non-Therapeutic Products) Clinical Indications: restenosis Drug Status: New Drug Molecular Code: 7151770000 LATEST INFORMATION: 1 December 2003: A double-stranded decoy oligonucleotide for the treatment of restenosis, AVT 003, is under development with AVONTEC, Dr Thomas Schulze, CEO, told R&D focus during an interview at Bio-Europe 2003, 17-19 November 2003, Frankfurt, Germany. Preclinical evaluation of AVT 003, which uses a decoy anion antiport mechanism for uptake into cells, in a mini pig model of hypercholesterolemia is ongoing. An agreement has been signed between AVONTEC and BIOTRONIK to develop dispatch catheters and a drug-eluting stent for the delivery of AVT 003. Phase I trials with AVT 003 are scheduled to initiate second half 2004. CURRENT DEVELOPMENT STATUS: Highest Phase: Preclinical (20) Development Phase/ Country/Indication: Preclinical--Germany--restenosis

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A Broader Approach to Searching Drug Delivery Systems in IMS R&D Focus

As was illustrated in the CYPHER record (page 67), IMS R&D Focus often identifies “drug delivery system” in the Drug Name field of product profiles.

The phrase may also appear in the Substance Origin portion of records, as illustrated below.

Recommendation: Search the phrase without qualification to a specific field.


02000541Drug Name: drug delivery system, polifeprosan 20, carmustine implant; drug delivery system, carmustine biodegradable implant; BIODEL BCNU implant; carmustine delivery systemBrand Name: GLIADEL; GLIADEL WaferR&D Focus - October 04, 2004 (20041004)

COMPANY INFORMATION: Originator: Scios; (USA); Johnson & Johnson; licensor; NA Licensee/Licensor: Guilford; (USA); NA; licensee : licensor; NA Link; (UK); NA; sub-licensee; UK, Ireland, Germany, France, Benelux, Austria, Switzerland Orion; (Finland); NA; sub-licensee; Finland, Sweden, Norway, Denmark Orphan Australia; (Australia); NA; sub-licensee ; Australia, New Zealand Patent Assignee: Massachusetts Institute of Technology Licensing Countries: Worldwide

COMPANY INFORMATION: Licensing Contact: Russell Wesdyk, Vice President of Business Development, Guilford Pharmaceuticals, 6611 Tributary Street, Baltimore, MD 21224, USA; Tel: +1 410 631 6340; Fax: +1 410 631 6819; Email: [email protected] INFORMATION: Pharmacological Action: alkylating agent Substance Origin: drug delivery system Therapeutic Class Code: L1A (Alkylating Agents); V7A (All Other Non-Therapeutic Products) Clinical Indications: cancer; solid tumor; neurological cancer; brain tumor; glioma Molecular Code: 5070101550

LATEST INFORMATION: 4 October 2004: Guilford announced on 27 September 2004 that the US FDA has awarded GLIADEL Wafer Orphan Drug designation for the treatment of patients with malignant glioma undergoing primary surgical resection. This entitles the product to seven years of market exclusivity extending until February 2010. GLIADEL Wafer (polifeprosan 20 with carmustine implant) comprises a biodegradable polymer that contains the drug carmustine, or BCNU, achemotherapeutic agent usually administered intravenously to treat malignant glioma. GLIADEL Wafer is approved in the USA, and 25 other countries, for treatment of newly-diagnosed high-grade glioma and recurrent glioblastoma multiforme (GBM), in conjunction with radiation and surgery.


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Additional records in IMS R&D Focus can be located by searching…

-- “Delivery System” or “Drug Design Technology in the Indications field-- The keyword “Technology” in Status indexing


02022619Brand Name: PROCISER&D Focus - June 07, 2004 (20040607)

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.DRUG INFORMATION: Therapeutic Class Code: V7A (All Other Non-Therapeutic Products) Clinical Indications: delivery system Drug Status: New Drug

LATEST INFORMATION: 7 June 2004: Mistral is seeking partners to utilize its PROCISE technology for drug delivery, it was announced by Bertrand Bolduc, President and CEO of the company, at BioFinance 2004, 11-13 May 2004, Toronto, Canada. PROCISE is a programmable, solid, oral drug delivery system that can be customized to the required release specification for a particular drug. PROCISE consists of a slow dissolving inert coat surrounding a cylindrical active core containing the drug of interest. Dissolution of the outer coating progresses over time, resulting in the controlled release of the active compound.

CURRENT DEVELOPMENT STATUS: Highest Phase: Preclinical (20) Development Phase/ Country/Indication: Technology--Canada



02022608Brand Name: NeuroTransR&D Focus - May 31, 2004 (20040531)

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.DRUG INFORMATION: Therapeutic Class Code: V7A (All Other Non-Therapeutic Products) Clinical Indications: drug design technology Drug Status: New Drug

LATEST INFORMATION: 31 May 2004: NeuroTrans, a drug delivery system that facilitates the

transport of therapeutic enzymes and drugs across the blood brain barrier, is available for licensing from BioMarin. The technology is under evaluation for the delivery of enzyme replacement therapies to brain cells for the treatment of lysosomal storage diseases including mucopolysaccharidosis I(MPS I) and neurological diseases of aging. An IND submission for these therapies is expected in December 2004, with subsequent initiation of phase I trials in 2005. This announcement was made at BioEquity Europe, 17-18 May 2004, Edinburgh, UK. [remainder of record omitted here]

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? S (DELIVERY()SYSTEM OR DRUG()DESIGN()TECHNOLOGY)/IN S2 965 (DELIVERY()SYSTEM OR DRUG()DESIGN()TECHNOLOGY)/IN

? S TECHNOLOGY/ST S3 873 TECHNOLOGY/ST

? S S2 OR S3 S4 966 S2 OR S3? DS

Set Items DescriptionS1 1260 DRUG()DELIVERY()SYSTEM/PROFILES2 965 (DELIVERY()SYSTEM OR DRUG()DESIGN()TECHNOLOGY)/INS3 873 TECHNOLOGY/STS4 966 S2 OR S3


? S S5/AVAIL S6 474 S8/AVAIL

? S S6 AND VACCINE? S9 53 S6 AND VACCINE?

? T S10/9/1-2

10/9/1 DIALOG(R)File 445:IMS R&D Focus (c) 2004 IMS Health & Affiliates. All rts. reserv. 02023242 Brand Name: CyaA R&D Focus - September 27, 2004 (20040927) COMPANY INFORMATION: Originator: BT Pharma; (France); NA; NA; NA Licensing Countries: Worldwide COMPANY INFORMATION: Licensing Contact: Benedikt Timmerman, CEO, BT Pharma, Prologue-Biotech, Rue Pierre et Marie Curie, BP 700, 31319 Labege-Innopole Cedex, France; Tel: +33 561 28 70 60; Fax: +33 561 28 70 69; Email: [email protected] DRUG INFORMATION: Pharmacological Action: vaccine; biotechnology Therapeutic Class Code: V7A (All Other Non-Therapeutic Products) Clinical Indications: delivery system Drug Status: New Drug Molecular Code: 7524200000

LATEST INFORMATION: 27 September 2004: BT Pharma's recombinant adenylate cyclase (CyaA) is available for partnering for use as a therapeutic vaccine vector , Benedikt Timmerman, CEO of BT Pharma, told R&D focus in an interview conducted at the European Partnering and Investment Conference, 16 September 2004, London, UK. The CyaA is engineered to target antigens to dendritic cells and activate dendritic cells in vivo, resulting in a strong and specific cytotoxic T lymphocyte response against inserted T-cell epitopes. The technology has application in vaccine development . BT Pharma is developing a cervical cancer vaccine utilizing CyaA. CURRENT DEVELOPMENT STATUS:

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Locates additional records not identified with previous strategy.

/AVAIL limits results to products available for licensing.

Because many of these records lack specific Therapeutic (TC) or Indications indexing, search keywords for potential applications as “free text” (without field qualification).

Highest Phase: Preclinical (20) Development Phase/ Country/Indication: Technology--France DEVELOPMENT HISTORY: SEP 2004: Available for partnering, Worldwide.

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10/9/2 DIALOG(R)File 445:IMS R&D Focus (c) 2004 IMS Health & Affiliates. All rts. reserv. 02023229 Drug Name: Powder Mediated Epidermal Delivery Brand Name: PMED R&D Focus - September 27, 2004 (20040927) COMPANY INFORMATION: Originator: PowderMed; (UK); NA; NA; NA Licensing Countries: Worldwide COMPANY INFORMATION: Licensing Contact: Brenda Reynolds, Chief Operating Officer, PowderMed Ltd, 4 Robert Robinson Avenue, The Oxford Science Park, Oxford, OX4 4GA, UK; Tel: +44 1865 501531; Fax +44 1865 501501; Email: [email protected] DRUG INFORMATION: Pharmacological Action: biotechnology Therapeutic Class Code: V7A (All Other Non-Therapeutic Products) Clinical Indications: delivery system Drug Status: New Drug Molecular Code: 7524180000 LATEST INFORMATION: 27 September 2004: At the European Partnering & Investment Conference, 16 September 2004, London, UK, R&D focus discussed PowderMed's proprietary Powder Mediated Epidermal Delivery (PMED) technology with Clive Dix, CEO of PowderMed, and Brenda Reynolds, COO. The PMED technology has utility in the development of therapeutic DNA vaccines, and PowderMed is seeking partners interested in collaborations using the PMED technology. The technology uses the PowderJect device to propel DNA precipitated onto microscopic gold particles into the epidermis. Microscopic gold particles, 1-3 mcM in diameter, have an appropriate density and size for direct DNA delivery into immunological active antigen presenting cells (APC). Once inside the APC, the DNA elutes off the gold and produces the encoded protein; the presentation of this protein by the APC to the lymphocytes results in the generation of T-cell-mediated immune responses. The technology can be used to develop vaccines that generate T-cell mediated responses to a broad range of viral and cancer antigens.

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Adis R&D Insight – Indexing of Drug-Eluting Stents

DIALOG(R)File 107:Adis R&D Insight(c) 2004 Adis Data Information BV. All rts. reserv.

00233841 014014DRUG NAME: Alprostadil - EndovascRECORD REVISION DATE: 20040901SYNONYMS: Liprostin; PGE 1; Prostaglandin E1; PROStentCHEMICAL NAME: (1R,2R,3R)-3-Hydroxy-2-((E)-(3S)-3-hydroxy-1-octenyl) -5- oxocyclopentane heptanoic acidMOLECULAR NAME: C20H34O5CAS REG. NO.: 745-65-3WHO ATC CODE: A10X - Other Drugs Used in Diabetes; C - Cardiovascular System; C01E-A01 - Alprostadil; C04A - Peripheral VasodilatorsEPHMRA ATC CODE: A10X - Other Drugs Used in Diabetes; C4A - Cerebral and Peripheral Vasotherapeutics; C6A - Other Cardiovascular ProductsMECHANISM OF ACTION: Prostaglandin E1 agonists; Prostaglandin E agonists; Prostaglandin agonists

ORIGINATOR COMPANY: Endovasc (Italy); Endovasc (USA)PARENT COMPANY: EndovascLICENSEE: MIV TherapeuticsOTHER COMPANY: Endovasc-TissueGen Research Sponsors LLC; Liprostin Development Corporation; Stentgenix

HIGHEST PHASE: Phase II...

TEXTIntroduction:Alprostadil - Endovasc (prostaglandin E1, PGE 1) as Liprostin(TM), is aliposomal encapsulation of prostaglandin E1, a potent vasodilator, plateletinhibitor and antithrombotic agent. It is being developed in the USA byEndovasc for the treatment of peripheral vascular disease. Development forother conditions including restenosis, myocardial infarction, veno-occlusive disease, diabetic ischaemic ulcers, liver disease and arthritis may proceed in the future.As PROStent(TM), alprostadil and a polymer form a stent coating to prevent restenosis. Alprostadil - Endovasc may also be a topical wound-healingagent.

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.CLINICAL OVERVIEW: Route(s) of Administration: Implant, Parenteral, Topical

? S STENT/TX AND RESTENOSIS/ST 46 STENT/TX 151 RESTENOSIS/ST S1 25 STENT/TX AND RESTENOSIS/ST

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STENT appears in the Text (rather than controlled indexing fields)

Some drug-eluting stents are indexed as IMPLANTs.

Locates other drugs under development using stent delivery for the same indication

In Adis R&D Insight, Route of Administration could be used to locate other products being investigated for implant delivery.

? S IMPLANT/CV S2 61 IMPLANT/CV

? DS

Set Items DescriptionS1 25 STENT/TX AND RESTENOSIS/STS2 61 IMPLANT/CV


? RANK CC ALPHA CONT;ALL

THERAPEUTIC APPLICATIONS OF NON-STENT PRODUCTS UNDER DEVELOPMENT AS IMPLANTS----------------------------------------------------------------------------RANK: S3/1-51 Field: CC= File(s): 107(Rank fields found in 51 records -- 73 unique terms)

RANK No. Items Term-------- ----- ---- 35 1 ALL OTHER ANTI-ALZHEIMER PRODUCTS 36 1 ALL OTHER CARDIAC PREPARATIONS 20 2 ALL OTHER CNS DRUGS 1 8 ALL OTHER MUSCULOSKELETAL PRODUCTS 3 7 ALL OTHER THERAPEUTIC PRODUCTS 37 1 ANALGESICS 38 1 ANTI-PARKINSON DRUGS 39 1 ANTIGROWTH HORMONES 13 3 ANTINEOPLASTICS 21 2 ANTITHROMBOTIC AGENTS 22 2 A1A 40 1 A10C9 23 2 A10X 14 3 BONE CALCIUM REGULATORS 24 2 B1 7 5 CYTOSTATIC GONADOTROPHIN-RELEASING HORMONE ANA 41 1 CYTOSTATIC HORMONES 42 1 CYTOSTATIC OESTROGENS 10 4 CYTOSTATICS 43 1 C1X 44 1 C6 8 5 C6A 45 1 D11A 15 3 D3A 46 1 FLUOROQUINOLONES 47 1 GONADOTROPHIN-RELEASING HORMONES 48 1 GONADOTROPHINS, INCLUDING OTHER OVULATION STIM 25 2 GROWTH HORMONES . . . 31 2 OESTROGENS, EXCLUDING G3A, G3E, G3F 65 1 OPHTHALMOLOGICAL CORTICOSTEROIDS 6 6 OTHER CARDIOVASCULAR PRODUCTS 18 3 OTHER CNS DRUGS 66 1 OTHER DERMATOLOGICAL PREPARATIONS

[remainder of RANK display omitted here]? V 65/9

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RANK CC on Dialog produces a quick snapshot of applications under investigation

There is no separate field for Route in Adis R&D Insight. Search Route keywords as part of the Clinical Overview ( /CV) portion of records.

--RANK 65 ITEM 1 --DIALOG(R)File 107:Adis R&D Insight(c) 2004 Adis Data Information BV. All rts. reserv.

00229450 014421 DRUG NAME: Fluocinolone acetonide ophthalmic - Bausch & LombRECORD REVISION DATE: 20031119BRAND NAME: Retisert(TM)SYNONYMS: Fluocinolone acetonide Envision TD implantCHEMICAL NAME: Pregna-1,4-diene-3,20-dione, 6,9-difluoro-11,21-dihyd roxy-16,17-((1- methylethylidene)bis(oxy))-, (6alpha, 11beta,16alpha)-MOLECULAR NAME: C24H30F2O6CAS REG. NO.: 67-73-2WHO ATC CODE: S01B-A - Corticosteroids, PlainEPHMRA ATC CODE: S1B - Ophthalmological CorticosteroidsMECHANISM OF ACTION: Glucocorticoid agonists; Corticosteroid agonists

ORIGINATOR COMPANY: Bausch & Lomb (USA); Control Delivery Systems (USA)PARENT COMPANY: Bausch & Lomb; Control Delivery Systems

HIGHEST PHASE: Phase III

DEVELOPMENT STATUS: Phase III, USA, Diabetic macular oedema Phase III, Singapore, Uveitis Phase III, USA, Uveitis Phase II, USA, Age-related macular degeneration Phase II, USA, Choroidal neovascularisation

TEXTIntroduction:Bausch & Lomb and Control Delivery Systems have developed an intravitrealimplant which can deliver the corticosteroid, fluocinolone acetonide(fluocinolone acetonide Envision TD sup(TM) implant, Retisert sup(TM)), tosurrounding eye tissue for up to 3 years. The implant uses Bausch & Lomb'sEnvision TD sup(TM) technology. This fluocinolone acetonide implant hasbeen designed for the treatment of posterior uveitis and other eyedisorders, which benefit from local anti-inflammatory therapy.


Caution: Not all implants are indexed as such in the Route of Administration portion of Adis R&D Insight records.

Adis does not provide systematic, controlled indexing for easy identification of products incorporating new drug delivery technologies. However, “textword” searches using terms illustrated here will help locate pertinent records – and could be combined with Indication keywords or Therapeutic Category codes.

File 107:Adis R&D Insight 1986-2004/Oct W2 (c) 2004 Adis Data Information BV.

Set Items Description --- ----- -----------? S DRUG()DELIVERY(3N)(SYSTEM OR TECHNOLOGY OR PLATFORM OR PROPRIETARY OR FORMULATION?)/TX S1 242 DRUG()DELIVERY(3N)(SYSTEM OR TECHNOLOGY OR PLATFORM OR PROPRIETARY OR FORMULATION?)/TX

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? T S1/K/1-5

1/K/1DIALOG(R)File 107:(c) 2004 Adis Data Information BV. All rts. reserv.

TEXT...an injection formulation of the nonsteroidal anti-inflammatory drug meloxicam (see separate profile) using its proprietary parenteral drug delivery Biochronomer(TM) system . The formulation is in preclinical development for the treatment of inflammation following arthroscopic surgery, as...


TEXT...see separate profile: Teriparatide injection) for this indication. The technology: Macroflux(TM) is a transdermal drug delivery technology, which utilises a titanium microprojection array to create superficial pathways through the skin barrier enabling...


TEXT...is developing a proprietary formulation of anaesthetic propofol (Propofol IDD-D(TM)) using its Insoluble Drug Delivery (TM) (IDD) technology . The IDD technology is complimentary to SkyePharma's proprietary nanoparticle technology that is developed to...


TEXT...an identified equianalgesic dose.DURECT is using DUROS sup((R)) implant technology coupled with a proprietary drug delivery catheter and drug formulation technology. DURECT licensed the DUROS sup((R)) technology for selected fields from ALZA Corporation in...


TEXT...an extended release formulation of metformin was developed using DepoMed's proprietary Gastric Retention (GR) System, a drug delivery technology designed for the oral delivery of agents that are preferentially absorbed high in the gastrointestinal...

...TM)), 500mg and 1000mg tablets. The 500mg dosage was developed by Depomed using its patented drug delivery GR sup(TM) technology, while Biovail developed metformin 1000mg dose using its proprietary Smartcoat delivery technology/1/. Biovail's...


TEXT...and became a wholly owned subsidiary of that company. Macroflux sup(TM)is a transdermal drug delivery technology which utilises a titaniummicroprojection array to create superficial pathways through the skinbarrier...

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Full-Text Subject Specialty News Sources for Monitoring Drug Delivery Developments

File 130:PHIND(Daily & Current) 2005/May 25 (c) 2005 T&F Informa UK Ltd *File 130: Effective 1 May 2005, ERA-News will change to EURALex. See HELP NEWS 130 for details. Set Items Description --- ----- -----------? E JN=

Ref Items Index-term E1 0 *JN= E2 185 JN=AGROW E3 129 JN=ANIMAL-PHARM E4 169 JN=ASI E5 75 JN=BIOVENTURE-VIEW E6 348 JN=CLINICA E7 10 JN=ERA-NEWS E8 18 JN=EURALEX E9 49 JN=HEALTHCARE-LOBBYIST E10 81 JN=INSTRUMENTA E11 684 JN=SCRIP E12 62 JN=SCRIP-ONLINE-PLUS E13 35 JN=TARGET

? S E13 S1 35 JN='TARGET'


Sontra granted US patent for SonoPrep:, May 24, 2005 (20050524) STORY TYPE: B WORD COUNT: 117 Orphan drug designation for doxorubicin Transdrug:, May 24, 2005 (20050524) STORY TYPE: B WORD COUNT: 115 Diatos and Servier announce oncology collaboration:, May 24, 2005 (20050524) STORY TYPE: B WORD COUNT: 116 Spectrum acquires global lucanthone licence:, May 24, 2005 (20050524) STORY TYPE: B WORD COUNT: 117 Phase I data for retinitis pigmentosa implant positive, May 23, 2005 (20050523) STORY TYPE: F WORD COUNT: 443 Company Profile: Vectura, May 23, 2005 (20050523) STORY TYPE: F WORD COUNT: 1451 Events calendar - June - July 2005, May 20, 2005 (20050520) STORY TYPE: F WORD COUNT: 1113 Tramadol Flashtabs approvable in US, May 20, 2005 (20050520) STORY TYPE: F WORD COUNT: 216 New low-cost family of nanostructures announced, May 20, 2005 (20050520) STORY TYPE: F WORD COUNT: 395 April Patent Applications, May 12, 2005 (20050512) STORY TYPE: F WORD COUNT: 739 Positive Phase III data for cancer vaccine, May 10, 2005 (20050510) STORY TYPE: F WORD COUNT: 205

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TARGET – Added in January 2002, this source focuses on the international drug delivery industry, with coverage of technologies and products research, launches, patents, licensing opportunities and agreements, and finance.

Scope includes:-- Noteworthy personnel changes-- Company alliances: licensing, partnering, m & a-- Clinical trial news-- Significant patent awards, with monthly summary tables-- Worldwide regulatory developments, including important product approvals, filings, orphan status designation-- Forthcoming conference calendar-- Feature articles offering informed commentary on trends

DIALOG(R)File 130:PHIND(Daily & Current) (c) 2005 T&F Informa UK Ltd. All rts. reserv. 00881718 April Patent Applications Target, May 12, 2005 (20050512) STORY TYPE: F WORD COUNT: 739 Target looks at April Patent Applications Assignee/Applicant Title Patent Number Name Acusphere Injectable, oral, WO05032523A1 or topical sustained- release formulations Alcon Sub-tenon drug EP1522289A2 delivery Alcon Bioerodible film for EP1521572A1 ophthalmic drug delivery Alcon Non-polymeric EP1521573A1 lipophilic intraocular implant Alexza Molecular Delivery of inhalable US2005075273A1 Delivery opioids Allergan Transdermal botulinum EP1521593A2 toxins Alza Osmotic controlled WO05030180A1 delivery of alprazolam Alza Controlled-release WO05030181A1 opioid and non-opioid analgesics Alza Osmotically driven WO05032524A2 delivery device for ascending release profile Alza/Atul Oros push-stick for WO05030166A1 controlled delivery Amylin Self-emulsifying WO05037250A1/ hydrophobic drug WO05037251A1 delivery systems Andrx Rapidly disintegrating WO05034921A1 formulation Angiotech Medicated stent with WO05030094A1 Biocoatings multi-layer polymer coating AstraZeneca Dry powder inhaler WO05035036A1 Astron Research Novel transmucosal WO05032554A1 delivery system Aventis Pharma Taste-masked oral EP1524966A1 telithromycin AVI Biopharma Delivery of compounds WO05030171A1 via microparticles or microbubbles Bang & Olufsen Inhaler EP1522325A1 Medicom Biogal Crystalline pravastatin EP1523978A2 forms Biomira Multilamellar EP1523977A1 coalescence vesicles (MLCV) with active compounds

[remainder of record, omitted here, includes 67 additional patents]

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Sample record

SYSTEM:OS - DIALOG OneSearch File 129:PHIND(Archival) 1980-2005/May W3 (c) 2005 T&F Informa UK Ltd File 130:PHIND(Daily & Current) 2005/May 25 (c) 2005 T&F Informa UK Ltd

Set Items Description --- ----- -----------? S DRUG()DELIVERY OR COMBINATION()PRODUCT OR DRUG(N)DEVICE S1 8135 DRUG()DELIVERY OR COMBINATION()PRODUCT OR DRUG(N)DEVICE

? S S1 AND PY=2004:2005 S2 1251 S1 AND PY=2004:2005

? RANK JNDIALOG RANK Results--------------------RANK: S2/1-1251 Field: JN= File(s): 129,130(Rank fields found in 1251 records -- 10 unique terms) Page 1 of 2 RANK No. Items Term-------- ----- ---- 1 859 TARGET 2 196 SCRIP 3 91 CLINICA 4 35 BIOVENTURE-VIEW 5 35 TARGET-ONLINE-PLUS 6 11 SCRIP-ONLINE-PLUS 7 10 AGROW 8 9 ANIMAL-PHARM

DIALOG(R)File 129:PHIND(Archival) (c) 2005 T&F Informa UK Ltd. All rts. reserv. 00879742 FDA ready to move on dual fees for innovative combi products Clinica 1154 p10, April 29, 2005 (20050429) STORY TYPE: F WORD COUNT: 362 Relief from double user fees may be in sight for some device companies seeking US approval of combination products that require a separate review or marketing application for the drug or biologic component. The FDA has determined that certain products may be in line for a partial waiver of the user fee paid to its biologics or drug centres, the agency explains in a new combination product guidance. The barrier to innovation provision under the Prescription Drug User Fee Act (PDUFA) allows a waiver or reduction of the fee for innovative technologies that hold promise for advancing patient care if companies are dissuaded from pursuing an application because of the fee. The FDA says it believes that the assessment of two marketing application fees for an innovative combination product could indeed present a significant barrier to its development. As a result, it has developed an innovative combination product waiver that reduces (but does not eliminate) the additional fee. In effect, the new waiver would mean that companies would pay the full device user fee plus a PDUFA fee reduced by the paid device user fee (under MDUFMA), bringing the total to the equivalent of one PDUFA fee. The current PDUFA fee for a new drug application or a biologic licence application is $672,000. The current fee for a premarket approval

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PHIND database coverage of drug delivery news is by no means limited to TARGET.

As a RANKed analysis of this broad-based “sampling” strategy indicates, other sources in Pharmaceutical & Healthcare Industry News (PHIND) include additional information.

application to the device centre is $239,237. Without waivers, a company would pay $911,237. With waivers, the PDUFA fee would be reduced to $432,763 so the total fee would be $672,000. The reduction is less marked for a 510(k). Companies with a combination product currently pay a $3,502 fee for that marketing application. Under the waiver, their PDUFA portion of the fee would be cut to $668,498, so their total fee would be $672,000. To qualify, the product itself must be innovative, the FDA must require two fee-eligible marketing applications and the company must be seeking approval of the two components for use together, not separately. However, applications for combinations of already-approved, independent, products generally would be eligible if two applications are required, it added. CLINICA - World Medical Device & Diagnostic News - www.clinica.co.uk FILED 22 April 2005 COPYRIGHT T&F Informa UK Ltd 2005

DIALOG(R)File 129:PHIND(Archival)(c) 2004 PJB Publications, Ltd. All rts. reserv.

00836620 Drug delivery continues to show results Scrip 2923 Review Issue 2003 p42, February 04, 2004 (20040204) STORY TYPE: F WORD COUNT: 1284

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.The drug delivery sector is growing at 10-15% a year, pushing the urrent volume of business of about US$46 billion to, some experts elieve, more than US$120 billion by the year 2007. According to PJB's Pharmaprojects database, almost 30% of marketed products are improved formulations of existing compounds. For the past five years, the proportion of marketed products that are reformulations rather than new chemical entities has been increasing steadily. If the current trend continues, more than half of all products willbe reformulations by the end of the decade.

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Figure 1: Selected 2003 approvals of products using novel drug delivery technologies.

Product Company(s) Indication Market Month ApprovedCipro XR Bayer/Ranbaxy urinary tract US Jan infectionsMitozytrex SuperGen cancer US JanTaxus stent Boston Scientific restenosis Europe FebArestin OraPharma periodontal disease Sweden FebOxytrol Watson urinary incontinence US MarInnopran XL Eurand/Reliant hypertension US MarRisperdal Alkermes/ schizophrenia Spain Mar Consta Johnson & JohnsonSomavert Pharmacia(1)/ acromegaly US Apr NektarCypher stent Cordis (Johnson & restenosis US Apr Johnson)UroXatral Sanofi-Synthelabo/ benign prostatic US May SkyePharma hyperplasiaNiaspan Kos/Merck KGaA dyslipidaemia UK MayLescol XL Novartis/Alkermes additional US May cardiology indicationsFluMist MedImmune/Wyeth intranasal flu US Jun vaccine

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Striant Columbia buccal testosterone US Jul Laboratories replacementTestim Bentley/Auxilium testosterone UK Jul deficiencyOlux Connetics scalp dermatitis UK JulWellbutrin GlaxoSmithKline/ depression US Aug XL BiovailPaxil CR GlaxoSmithKline/ premenstrual US Sept SkyePharma dysphoric disorderTaxus stent Boston Scientific restenosis Canada SeptNascobal Questcor intranasal US Sept first-line vitamin B12 deficiencyDepakote ER Abbott paediatric epilepsy US Sept LaboratoriesRisperdal Alkermes/ schizophrenia France Oct Consta Johnson & JohnsonEstrasorb Novavax/King vasomotor menopausal US Oct symptomsPaxil CR GlaxoSmithKline/ social anxiety US Oct SkyePharma disorderRisperdal Alkermes/ schizophrenia US Nov Consta Johnson & JohnsonNebido Schering AG hypogonadism Finland DecClimara Pro Schering AG menopausal symptoms US Dec (Berlex)(1) Now Pfizer

Figure 2: Selected deals/terminations in the drug delivery sector, 2003

Partner Nature of deal Month companiesAlkermes/Lilly Alkermes assumes all development Jan costs for AIR pulmonary insulinSkyePharma/Endo Pharma US/Canadian rights to Depomorphine Jan and Propofol licensed to EndoSkyePharma/Enzon Pharma US/Canadian rights to Depocyt Jan licensed to Enzon; collaboration on three new drugsSkyePharma/Micap Option rights for SkyePharma to Jan use Micap microencapsulation technologyBiovail/GlaxoSmithKline Biovail licenses Wellbutrin XL Jan in Canada

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References from Scrip-Online-Plus often include publication announcements that provide substantial extracts from the primary source cited, as well as detailed tables of contents. [See also the Scrip Report record cited on page 3.]

DIALOG(R)File 129:PHIND(Archival)(c) 2004 PJB Publications, Ltd. All rts. reserv.

00832316 PUBLICATIONS - New from Scrip Reports - Nanotechnology in Drug Delivery: Commercial opportunities for pharma Scrip-Online-plus, February 09, 2004 (20040209) STORY TYPE: F WORD COUNT: 1339

Drug delivery - controlling the precise place in the body and theexact time that pharmaceutically active compounds are released, inorder to optimise their safety and efficacy.

Nanotechnology - the manipulation, precision placement,measurement, modelling or manufacture of sub-100 nanometre-scalematter.

Governments, investment analysts, and industry writers in general,have published many hundreds of articles and reports onnanotechnology in the past few years. It is noteworthy that eventhough nanotechnology has the potential to effect every aspect ofglobal industry significantly, most of the publicationsspecifically highlighted drug delivery, a relatively small sector,as one of them. This shows that drug delivery is already widelyrecognised as a key area where nanotechnology can be applied togreat effect. Why should this be?

The two fields have a lot in common. They are both growingrapidly. They each take their inspiration from various scientificdisciplines. Indeed, inter-disciplinary development projects thatincorporate physics, chemistry, engineering, electronics andbiology, for example, are a feature of both fields.

However, the principle reason why nanotechnology holds suchpromise in drug delivery is not a similarity between them. It isthat they complement each other so well. Nanotechnology offers thedrug delivery industry solutions to its biggest ever challenges,just at the time when these problems are arising.

Buoyed up by the increasing need for delivery technologies toaccommodate insoluble small-molecule NCE's, and the growing numberof new macromolecules arising from biotech, which also needeffective delivery systems; the drug delivery sector has beenshifting into new territories over the past few years.

To be effective enablers at the earliest stages of drugdevelopment, highly sophisticated delivery technologies arerequired. The recent wave of novel advanced drug deliverytechnologies uses an understanding of the cellular andbiomolecular processes that the formulations being deliveredencounter, once inside the body. Thus, the technologies beinggenerated have their routes in biochemical and biomolecularscience.

How fitting that nanotechnology, at the very core of which is theability to interact directly and precisely with materials(including biological systems) at the molecular level, arrives onthe scene now. The most significant applications of nanotechnologyin drug delivery include, reduction of particle size and increaseof surface area, enhancing solubility for injection or increasingoral bioavailability and targeting of tissues and cells. It alsoallows the crossing of biological membranes, gene and vaccinedelivery, artificial nanoporous membranes for controlled-release

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devices, surface engineering of implants to increasebiocompatability and the use of smart devices.

The main reasons why we are now able to enter the age of drugdelivery nanotechnologies are three-fold. Firstly, techniques suchas scanning tunnelling microscopy, scanning near-field opticalmicroscopy, atomic force microscopy have given us the ability tomake useful observations and measurements at the nanometre scale.Secondly, our understanding at the nanometre scale of thebiological systems that any potential drug delivery technologymust interact with has progressed. Third is in our ability to makecontrolled, reproducible changes to materials at the nanometrescale.

Currently, nanotechnology is applied in around 1% of drug deliverytechnologies under development. However, it is estimated that by2015, more than 14% of drug delivery technologies will incorporatenanotechnology. By 2015, the global nanotechnology market ispredicted, to grow to $1 trillion. This $1 trillion figure,although often treated with scepticism, does have a reasonedbasis. An introduction to nanotechnology and drug delivery is inChapter 1 of this report.

Among the materials being used to develop such technologies aredendrimers, nanoporous silicon, buckminster fullerenes and carbonnanotubes, colloidal gold-coated nanoshells, and variousnanopolymers. Full details of these and other drug deliverynanotechnology approaches can be found in Chapter 2 of the report.

By far the majority of the nanotechnology R&D under-way at presentis funded by government grants. Government's worldwide arerecognising the potential nanotechnology holds. In order toestablish infrastructure and stimulate growth, they are setting upinitiatives and investing heavily in the sector. These funds areflowing into government laboratories, non-profit nanotechnologyorganisations, academic projects and commercial ventures.

In 2001 and 2002, more than $2 billion was spent on funding fornanotechnology, and this is set to increase significantly from2003 onwards. It is predicted that US Government spending onnanotechnology will be the most spent on one area since the spacerace and greater than it was for the human genome project. Thenanotechnology drug delivery market is examined in Chapter 3 ofthis report.

However, in contrast to the microtechnology sector, in which theUS took and maintained a clear lead, it is important to note thatdominance in nanotechnology is still wide open. Europe taken aswhole, individual European countries like Germany, and Japan, allhold a position in nanotechnology that can compete healthily withthe US effort.

The total investment in nanotechnology business in 2002 was about$1 billion, as estimated by the Nanobusiness Alliance, of which20% was from the venture capital (VC) community (Robert Ulrich,Vanguard Venture Partners). While total venture capital declinedbetween 2001 and 2002, venture investments in nanotechnologyincreased, by 251% in electronics, 211% in industrial products andby 313% in life sciences and nanobiotechnology. Investment innanotechnology including funding and the current climate arediscussed further in Chapter 4 of this report.

Seven companies prominent in nanotechnology development in thefield of drug delivery will be profiled in Chapter 5 of thisreport.

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CONTENTSABBREVIATIONS/GLOSSARY 9CHAPTER 1 NANOTECHNOLOGY IN DRUG DELIVERY - INTRODUCTION 111.1 Definitions of drug delivery and nanotechnology 111.2 Nanotechnology - a short history and common tools and techniques 131.3 The significance of nanotechnology in drug delivery 141.4 The emergence of drug delivery nanotechnology 17CHAPTER 2 NANOTECHNOLOGIES IN DEVELOPMENT 212.1 Introduction 212.2 Early applications of nanotechnology in drug delivery 21 2.2.1 Dendrimers 21 2.2.2 Silicon 27 2.2.3 Carbon 31 2.2.4 Synthetic polymers 34 2.2.5 Gold-coated silica nanoshells 35 2.2.6 Mesoporous silica (MCM-41) 362.3 Examples of 'branded' commercial drug delivery nanotechnologies 37 2.3.1 NanoCrystal 37 2.3.2 NanoMorph 38 2.3.3 NanoCure 38 2.3.4 Medusa 39 2.3.5 Colloidal Gold 39 2.3.6 Layer-by-Layer Encapsulation 40 2.3.7 Calcium Phosphate nanoparticles 41CHAPTER 3 ANALYSIS OF THE DRUG DELIVERY/NANOTECHNOLOGY MARKET 433.1 Nanotechnology market 43 3.1.1 Light shed on the 'trillion dollar market' figure 43 3.1.2 Timelines for the emergence of a new technology 453.2 Drug delivery market overview 48 3.2.1 Drivers of growth 48 3.2.2 Business strategies 503.3 Nanotechnology in drug delivery 51 3.3.1 Dovetailing of two complimentary areas 51 3.3.2 Convergence of nanotechnology and drug delivery 52 3.3.3 Drug delivery nanotechnologies development timeline 53 3.3.4 Drug delivery nanotechnology products pipeline 54CHAPTER 4 NANOTECHNOLOGY INVESTMENT CLIMATE AND FUNDING STRATEGIES 554.1 Introduction 55 4.1.1 Pure nanotechnology 554.2 Government funding 56 4.2.1 United States 58 4.2.2 European Union 61 4.2.3 Other national government funding 634.3 Venture Capital investment climate 654.4 Drug delivery nanotechnology partnerships 67CHAPTER 5 COMPANY PROFILES 735.1 Advectus Life Sciences 73 5.1.1 General 73 5.1.2 Technologies overview 73 5.1.3 Investment history 73 5.1.4 Collaborations 74


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File 441:ESPICOM Pharm&Med DEVICE NEWS 2005/May W1 (c) 2005 ESPICOM Bus.Intell. Set Items Description --- ----- -----------? S DRUG()DELIVERY OR COMBINATION()PRODUCT? OR DRUG(N)DEVICE S1 2469 DRUG()DELIVERY OR COMBINATION()PRODUCT? OR DRUG(N)DEVICE

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? RANK JN CONT;ALLEnter title for continuous output or press ENTER for current title option

? ESPICOM NEWSLETTERS COVERING DRUG DELIVERY TOPICS Adding title to results...ESPICOM NEWSLETTERS COVERING DRUG DELIVERY TOPICS-------------------------------------------------RANK: S2/1-672 Field: JN= File(s): 441(Rank fields found in 672 records -- 12 unique terms) RANK No. Items Term-------- ----- ---- 1 329 DRUG DELIVERY INSIGHT 2 70 PHARMA AGREEMENT NEWS 3 56 PHARMA COMPANY INSIGHT 4 53 CANCER DRUG NEWS 5 33 MEDICAL INDUSTRY WEEK 6 31 CNS DRUG NEWS 7 30 ANTI-INFECTIVE DRUG NEWS 8 29 CARDIOVASCULAR DEVICE BUSINESS 9 19 CARDIOVASCULAR DRUG NEWS 10 14 WORLD GENERIC MARKETS 11 6 AUTOIMMUNE DRUG FOCUS 12 2 ORTHOPAEDICS BUSINESS ---end of results---

? S JN=DRUG DELIVERY INSIGHT/2005 S3 582 JN=DRUG DELIVERY INSIGHT/2005

? S S3 AND PD=200505? S4 49 S3 AND PD=200505?

Sample titles…

FDA approvable letter for Alcon's Retaane suspension 25 May 2005 (20050525) RECORD TYPE: FULLTEXT WORD COUNT: 272

Novavax reveals positive preclinical MNP studies 25 May 2005 (20050525) RECORD TYPE: FULLTEXT WORD COUNT: 329

Preliminary data show Lucentis maintains or improves vision in wet AMD patients 25 May 2005 (20050525) RECORD TYPE: FULLTEXT WORD COUNT: 521

TIPHON study finds Spiriva improves health-related quality of life in patients with COPD 25 May 2005 (20050525)

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Broad “sampling” strategy to assess coverage & locate (through RANKing) relevant resources included in this database

The ESPICOM database includes several full-text publications, including one devoted to drug delivery news (updated daily).

Wound healing effects of TB4 presented at Wound Healing Society meeting 23 May 2005 (20050523) RECORD TYPE: FULLTEXT WORD COUNT: 199

Final approval granted for fluticasone nasal spray in UK 16 May 2005 (20050516) RECORD TYPE: FULLTEXT WORD COUNT: 111

INEX provides update on Marqibo commercialisation 16 May 2005 (20050516) RECORD TYPE: FULLTEXT WORD COUNT: 445

Oriel receives US patent 10 May 2005 (20050510) RECORD TYPE: FULLTEXT WORD COUNT: 144 pSivida receives Chinese patent for BrachySil 10 May 2005 (20050510) RECORD TYPE: FULLTEXT WORD COUNT: 153

DIALOG(R)File 441:ESPICOM Pharm&Med DEVICE NEWS (c) 2005 ESPICOM Bus.Intell. All rts. reserv. 00086003 00091096 (THIS IS THE FULLTEXT) Wound healing effects of TB4 presented at Wound Healing Society meeting Drug Delivery Insight 23 May 2005 (20050523) RECORD TYPE: FULLTEXT WORD COUNT: 199 TEXT: RegeneRx Biopharmaceuticals has reported that Dr Hynda Kleinman, Chief of the Laboratory of Cell Biology at the National Institutes of Health's (NIH) Dental and Craniofacial Research Institute in Bethesda, MD, has presented data showing how Thymosin beta 4 (TB4) accelerates wound healing, as well as the stimulation of hair follicles in laboratory animals. In her presentation at the 15th annual meeting of the Wound Healing Society in Chicago, IL, Kleinman emphasised TB4's ability to upregulate or "turn on" two genes, zyxin and laminin-5, both of which are important for cellular adhesion and cell migration, two key biological activities necessary for successful wound healing. Kleinman also presented confirmatory data indicating TB4's ability to enter the nucleus of the cell due to the presence of actin, a major cell-building protein to which TB4 readily attaches. The ability of TB4 to enter the cell nucleus offers the possibility that it could be used as a carrier or 'chaperone molecule' to allow manipulation of cells at the nuclear level. This capability could open up a whole new avenue for delivering specialised chemotherapeutic agents, or other drugs, to cells in a very efficient and targeted manner and further broadens the possible uses of TB4. COMPANY: RegeneRx Biopharmaceuticals

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Prous Science Daily Essentials

Full-text newsletter focusing on timely reporting of pharmaceutical R&D and market developments, compiled by Prous Science (producers of Drug Data Report, Drugs of the Future, and Drug News & Perspectives)

Special features:

Daily addition of records documenting new molecular entities identified in recent patents, at subject specialty congresses/scientific conferences, or cited in the current biomedical literature

Chemical structure image display for these compounds

Controlled indexing of key factors, such as therapeutic class, development status, source document type

DIALOG(R)File 458:Daily Essentials (c) 2005 Prous Science. All rts. reserv. 00069565 SCH-391 REDUCES SERUM TESTOSTERONE AND TUMOR VOLUME IN MOUSE XENOGRAFT MODEL Daily Essentials May 04, 2005 (20050504) DOCUMENT TYPE: Congress DEVELOPMENT STATUS: New Compound LANGUAGE: English RECORD TYPE: Fulltext; Image The main function of 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3), which is expressed mainly in the testes, is to catalyze the conversion of androstenedione to testosterone. Researchers at Schering-Plough have developed SCH-391, an inhibitor of 17beta-HSD3. The compound blocked the conversion reaction in murine recombinant and human recombinant 17beta-HSD3 as well as in human testicular homogenates (IC50 = 3, 15 and 22 nM, respectively). It also exhibited a more than 1500-fold selectivity for 17beta-HSD3 over other recombinant human steroid metabolic enzymes. In vivo, oral single dose administration of SCH-391 to mice bearing androgen-dependent tumors decreased testosterone levels and augmented the ratio of androstenedione/testosterone in the serum. In a mouse model of androgen-dependent Shionogi carcinoma, treatment with SCH-391 reduced serum testosterone by 63% and decreased tumor volume by up to 70% in a dose-dependent manner. The compound shows potential to emerge as a therapeutic agent for prostate cancer (Pachter, J.A. et al. 96th Annu Meet Amer Assoc Cancer Res (April 16-20, Anaheim) 2005, Abst 2382). This compound is described in patent literature (WO 04060488). NAMED COMPANIES: Schering-Plough NAMED DRUGS: SCH-391 [397043]

THERAPEUTIC CLASS: Drug Design, Drug Delivery & Technologies; Oncolytic

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Drugs; Inhibitors of Signal Transduction Pathways File 182:FDA News Mar. 2002-2005/May 25 (c) 2005 Washington Business Info. *File 182: For details on titles, see HELP NEWS182. Set Items Description --- ----- -----------? S DRUG()DELIVERY OR COMBINATION()PRODUCT? OR DRUG(N)DEVICE S1 541 DRUG()DELIVERY OR COMBINATION()PRODUCT? OR DRUG(N)DEVICE

? RANK JN CONT;ALL DIALOG RANK Results--------------------RANK: S1/1-541 Field: JN= File(s): 182(Rank fields found in 541 records -- 15 unique terms) RANK No. Items Term-------- ----- ---- 1 112 DRUG INDUSTRY DAILY 2 85 DEVICES & DIAGNOSTICS LETTER 3 72 FDANEWS DRUG DAILY BULLETIN 4 67 FDANEWS DRUG PIPELINE ALERT 5 59 FDANEWS DEVICE DAILY BULLETIN 6 46 WASHINGTON DRUG LETTER 7 26 GENERIC LINE 8 26 THE FOOD & DRUG LETTER 9 19 DRUG GMP REPORT 10 9 THE GMP LETTER 11 7 DAILY INTERNATIONAL PHARMA ALERT 12 5 PART 11 COMPLIANCE REPORT 13 4 PHARMACEUTICAL CORPORATE COMPLIANCE REPORT 14 3 CLINICAL TRIALS ADVISOR 15 1 THE BIODEFENSE FUNDING REPORT ---end of results---

DIALOG(R)File 182:FDA News Mar. (c) 2005 Washington Business Info. All rts. reserv. 0001899032 I4FA0A50095A911D99ED3FC7A77205D97 (THIS IS THE FULLTEXT) RAPS Issues Draft of Final Summit Report on Combination Products Drug Industry Daily, v4, n53 Tuesday, March 15, 2005 JOURNAL CODE: DRID LANGUAGE: ENGLISH RECORD TYPE: FULLTEXT DOCUMENT TYPE: Newswire WORD COUNT: 529 TEXT: The FDA needs to provide for greater specificity in the cross-labeling of combination products and give its Office of Combination Products (OCP) a greater role in product reviews, according to a report issued this month by a panel of regulatory professionals. As a result of a Jan. 11-12 summit (DID, Jan. 17, Page 3), the Regulatory Affairs Professionals Society (RAPS), along with the Combination Products Coalition, this month released a draft final summit report that lays the foundation for an eventual guidance that will be submitted to the FDA in an attempt to regulate combination products within the agency's breadth. The panel announced a multitude of recommendations that fell under three main objectives: labeling for combination products, proposed enhancements to the role of the OCP and the regulatory process for modifications to approved combination products. Combination products can consist of a combination of a drug and a medical device; a biological product and a medical device; a drug and a biological

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product; or a blend of a drug, a device and a biological product. The FDA's definition of combination products can be found under 21 CFR 3.2(e). Due to the mixing of products that require different regulations, labeling of a newly formed product becomes a significant issue. The panel identified two areas of labeling for combination products that required discussion: cross-labeling of branded products intended for use in combination and the labeling of integral combination products. The primary concern regarding the cross-labeling of branded products was the need for greater consistency and predictability for when specificity is -- and is not -- required. The panel agreed that labeling should guide and inform the user of the product, but should not dictate the practice of medicine. The panel also recommended that the FDA review labeling through the eyes of the end-user, possibly requiring branded cross-labeling to assure safe and efficacious use of a product and to determine whether branded cross-labeling even remains necessary. As for labeling integral combination products, the panel found that consistency in the FDA's approach to the products' regulation and a clear, agreeable definition of the products themselves were needed. The panel thought the FDA should draft a guidance providing: necessary content for each of the labeling elements (directions for use, product labels, etc.); a labeling format for various audiences (patients, consumers, professionals, etc.); and content requirements for small-container labeling. The panel also recommended that OCP have a more visible role in combination product review. This new visibility "would help to drive reviews in a timely manner, while still not making OCP a full, independent FDA center." The panel suggested that OCP continue and increase such tasks as cross-training and facilitating harmonization between FDA centers involved with combination products. The cross-training, the panel said, would lead "to better communication and more consistency in approval criteria." Along with cross-training, the panel suggested that representatives from the different centers get together at summits in order to alleviate questions and issues that come about during the review process. This summit would be convened by OCP at sponsor request. The draft final summit report can be found online at http://www.raps.org/s--raps/docs/25000/24994.pdf. -- DC Copyright (c) 2005 Washington Business Information, Inc. COMPANY NAMES: OCP DESCRIPTORS: RAPS; FDA DIALOG UPDATE DATE: 20050315; 19:31:08 EST INDUSTRY NAMES: INTERNATIONAL ECONOMIC RELATIONS

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File 135:NewsRx Weekly Reports 1995-2005/May W3 (c) 2005 NewsRx

Set Items Description --- ----- -----------? S DRUG()DELIVERY OR COMBINATION()PRODUCT? OR DRUG(N)DEVICE S1 3013 DRUG()DELIVERY OR COMBINATION()PRODUCT? OR DRUG(N)DEVICE

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? NEWSRX SOURCES COVERING DRUG DELIVERY TOPICS Adding title to results...NEWSRX SOURCES COVERING DRUG DELIVERY TOPICS--------------------------------------------RANK: S2/1-640 Field: JN= File(s): 135(Rank fields found in 640 records -- 19 unique terms) RANK No. Items Term-------- ----- ---- 1 345 BIOTECH BUSINESS WEEK 2 126 LIFE SCIENCE WEEKLY 3 19 ANTI-INFECTIVES WEEK 4 19 CANCER GENE THERAPY WEEK 5 18 ANGIOGENESIS WEEKLY 6 18 CANCER WEEKLY 7 16 IMMUNOTHERAPY WEEKLY 8 13 CANCER VACCINE WEEK 9 9 AIDS VACCINE WEEK 10 9 CLINICAL TRIALS WEEK 11 8 CARDIOVASCULAR WEEK 12 8 GASTROENTEROLOGY WEEK 13 7 AIDS WEEKLY 14 7 BLOOD WEEKLY 15 7 DIABETES WEEK 16 5 GENE THERAPY WEEKLY 17 3 HEPATITIS WEEKLY 18 2 GENOMICS & GENETICS WEEKLY 19 1 BIOTERRORISM WEEK ---end of results---

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File 636:Gale Group Newsletter DB(TM) 1987-2005/May 26 (c) 2005 The Gale Group Set Items Description --- ----- -----------? S DRUG()DELIVERY OR COMBINATION()PRODUCT? OR DRUG(N)DEVICE S1 12181 DRUG()DELIVERY OR COMBINATION()PRODUCT? OR DRUG(N)DEVICE

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? RANK JN CONT;ALL DIALOG RANK Results--------------------RANK: S3/1-678 Field: JN= File(s): 636(Rank fields found in 678 records -- 54 unique terms) RANK No. Items Term-------- ----- ---- 1 188 BIOWORLD TODAY 2 177 M2 PRESSWIRE 3 50 BBI NEWSLETTER 4 33 BIOTECH PATENT NEWS 5 30 BIOMEDICAL MATERIALS 6 22 HOSPITAL MATERIALS MANAGEMENT 7 20 BIOTECH EQUIPMENT UPDATE 8 17 WALL STREET TRANSCRIPT DIGEST 9 11 WORLDWIDE BIOTECH 10 10 ADVANCED MATERIALS & PROCESSES 11 9 BIOTECH BUSINESS 12 9 EUROPEAN VENTURE CAPITAL JOURNAL 13 8 BIOTECH FINANCIAL REPORTS 14 8 HEALTH CARE STRATEGIC MANAGEMENT 15 6 MEMBRANE & SEPARATION TECHNOLOGY NEWS 16 5 HIGH TECH CERAMICS NEWS 17 5 OZONE DEPLETION TODAY 18 5 VENTURE CAPITAL JOURNAL 19 4 BT CATALYST 20 4 GROUNDS MAINTENANCE 21 4 NUTRACEUTICALS INTERNATIONAL 22 3 ADVANCED CERAMICS REPORT 23 3 CD COMPUTING NEWS 24 3 HARVARD HEART LETTER 25 3 MEDICAL TEXTILES 26 3 MERGERS & ACQUISITIONS REPORT 27 3 SENSOR BUSINESS DIGEST 28 2 ANALYTIC SEPARATIONS NEWS 29 2 BATTERY & EV TECHNOLOGY 30 2 CORPORATE FINANCING WEEK 31 2 HIGH PERFORMANCE PLASTICS 32 2 INDUSTRIES IN TRANSITION 33 2 MANUFACTURING & TECHNOLOGY NEWS 34 2 MANUFACTURING AUTOMATION 35 2 TELECOMWORLDWIRE 36 1 ADVANCED COMPOSITES BULLETIN 37 1 ADVANCED MATERIALS & COMPOSITES NEWS 38 1 ADVANCES IN TEXTILES TECHNOLOGY

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The Gale Group Newsletter Database provides cover-to-cover full-text access (excluding graphics & advertising) to all titles cited.

Overlap: Although many titles are also cited in other Gale Group databases (such as PROMT, Trade & Industry Database, and Business & Industry), it’s important to remember that coverage offered in other files is, typically, selective—versus the complete transcription included in the Newsletter Database.

Source of “Hidden Treasures”

Many healthcare titles not available elsewhere online Subject specialty publications easily overlooked, due to their limited hardcopy distribution, but tailor-made for focused current awareness.

Examples of Full-Text Healthcare Industry News Sources Found in General Business Databases

Biomedical Market Newsletter monitors business, marketing, and regulatory issues with potential impact on biomedical equipment, device, diagnostic test, and supply industries. Issued monthly by Biomedical Market Newsletter, Inc. Selected full-text articles in the Business & Industry database.

Biomedical Materials focuses on research and development related to materials used in medicine, including ceramics, composites, metals, and polymers. Issued monthly by Elsevier Advanced Technology publications. Cover-to-cover full-text access in the Gale Group Newsletter Database.

BioPharm focuses on the science and industry of developing biotechnology-derived pharmaceutical products and biotherapeutic methods. It covers scientific and technical applications, as well as regulatory affairs and business news. Issued monthly by Advanstar Communications Inc. Complete text access in Gale Group PROMT.®

Biotech Business provides detailed reporting on biotechnology products and companies, with growth forecasts and periodic financial assessments, as well as news of licensing opportunities. Issued monthly by Worldwide Videotex. Complete full-text in Gale Group Newsletter Database™.

Biotech Equipment Update relays news on laboratory equipment, drug delivery systems, test kits, and related technological developments and new product approvals. Issued monthly by Worldwide Videotex. Complete full-text coverage in the Gale Group Newsletter Database™.

Biotech Financial Reports covers news of public offerings, venture capital financing, and other financial events and opportunities related to the biotechnology industry. Issued monthly by Worldwide Videotex. Cover-to-cover full-text access in the Gale Group Newsletter Database™.

Biotech Patent News reports on patenting, licensing, and related litigation, government actions, and special interest group activities. Issued monthly by Biotech Patent News. Complete full text from February 1991 to date in the Gale Group Newsletter Database.

Biotechnology Newswatch follows developments from the laboratory to the marketplace, featuring company profiles, regular review of patent filings, and news related to biotechnology applications in pharmaceuticals, agriculture, and bioremediation. Issued two times/month by McGraw-Hill, Inc. Full-text online coverage dates from September 1986 in McGraw-Hill Publications Online.

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BIOWORLD Today reports on licensing, legal actions, evolving research, new patents, and company news in the biotechnology industry. Issued daily by American Health Consultants, Inc. (Medical Economics/Thomson Healthcare). Cover-to-cover full-text access in the Gale Group Newsletter Database. Selected full-text articles also in Gale Group PROMT.

BT Catalyst covers biotechnology news, with special emphasis on university and industry programs. Issued 10 times/year by the North Carolina Biotechnology Center. Complete full text in the Gale Group Newsletter Database.

Hospital Materials Management posts positions available, executive personnel changes, and product pricing/financial news for its intended audience of healthcare system administrators, group purchasing organizations, and companies supplying medical equipment, supplies, and services to them. Issued monthly by Business Word, Inc. Complete full text in the Gale Group Newsletter Database.

Instrument Business Outlook is a trade-oriented publication that relays news of interest to the medical instrument industry, including both business and R&D developments in its coverage. Issued semimonthly by Strategic Directions International, Inc. (SDI). Complete full text in the Gale Group Newsletter Database.

Medical Textiles surveys new applications for textiles used in medicine, covering design, production, and industrial research developments and business opportunities. Issued monthly by International Newsletters (UK). Complete full-text in the Gale Group Newsletter Database™ and selected articles in Gale Group PROMT.

Pharmaceutical Executive highlights the latest marketing techniques, industry trends, sales, promotional strategies, and legal and regulatory issues influencing product development and management. Issued monthly by Advanstar Communications, Inc. Complete full-text coverage in Gale Group PROMT.

Worldwide Biotech reports news and information on the industry from a global viewpoint, monitoring the emerging European Community marketplace, Japan's growing involvement, and international deals between companies. Issued monthly by Worldwide Videotex. Complete full text in the Gale Group Newsletter Database. Selected articles also in Gale Group PROMT.

DIALOG(R)File 636:Gale Group Newsletter DB(TM)(c) 2004 The Gale Group. All rts. reserv.

05800680 Supplier Number: 117422939 (THIS IS THE FULLTEXT) Drug delivery: patent for sustained release technology.(Research Alert)Biomedical Materials, p8June, 2004ISSN: ISSN: 0955-7717Language: English Record Type: FulltextDocument Type: Newsletter; TradeWord Count: 512TEXT: A US company, specializing in porous microparticle technology forsustained release formulations, has won a third US patent Matrices Formedof Polymer and Hydrophobic Compounds for Use in Drug Delivery (number 6 730322). Acusphere Inc, based in Massachusetts, is focusing particularly onhydrophobic drugs. It is difficult to create sustained release formulationsfor many hydrophobic drugs because they release too slowly from themicroparticles used to deliver the drug, diminishing the efficacy of thedelivery system. Many of the leading asthma drugs, including most inhaledcorticosteroids, are hydrophobic drugs. The patent relates to methods of producing certain porousmicroparticle formulations using slowly dissolving shell materials tocreate sustained release formulations of a variety of drugs, particularly

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the hydrophobic drugs, which do not dissolve well in water. Acusphere has developed a means of modifying water uptake into themicroparticles by adjusting the porosity of the microparticles duringmanufacturing and by choosing from a wide variety of materials to includein the microparticle shell. This can speed the release, while retaining thedesired sustained release profile of these drugs. Acusphere is currently using this patented technology to developAI-128, a sustained release formulation of a hydrophobic, inhaledcorticosteroid. AI-128 is designed slowly to release the drug locally intothe lungs so that it has the potential to reduce the multi-dosing per dayregimen to a longer-lasting, once per day regimen which should improvepatient compliance. Most of these corticosteroids are administered multipletimes per day and, as a result, poor patient compliance can be a problemthat may lead to acute asthma attacks. Results from a human study of AI-128 indicated that it delivered alower concentration of the drug into the systemic circulation relative tothe approved formulation of this inhaled corticosteroid, thus making itpotentially safer. The problem with inhaled corticosteroids is that theformulations can deliver some of the drug unintentionally into the systemiccirculation, where it may have undesirable side effects. These effects include the slowing of bone growth. This evidently isa particular concern with children whose growth can be stunted. Doctors areoften reluctant, therefore, to prescribe them to children. Acusphere's formulations have tightly controlled size distributionsand have the potential to release drugs over periods ranging from days toweeks via a range of methods, including intravenous, inhalation,subcutaneous or oral routes of administration, according to the company'sPresident Sherri Oberg. Acusphere's lead product candidate, AI-700, is a cardiovascular drugin Phase III clinical development. AI-700 is designed to be an alternativeto the estimated 9.5 million procedures done each year in the USA alone todetect coronary artery disease, the leading cause of death in the USA. For further information, contact: John Thero, Investor Relations,Acusphere Inc, 500 Arsenal Street, Watertown, MA 02472, USA; tel:+1-617-925-3444; fax: +1-617-926-4750; E-mail: [email protected] Internetaddress: www.Acusphere.com THIS IS THE FULL TEXT: COPYRIGHT 2004 International Newsletters Subscription: $474.00 per year. Published monthly. 9A Victoria Square, Droitwich Spa, Worcestershire WR9 8DE., United Kingdom COPYRIGHT 2004 Gale GroupPUBLISHER NAME: International NewslettersDESCRIPTORS: *Antiasthmatic agents--Intellectual property Drug delivery systems--Intellectual property CorticosteroidsEVENT NAMES: *370 (Patents & copyrights)PRODUCT NAMES: *2834481 (Antiasthmatic Preparations); 2834030 (Drug Delivery Systems)INDUSTRY NAMES: CHEM (Chemicals, Plastics and Rubber); HLTH (Healthcare - Medical and Health)SIC CODES: 2834 (Pharmaceutical preparations)NAICS CODES: 325412 (Pharmaceutical Preparation Manufacturing)

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Other Sources of Drug Delivery & Combination Product Information: Syndicated Market Research Reports + Investment Analysts’ Reports

Examples…

DIALOG(R)File 764:BCC Market Research (c) 2005 Business Communication Co. All rts. reserv. BIOSENSORS & BIOELECTRONICS: OVERVIEW: BIOMEDICAL & LIFE SCIENCES: DRUG DELIVERY & DRUG DEVELOPMENT Main Title: BIOSENSORS & BIOELECTRONICS Pub. Date: APRIL 2005 Source: BUSINESS COMMUNICATION COMPANY, INCORPORATED

DIALOG(R)File 759:Business Insights (c) 2005 Datamonitor. All rts. reserv. EFFECTIVE BRAND PROTECTION THROUGH PATENT, FORMULATION, OTC AND DTC STRATEGIES: 1.2 FORMULATION STRATEGIES Main Title: GENERICS DEFENSE STRATEGIES Pub. Date: March 30, 2005 Source: DATAMONITOR

DIALOG(R)File 767:Frost & Sullivan Market Eng (c) 2005 Frost & Sullivan Inc. All rts. reserv. NEEDLE-FREE INJECTABLES MARKETS: Overview: Introduction: Types of Drug Delivery Systems (1/2) Main Title: U.S. NEEDLE-FREE INJECTABLES MARKETS Pub. Date: March 2005 Source: Frost & Sullivan

DIALOG(R)File 761:Datamonitor Market Res. (c) 2005 Datamonitor. All rts. reserv. GLOBAL INDUSTRY GUIDE: 14.0 DRUG DELIVERY IN THE UNITED STATES Main Title: DRUG DELIVERY Pub. Date: February 04, 2005 Source: DATAMONITOR

DIALOG(R)File 763:Freedonia Market Res. (c) 2005 Freedonia Group Inc. All rts. reserv. MARKET OVERVIEW - WORLD NANOMATERIALS TO 2008: Pharmaceuticals - Nanomaterials as Drug Delivery Systems (1 of 2) Main Title: WORLD NANOMATERIALS TO 2008 Pub. Date: MARCH 2005 Source: THE FREEDONIA GROUP, INC.

DIALOG(R) File 764: BUSINESS COMMUNICATION COMPANY, INCORPORATED

Main Title: ADJUNCTIVE THERAPIESDate: December 2004

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DIALOG(R)File 745:Investext(R) PDF Index (c)2005 Thomson Fin. Networks. All rts. reserv. 03704638 DRUG DELIVERY TECHNOLOGY: IMPROVING SAFETY, EFFICACY & CONVENIENCE RAYMOND JAMES & ASSOCIATES, INC. KRENSAVAGE, M., ET AL FLORIDA (STATE OF) DATE: April 6, 2004 INVESTEXT(tm) REPORT NUMBER: 7970138, 205 Pages CONTENTS RECORD LANGUAGE: ENGLISH This is a(n) Industry report. SECTION/TABLE HEADINGS: Pages ----------------------- ----- Disclosure (No charge for this page) ..................................... 1 Introduction ............................................................. 3 Table/Chart: Drug Delivery Industry At-A-Glance .......................... 3 Introduction (CONT) ...................................................... 4 Graph - Raymond James Drug Delivery Index Vs. S&P Large Cap Drugs (Current Value Of A $100 Investme ........................................ 4 Industry Profile ......................................................... 4-5 Table/Chart: Selected Specialty Drug Companies ........................... 5 Drug Delivery Pioneers Include Glaxo, Alza, & Elan ....................... 6 Graph - Drug Delivery Industry Timeline 1940-2004 ........................ 7 Drug Delivery Pioneers Include Glaxo, Alza, & Elan (CONT) ................ 7 New Drug Delivery Companies Begin to Emerge in the 1980s ................. 7-8 Drug Delivery Companies Fall Into Four Segments .......................... 8 Table/Chart: Drug Delivery: Greatest-Selling Marketed Products & Significant New Drugs ( U.S. sales ....................................... 9 Drug Delivery Companies Fall Into Four Segments (CONT) ................... 9 Table/Chart: Selected Drug Delivery Company Data ( $ millions ) 2003 ..... 10 Drug Delivery Companies Fall Into Four Segments (CONT) ................... 10 Drug Delivery Company Sales to Grow 16% Through 2008 ..................... 10-11 Graph - Sales Of Drugs Using Advanced Delivery 1999-2008 ................. 11 Drug Delivery: Improving Safety .......................................... 11-12 Table/Chart: Drug Delivery Technology: Making Drugs Safer ( Global Sales; $ millions ) 2003 ................................................. 12 Drug Delivery: Improving Safety (CONT) ................................... 13 Drug Delivery: Improving Efficacy ........................................ 13 Table/Chart: Drug Delivery Technology: Making Drugs More Effective ( $ millions ) 2003 ...................................................... 13 Drug Delivery: Improving Convenience ..................................... 14 Table/Chart: Drug Delivery Technology: Making Drugs More Convenient ( $ millions ) 2003 ...................................................... 14 Drug Delivery: Improving Convenience (CONT) .............................. 15 Graph - Sales Of U.S. Branded Diabetes Treatments 1999-2003 .............. 16 Drug Delivery: Improving Convenience (CONT) .............................. 16 Drug Delivery Routes of Administration: Oral, Transdermal, Mucosal, Injectable, and Inhaled .................................................. 17 Graph - Drug Delivery: Routes Of Administration 2003 ..................... 17 Graph - Dollar Market Share For Drugs Other Than 1999-2003 ............... 18 Drug Delivery Routes of Administration: Oral, Transdermal, Mucosal, Injectable, and Inhaled (CONT) ........................................... 18 Table/Chart: Drug Delivery: Tradeoffs for Efficacy, Safety, & Convenience .............................................................. 18 Drug Delivery Routes of Administration: Oral, Transdermal, Mucosal, Injectable, and Inhaled (CONT) ........................................... 19 Popping Pills: A Convenient, But Inefficient, Way to Take Your Medicine .. 19 Graph - 2003 Global Sales Of Selected Pills .............................. 19 Popping Pills: A Convenient, But Inefficient, Way to Take Your Medicine (CONT) .......................................................... 20 Table/Chart: Anti-Depressant Life Cycle Management ( U.S. sales; $ millions ) 2003 .......................................................... 20 Popping Pills: A Convenient, But Inefficient, Way to Take Your Medicine (CONT) .......................................................... 21 Transdermal Patches and Gels Represent Fastest Growing Segment ........... 21 Graph - Transdermal Patches Can Include Up To Five Layers ................ 21 Table/Chart: Marketed Transdermal Drugs ( U.S.sales; $ millions ) 2003 ... 22 Transdermal Patches and Gels Represent Fastest Growing Segment (CONT) .... 22

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Graph - E-Trans: A Transdermal Painkiller ................................ 22 New Biologics Boost Sales Growth of Injectable Drugs ..................... 22-23 Marketed Injectable Drugs ( $ millions ) 2003 ............................ 23 Graph - 2003 Global Sales Of Injectables Launched Since 2001 ............. 24 New Biologics Boost Sales Growth of Injectable Drugs (CONT) .............. 24 Respiratory Medicine Delivers Improved Convenience, At a Price ........... 24 Table/Chart: Marketed Inhaled & Intra-nasal Drugs ( $ millions ) 2003 .... 25 Respiratory Medicine Delivers Improved Convenience, At a Price (CONT) .... 25 Graph - Respiratory Drug Delivery: Advair For Asthma ..................... 25 Respiratory Medicine Delivers Improved Convenience, At a Price (CONT) .... 26 Liquids and Topical Treatments Could Grow Amid Aging Population .......... 26 Table/Chart: Marketed Oral Liquids, Eye Drops, & Topical Drugs ( $ millions ) 2003 .......................................................... 27 Liquids and Topical Treatments Could Grow Amid Aging Population (CONT) ... 27 Drug Delivery Technology ................................................. 27 Graph - Market Share For Controlled-Release Pills ........................ 28 Drug Delivery Technology (CONT) .......................................... 28 Controlled-Release is Most Widely Used Technology ........................ 28 Table/Chart: Marketed Drugs Using Controlled-Release Technology ( $ millions ) 2003 .......................................................... 29 Controlled-Release is Most Widely Used Technology (CONT) ................. 29 Table/Chart: Selected Developers of Controlled-Release Drugs ............. 30 Controlled-Release is Most Widely Used Technology (CONT) ................. 30 Graph - Sales Of Controlled-Release Pills 1999-2008 ...................... 30 Controlled-Release is Most Widely Used Technology (CONT) ................. 31 Convenient Quick- Dissolve Drugs are Fastest-Growing Segment ............. 31 Graph - Sales Of Drugs Using Emerging Delivery Technology 1999-2008 ...... 31 Table/Chart: Marketed Drugs Using Quick-Dissolve Technology ( $ millions ) 2003 .......................................................... 32 Convenient Quick- Dissolve Drugs are Fastest-Growing Segment (CONT) ...... 32 Graph - Monthly Zyprexa Sales 1998-2003 .................................. 32 Convenient Quick- Dissolve Drugs are Fastest-Growing Segment (CONT) ...... 33 Improved Absorption Technology Boosts Efficacy, Safety ................... 33 Table/Chart: Existing & New Drugs Using Improved Absorption Technology ( $ millions ) 2003 ........................................... 33 Improved Absorption Technology Boosts Efficacy, Safety (CONT) ............ 34 Targeted Delivery Boosts Efficacy, Reduces Side Effects .................. 34 Graph - Targeted Drug Delivery: Magnetic Technology ...................... 35 Targeted Delivery Boosts Efficacy, Reduces Side Effects (CONT) ........... 35 Growth Drivers for Drug Delivery Technology .............................. 35-36 Large Drug Companies Value Drug Delivery Technology ...................... 36 Table/Chart: Blockbuster Drug Approvals and Exclusivity Expirations ( $ billions ) 1991-2003 ................................................. 36 Graph - New Drug Approvals 1986-2002 ..................................... 37 Large Drug Companies Value Drug Delivery Technology (CONT) ............... 37 Graph - Value Of Drugs Coming Off Patent (1) Based On 2002 Worldwide Sales .......................................................... 37 Large Drug Companies Value Drug Delivery Technology (CONT) ............... 38 Graph - Generic Drug Applications & Approval Times 1993-2003 ............. 38 Graph - Generic Glucophage Penetration 2002 .............................. 38 Graph - Generic Zantac, Carafate Penetration 1996-98 ..................... 39 Large Drug Companies Value Drug Delivery Technology (CONT) ............... 39 Graph - Generic Pharmaceutical Market Share 1984-2002 .................... 39 Large Drug Companies Value Drug Delivery Technology (CONT) ............... 40 Table/Chart: Prescription Drugs Facing Over-the-Counter Switches ( Global sales; $ millions ) 2003 .......................................... 40 Table/Chart: Drug Delivery Industry Selected Acquisitions ( $ millions ) . 41 Large Drug Companies Value Drug Delivery Technology (CONT) ............... 42 Technology Could Alleviate Biotech Delivery Challenge .................... 42 Graph - 2003 Global Sales Of Injectable Biologics ........................ 42 Technology Could Alleviate Biotech Delivery Challenge (CONT) ............. 43 Drug Delivery Taps Demand for Currently Marketed Products ................ 43-44 Investment Themes ........................................................ 44 Drug Delivery Technology Commands Premium Pricing ........................ 44 Table/Chart: Innovative Drug Delivery Technology Enables Premium Pricing ( $ millions ) 2003 .............................................. 44 Drug Delivery Technology Commands Premium Pricing (CONT) ................. 45 Barriers to Entry: Patent Protection ..................................... 45 Table/Chart: Barriers-to-Entry for Branded, Generic, and Drug Delivery ... 45 Barriers to Entry: Patent Protection (CONT) .............................. 46 Drug Delivery Research & Development: Attractive Economics ............... 46 Table/Chart: Estimated Cost of New Drug Development ...................... 47 Drug Delivery Research & Development: Attractive Economics (CONT) ........ 47

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