Why not bring medications and their use out of the dark ages?

Jake J. Thiessen, B.Sc.(Pharm), Ph.D.

Presentation Outline

Identity Identity

“Therapeutic Enlightenment by Harnessing Comprehensive Identity”

Who Am I?

“Obligatory Identity”

“Crunch time: Come Tuesday, all Canada-U.S. air travellers must

have passport”

The chance of two iris (irides) being identical is 1 in 1078

Elements of “Who I am”

DemographicGeneticAnatomicalStructuralOrganizationalCulturalSpiritualEmotional

James J. Lynch, PhDDirector of the Life Care Health Center in Baltimore, Maryland (www.lifecarehealth.com)

Elements of “Who I am”

DemographicGeneticAnatomicalStructuralOrganizationalCulturalSpiritualEmotional

PhysiologicChronologicalHormonalCyclicalElectricalChemicalBiochemicalEtc.

Identity “Force Vectors”

Genetic

Physiologic

Behavio

r

Cycles Anatomic

Emotional

Biochemical

Organiza

tional

Chemical

Etc.

Chemical

Magnetic“Radia

tion”

Biolo

gic

Not fixed or constant.An individual, who reflects the complicating interaction between intrinsic and environmental forces.Surprisingly “elastic”.Amazingly homeostatic.

Innately tracking towards a prescribed harmony wherein the vector sum of all intrinsic and environmental forces adds up to zero.Ps 139:14 ….. I am fearfully and wonderfully made…

Who Am I?

Focus: Chemical Environment

Beneficial vs. harmfulNatural vs. synthetic

Source: Draves AH. Walker SE: Canadian Journal of Clinical Pharmacology. 10(3):114-8, 2003

St. John’s WortFifty-four US and Canadian products analyzedLabel claim varied widely: Capsules from 0% to 108.62%; Tablets from 31.34% to 80.18%; Tinctures from zero to 118.58 microg/ml. Only two products were observed to have a total naphthodianthroneconcentrations within 10% of their label claimOn average, most labels overestimate the hypericin and pseudohypericin content by a factor of almost two

Source: Good Housekeeping, November, 2006, pp 87-91

Focus: Chemical Environment

Natural vs. syntheticBeneficial vs. harmfulEssential vs. optional (e.g. vitamins, minerals, etc.)Endogenous vs. foreignSelf-selected vs. prescribedNutritional

Early Development of Medicines"Ancient humans have experimentally sampled many kinds of plants in their search for nourishment. Plants that were palatable were used for food; those with toxic or unpleasant effects were avoided or used against enemies; others that produced physiological effects such as perspiration, defecation, healing, or hallucination were saved for medicinal purposes and divination. Over a period of thousands of years, people learned to use a variety of plants as medicines for different ailments."

Quote: Grolier Multimedia Encyclopedia

Origins of Medicines: The Story of Aspirin400 B.C. Hippocrates – bark and leaves of willow tree to relieve pain and fever

“Salicin” – place bark or leaves in water for 8-10 hours

1832 – a German chemist experiments with salicinand creates salicylic acid [purification]1897 - Felix Hoffman, a chemist at Bayer in Germany modified sal. acid to produce acetylsalicylic acid (ASA) to treat his father’s rheumatism. It was embraced by Bayer and called Aspirin1899 – Bayer distributes Aspirin to physicians1915 – Aspirin is available without a prescription1948 – Dr. Lawrence Craven notices that the 400 men he prescribed Aspirin hadn’t suffered heart attacks1980 – FDA approves Aspirin to reduce risk of stroke

The Story of Aspirin (cont’d)

1982 – John R. Vane (British Pharmacologist) receives Nobel Prize for showing Aspirin acts by inhibiting prostaglandin synthesis1985 – FDA approves Aspirin to prevent heart attacks1996 – FDA directive – use Aspirin if suspected heart attackPrevention of colon cancer – COX inhibitorAspirin resistance emerges – April 2003 –Creative Clinical Concepts in Denver brings out “AspirinWorks” to test for responsiveness to the drug; need to tailor Aspirin for some peopleField of similar compounds opens up

A Company’s HistoryEli Lilly and Company was founded in May 1876 by Colonel Eli Lilly in Indianapolis, Ind., a 38-year-old pharmaceutical chemist. Lilly was frustrated by the poorly prepared, often ineffective medicines of his day. He founded a company that manufactured pharmaceutical products of the highestpossible quality. His developed only medicines that would be dispensed at the suggestion of physicians rather than by eloquent sideshowhucksters. Lilly pharmaceuticals would be based on the best science of the day.

Source: Eli Lilly Historical Information

Historical Developments“One June 30, 1906, a broiling day in Washington, President Theodore Roosevelt went to the Capitol to sign into law nearly a hundred bills hurried through the Congress as its session came to an end. Among them was one passed the day before by both Senate and House in a form agreed to in conference committee, the Food and Drugs Act. Although a latecomer to the cause of a pure food law, Teddy Roosevelt had used his weight decisively in 1906 to ensure that this time Congress would not adjourn, as so often before, leaving such legislation languishing.” FDA

The Drug Development ProcessDisco

very

and

Scr

eening

Pre/Non-Clinical Research

Disco

very

and

Scr

eening

•Synthesis•Purification•Analytics•Phys.Chem.•Etc.

AnimalTesting

Long Term

Short Term

Clinical StudiesPre/Non-Clinical Research

Disco

very

and

Scr

eening

•Synthesis•Purification•Analytics•Phys.Chem.•Etc.

AnimalTesting

Short Term

Long Term

Phase III

Phase I

Phase II

File the IND/CTA

Clinical Studies NDS/A ReviewPre/Non-Clinical Research

Disco

very

and

Scr

eening

•Synthesis•Purification•Analytics•Phys.Chem.•Etc.

AnimalTesting

Short Term

Long Term

Phase III

Phase I

Phase II

File the IND/CTA

File the NDS/A

Clinical Studies NDS/A Review Post-ApprovalPre/Non-Clinical Research

Disco

very

and

Scr

eening

•Synthesis•Purification•Analytics•Phys.Chem.•Etc.

AnimalTesting

Short Term

Long Term

Phase III

Phase I

Phase II

Phase IV

•Prescription Drug

•Marketing •Advertising•Surveillance•Adverse

ReactionsReporting

•Inspections•Surveys

File the IND/CTA

File the NDS/A

APPROVAL!!!

Review Period(Agency)

1 - 2 years

Clinical Development(Phase I -III)5 - 7 years

Preclinical/Discovery4 – 6 yearsAverage time to approval of new compounds

12 years

Time to Develop and Registera New Pharmaceutical

What are some Drug Development Strategies?

Exclusivity treatment goalLarge target patient populationMinimize risks – SAFE!Efficient – One size fits all.Efficient – production simplicityPrescribing simplicityOther

What are some Benefits of this “System”?

StandardizationObjective testing of discoveriesHistorical inventory of informationAuthenticity and purity of pharmaceuticalsRigid manufacturing controls (GMP)

Consistency of the productsStability to ensure shelf-lifeOrganizational requirements

Developments under ethical controlControlled rhetoric (advertising)

0 4 8 12 16

COMPOUND SUCCESS RATES BY STAGES

Discovery(2-10 Years)

Preclinical TestingLaboratory and animal testing

Phase I20-80 healthy volunteers used to determine safety and dosage

Phase II100-300 patient volunteers used to look for efficacy and side effects

Phase III1,000-5,000 patient volunteers used to

monitor adverse reactions to long-term use

Approval

Additional Post-marketing Testing

Compound SuccessRates By Stage

________________5,000 – 10,000

screened

250Enter pre-clinical

testing

10Enter clinical testing

1Approval

Years

Source: Pharmaceutical Research and Manufacturers of America, c2002-2003 [Internet].Industry Profile 2002, Chapter 2. Research and Development – The Key to Innovation.

Cost: $880 Million TotalApproximate Cost ($M)

165

20540

120

165

260

Drug R & D Is Expensive and Time-Consuming

Pharmaceutical R&D Statistical Sourcebook 2000..

Biology

Target ID Target Validation

Chemistry

Screening Optimization Clinical

Development

Preclinical

What is the Overall Impact of Medicines on Society?

Leading Benefits of Pharmaceuticals

Antibiotics for numerous diseasesHeart drugs that changed outcomesAnticancer drugs (eg. Testicular)Breakthroughs in asthma treatmentPain relieving medicinesRevolutionary discoveries permitting successful transplantsNumerous others

Source: PriceWaterhouseCoopers Report - 2001

Positive Outcome of Pharmaceuticals

What About the Disappointments?

Unhappy Outcomes

Unfulfilled promises; unsuccessful treatmentsTrial and Error “experimentation”High incidence of adverse effects – “adverse drug reactions (ADRs) is estimated to cost the US society 100 billion USD and over 100 000 deaths per year”Worrying multiplicity of treatments, notably in the elderlyCost in paying for medication useAlarming escalation in the drug budgetsOthers

Unhappy (Ineffective) Outcomes

Source: The Case for Personalized Medicine: Personalized Medicine Coalition Washington, DC 20005

Concerns About Expenditures

Source: Statistics Canada

Why are Medicines Sometimes Withdrawn due to Catastrophic

Outcomes?

Clinical Trial Size Per NDA[Studies to Test Safety and Efficacy]

1,321

3,2333,567

4,237

1,576

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

1977-80 1981-84 1985-88 1989-92 1994-95

Source: Boston Consulting Group, 1993; Peck, C., “Drug Development: Improving the Process,”Food Drug Law Journal, Vol. 52, 1997.

What is the probability that at least one serious adverse event will surface?

N

Event Rate 300 3 000 30 000 300 000

1 / 100 95% ~ 100% ~ 100% ~100%

1 / 1 000 25% 95% ~ 100% ~ 100%

1 / 10 000 2% 25.9% 95% ~ 100%

1 / 100 000 0.3% 2.9% 25.9% 95%

Evidence of Dark Ages?

“One-size fits all” to optimize efficiencyGeared to mass production“Silver bullet” expectationsDumbed-down moleculesDogmatic attitudesRigid regulatory system

“Medicine is a science of uncertainty and an art of

probability.”

Sir William OslerCanadian Physician

1849-1919

Is There Enlightenment?

Can we do Reduce the Unhappy Outcomes?

What are Potential Solutions?

Central Tenant:

“One size fits all” thinking is at the heart of the problemPersonalized treatment is the solution“Personalized” entails comprehensive identity, optimized pharmacotherapy and feedback monitoring

Customization/Individualization

Source: COMPREHENSIVE REVIEWS IN FOOD SCIENCE AND FOOD SAFETY—Vol. 3, 152-159 (2004)

BarrierBiophase

Blood/Int. fluid

Response to Medications

Receptor

Homeostasis

Endogenous

AgonistDrug Drug

Response

Toxic

Sub-therapeutic

M Rowland and TN Tozer: Clinical Pharmacokinetics, 3rd Ed. 1995; p. 6

Accepted

Therapeutic

Window

“Standard” Dose

Phenytoin Patient Observations

Identity “Force Vectors”

Genetic

Physiologic

Behavio

r

Cycles Anatomic

Emotional

Biochemical

Organiza

tional

Chemical

Etc.

Chemical

Magnetic“Radia

tion”

Biolo

gic

Effective Personalized Medicine“Personalized Medicine” reduces trial-and-error by suitably tailoring the use of drugs through genomic, proteomic, metabonomic, and environmental (-omic) characteristics of a patient.

Predicts responders and non-respondersPersonalized Medicine, via effective biodiagnostics, monitors and harnesses comprehensive identity to optimize treatment. Personalized Medicine employs Bioinformatics and Information-Based Medicine.

Optimizing PharmacotherapyThe appropriate individual patientAssembling the right identity informationUsing the most appropriate drug(s)In the correct contextThe optimal doseThe correct pharmaceutical productThe appropriate routeThe correct dosing scheduleUsing effective communicationAchieving the best complianceMaking the right outcome assessment

Limitations of Genetic Identity

Source: Goodman & Gilman's The Pharmacological Basis of Therapeutics - 11th Ed. Figure 4-1; Originally by E. S. Vesell

Optimizing TherapyRequires

Supporting Technology

Automobile Sensor Technology

A modern automobile has about 50 sensors.

•There are 117 miles (188 km) of electrical wiring in a 767-300ER.

•Also, about 10,000 sensors are constantly recording information, not only to inform pilots about the plane's performance but also to forecast mechanical problems that can be corrected during routine maintenance

Analogy of the BiodiagnosticFuture for Pharmacotherapy

“Signature Sensors”

“Flight Monitoring/Control Sensors”

The Requirement:Biodiagnostic sensors that

can accurately, conveniently and cost-effectively monitor the complex individual identity.

The tools of informatics.Translation of the

information to provide optimal, individualized therapy.

Is Such a Future Possible?

Identity

Sensor

“Analysis”

Therapy

Example: Glucose Sensor

Glucowatch

Animas Corporation, which is now a Johnson & Johnson company, purchased the intellectual property and all of the assets of the original manufacturer of the GlucoWatch G2 Biographer, Cygnus Inc. in Redwood City, California. Animas continues to sell the GlucoWatch G2 Biographer in the U.S. and the U.K. You can contact Animas by calling (877) 937-7867 or visit the company's webpage at http://www.glucowatch.com/. A “Special price offer expires April 30, 2006 or when 10,000 G2 Biographers and 500,000 AutoSensors have been sold.” Until then the price of the G2 Biographer is $299.99 (regularly $872.50), and 16 AutoSensors is $63.99 (regularly $149.99).

Dermal Detection Sensor

Source: PAUL W. BARONE, SEUNGHYUN BAIK, DANIEL A. HELLER AND MICHAEL S. STRANO: Near-infrared optical sensors based on single-walled carbon nanotubes. Nature Materials VOL 4: 86-92, JANUARY 2005

Source/After: http://www.micohealth.com

Continuous Monitoring Device

Fig. 1. A microchip-based electronically controlled drug release device (45). Panel A. A prototype implantable microchip-based device forcontrolled release: the microchip is mounted in a biocompatible case containing electronics, power source, and antenna for wirelesscommunication (45). Panel B. Drug Delivery/Biosensor Array: A microchip for controlled release showing the reservoir array and the shapeof single reservoirs for delivery or sensor applications (45). Panel C. A microchip for controlled release: one side is filled with drug (left); theother side (right) exhibits circuitry and membranes (source: MicroCHIPS, Inc.; photo credit: Dana Lipp Imaging). Panel D. In vivo Release YLeuprolide (Model Peptide); n = 6 dogs, error bars are T 1 SD (45). Each reservoir on the 15 mm 15 mm 1.0 mm microchip was filled with25 2g leuprolide in 125 nL solution, followed by lyophilization and a secondary fill of 125 nL of molten polyethylene glycol. The backs of thefilled reservoirs were individually sealed with solder. One device (approximate dimensions for the device 4.5 cm 5.5 cm 1 cm, volumeapproximately 30 mL) was implanted into the subcutaneous tissue of each dog. Dosing was conducted at weekly to monthly intervals over sixmonths. The devices were programmed by RF telemetry to open selected reservoirs, thereby initiating drug release.Mark Staples, Karen Daniel, Michael J. Cima, and Robert LangerPharmaceutical Research, Vol. 23, No. 5, May 2006

The Challenge:A Quantum Advance in Healthcare Certaintyand the probability of optimal treatment outcomesviaResearch, Technology, Innovation and Education

Why not bring medications and their use out of the dark ages?

“Therapeutic Enlightenment by Harnessing Comprehensive Identity”

The End