department of health center for biologics and human servicesevaluation and research and human...

DEPARTMENT OF HEALTHDEPARTMENT OF HEALTH CENTER FOR BIOLOGICS CENTER FOR BIOLOGICS AND HUMAN SERVICESAND HUMAN SERVICES EVALUATION and RESEARCHEVALUATION and RESEARCH

Update on OCTGT Guidance Development

Program

Cellular, Tissue, and Gene Therapies Advisory Committee Meeting

April 11, 2008

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FDA Good Guidance Practices(GGP)

Ensures proper development, formatting, processing, Ensures proper development, formatting, processing, routing, and use of FDA guidance documents routing, and use of FDA guidance documents Mandated by “Food and Drug Administration

Modernization Act of 1997" (FDAMA) Administrative Practices and Procedures; Good Guidance

Practices,” 21 CFR 10.115 CBER SOPP 8002 Annual Guidance Agenda published in Federal Register

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Guidance Documents

Documents prepared for FDA staff, Documents prepared for FDA staff, applicants/sponsors, and the public that: applicants/sponsors, and the public that: Describe the agency’s interpretation of or policy

on a regulatory issue; Relate to the processing, content, and

evaluation/approval of submissions; Relate to the design, production, manufacturing,

testing, labeling, and promotion of regulated products;

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Other Documents Guidance documents do NOT include documents Guidance documents do NOT include documents

related to:related to:

Internal FDA procedures; Agency reports; General information provided to consumers or health

professionals; Speeches; Journal articles and editorials; Media interviews and press materials; Warning letters; Memoranda of understanding; Other communications or actions taken by individuals at FDA or

directed to individual persons or firms; Documents directed at public health emergencies

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Guidance Documents

Guidance documents are intended to Guidance documents are intended to represent our current thinking on matters represent our current thinking on matters discussed in the documents.discussed in the documents. CBER staff may depart from guidance documents

only with appropriate justification and supervisory concurrence (21 CFR 10.115(d)(3)).

Any consistent deviation from a guidance document indicates that we should revise it

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Level 1 Guidance Documents Federal Register announcing the availability of the Federal Register announcing the availability of the draftdraft

guidance for public commentguidance for public comment Placed on CBER web sitePlaced on CBER web site FDA offers a comment period (usually 60 to 90 days) FDA offers a comment period (usually 60 to 90 days) After reviewing the public comments, CBER will revise the After reviewing the public comments, CBER will revise the

guidanceguidance Federal Register, announcing the availability of the final Federal Register, announcing the availability of the final

guidance. guidance. The public may submit comments on the final guidance at any The public may submit comments on the final guidance at any

time. time. CBER may issue a level 1 guidance for immediate CBER may issue a level 1 guidance for immediate

implementationimplementation

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Level 2 Guidance Documents All guidance documents not considered to be All guidance documents not considered to be

Level 1Level 1 Level 2 documents set forth existing practices Level 2 documents set forth existing practices

or minor changes in interpretation or policyor minor changes in interpretation or policy

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Communication with the Public During Guidance Development

When When consideringconsidering the development of guidance the development of guidance CBER may freely discuss issues with the public.

If the issues to be addressed are particularly complex or controversialIf the issues to be addressed are particularly complex or controversial Holding a public meeting Holding advisory committee meeting on the issues Before drafting the guidance

Once preparation of a draft guidance document has been initiated Once preparation of a draft guidance document has been initiated Specifics of the guidance are not discussed with the public.

When the guidance has been issued in draftWhen the guidance has been issued in draft Issues related to the draft guidance may be discussed Issues related to specific intentions regarding the finalization of the guidance

are not discussed 21 CFR 10.80

FDA may solicit information from the public at any time during the FDA may solicit information from the public at any time during the guidance development process. guidance development process.

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Published Guidances in Current FDA Annual Guidance Agenda (71 FR

51225, September 1, 2006)

Umbilical Cord Blood Intended For Hematopoietic Reconstitution in Patients With Hematological Malignancies Draft, 1/2007 CTGTAC Discussions- 2/2003, 3/2007

Preparation of Investigational Device Exemptions and Investigational New Drugs for Products Intended to Repair or Replace Knee Articular Cartilage Draft 7/2007 CTGTAC Discussions- 3/2005

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Published Guidances in Current FDA Annual Guidance Agenda (71 FR

51225, September 1, 2006)

Validation of Rapid Microbiological Methods for Assessing Sterility of Cellular and Gene Therapy Products Draft 2/2008

Certain Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Recovered From Donors Who Were Tested For Communicable Diseases Using Pooled Specimens or Diagnostic Tests Final, 1/2007

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Additional Published Guidances 2006-2007

Regulation of Human Cells, Tissues and Cellular and Tissue-Based Products (HCT/Ps)- Small Entity Compliance Guidance Immediate Implementation, 8/2007

Eligibility Determination for Donors of Human Cells, Tissues and Cellular and Tissue-Based Products Final 8/2007

Cell Selection Devices for Point of Care Production of Minimally Manipulated Autologous Peripheral Blood Stem Cells (PBSCs) Draft 7/2007

Class II Special Controls Guidance Document: Cord Blood Processing System and Storage Immediate Implementation, 1/2007

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Additional Published Guidances 2006-2007

Gene Therapy Clinical Trails – Observing Subjects for Delayed Adverse Events Final 11/2006 CTGTAC Discussions- 3/1999, 11/2000, 4/2001, 10/2001

Supplemental Guidance on Testing for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and During Follow-up of Patients in Clinical Trials Using Retroviral Vectors Immediate Implementation, 11/2006 CTGTAC Discussions- 3/1999, 11/2000, 4/2001, 10/2001

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Recently Finalized Guidances

Content And Review Of Chemistry, Manufacturing, And Control (CMC) Information For Human Somatic Cell Therapy Investigational New Drug Applications (INDs) Final 4/2008 CTGTAC Discussions- Topics included in discussion at

numerous meetings Content And Review Of Chemistry, Manufacturing,

And Control (CMC) Information For Human Gene Therapy Investigational New Drug Applications (INDs) Final 4/2008 CTGTAC Discussions- Topics included in discussion at

numerous meetings

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Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee

Cartilage

Written by Cross-Center TeamWritten by Cross-Center Team CDRH CBER Reflects CTGTAC input

CDRH participated in meetingCDRH participated in meeting March 2005March 2005

Leverages ASTM document Leverages ASTM document Written by ASTM subcommittee FDA staff participation according to FDA policies and

ASTM process

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CartilageScopeScope IND/IDE products to repair or replace articular IND/IDE products to repair or replace articular

cartilage of the kneecartilage of the knee Devices Biologics Combinations Products

ExcludesExcludes Unicondylar and total knee implants Meniscus replacement products “361” HCT/P products

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Cartilage

Manufacturing and CMC InformationManufacturing and CMC Information Brief explanation of requirements forBrief explanation of requirements for

Devices Biologics Combination Products

Tailored for specifics of product Tailored for specifics of product compositioncomposition

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CartilageNonclinical Data and TestingNonclinical Data and Testing Purposes of Animal StudiesPurposes of Animal Studies

Biological response to products Durability of response (1 year) Toxicology Dose response

Mechanical Testing Mechanical Testing Compare to normal cartilage Justify why not possible

BiocompatibilityBiocompatibility ISO 10993 and/or ASTM F748-04

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Cartilage

Nonclinical Data and TestingNonclinical Data and Testing ASTM document- F2451-05, “Standard Guide

for in vivo Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage,”

cartilage defect locations; cartilage defect locations; discussion of articular cartilage defect preparation;discussion of articular cartilage defect preparation; description of gross and histological assessments;description of gross and histological assessments; description of various mechanical evaluations and description of various mechanical evaluations and

their applicability. their applicability.

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Cartilage

Clinical Study ProtocolsClinical Study Protocols Exploratory Trials-design featuresExploratory Trials-design features Exploratory Trials-knowledge learnedExploratory Trials-knowledge learned

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Cartilage

Clinical Study ProtocolsClinical Study Protocols Confirmatory TrialsConfirmatory Trials

Recommend randomized, controlled trial Double blind Blinded evaluators of major endpoints

Alternative design may be consideredAlternative design may be considered

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Preparation of IDEs and INDs for Products Intended to Repair or Replace

Knee Cartilage

Study EndpointsStudy Endpoints Clinically meaningful endpoints as primary Clinically meaningful endpoints as primary

in confirmatory studiesin confirmatory studies Improvement in pain Improvement in physical function

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Knee Cartilage

Study EndpointsStudy Endpoints Examples of secondary endpointsExamples of secondary endpoints

Arthroscopic examination Physical examination Histologic examination at short and long term Serological assessment for antibody and

evidence of inflammation Synovial fluid examination

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Knee Cartilage

Investigational Product AdministrationInvestigational Product Administration Detailed description of procedures

Surgical techniqueSurgical technique Plans for post-operativePlans for post-operative

Follow-upFollow-up Length of follow-up to be based on in vivo and

in vitro studies Two-year follow-up for subset of subjects

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Knee Cartilage

Adverse event (AE) reportingAdverse event (AE) reporting AE reporting per regulations (IND or IDE)AE reporting per regulations (IND or IDE) Subsequent surgical interventionsSubsequent surgical interventions

Revision Removal Reoperation

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Resources on the Web

Consolidation of OCTGT guidancesConsolidation of OCTGT guidances Cellular and Gene Therapies

http://www.fda.gov/cber/genetherapy/gtpubs.htm

Tissues http://www.fda.gov/cber/tissue/docs.htm

References for the Regulatory Process for References for the Regulatory Process for the Office of Cellular, Tissue and Gene the Office of Cellular, Tissue and Gene Therapies (OCTGT)Therapies (OCTGT) www.fda.gov/cber/genadmin/octgtprocess.htm

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Summary FDA guidance process to communicate with FDA guidance process to communicate with

stakeholdersstakeholders Good Guidance Practices (GGP) Governed by regulations 21 CFR 10.115

OCTGT Recent GuidancesOCTGT Recent Guidances Current Annual Guidance Agenda Additional Guidances to meet needs arising between Annual

Guidance Agendas FDA Guidance on Cartilage Repair ProductsFDA Guidance on Cartilage Repair Products

CBER and CDRH Joint Guidance CTGTAC Meeting provided input for guidance development Leveraged FDA participation in Standards Development

Organization (ASTM)

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Conclusions OCTGT has an active guidance development OCTGT has an active guidance development

program that includesprogram that includes Strategic Guidance Planning (Annual Agenda) Responds to changing needs

OCTGT Guidance Program leveragesOCTGT Guidance Program leverages Input from CTGTAC meetings Other public meetings (NIH RAC, Workshops,

Scientific Meetings, Industry Liaison Meetings) Cross-center efforts within FDA Participation with Standards Development

Organizations

department of health center for biologics and human servicesevaluation and research and human...

Documents

research update

human servicesevaluation

human services evaluation

department of health