wei liang, ph.d. fda / cber / octgt [email protected] ethical and social policy considerations...
TRANSCRIPT
Wei Liang, Ph.D.Wei Liang, Ph.D.FDA / CBER / OCTGTFDA / CBER / OCTGT
[email protected]@fda.hhs.gov
Ethical and Social Policy Considerations of Novel Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission Techniques for Prevention of Maternal Transmission
of Mitochondrial DNA Disease: Workshopof Mitochondrial DNA Disease: WorkshopInstitute of MedicineInstitute of Medicine
March 31 - April 1, 2015March 31 - April 1, 2015Washington, DCWashington, DC
Mitochondrial Manipulation Technologies: Mitochondrial Manipulation Technologies: Preclinical ConsiderationsPreclinical Considerations
1
Objectives of Preclinical Objectives of Preclinical TestingTesting
Support the safety and provide the Support the safety and provide the scientific basis of the administration of an scientific basis of the administration of an investigational product in the target investigational product in the target patient populationpatient population
Provide evidence of an acceptable Provide evidence of an acceptable benefit : risk profilebenefit : risk profile
Inform the design of the proposed clinical Inform the design of the proposed clinical studystudy
Enrollment of appropriate patient populationEnrollment of appropriate patient population Safe starting dose and dosing regimenSafe starting dose and dosing regimen Adequate monitoring plan and stopping rulesAdequate monitoring plan and stopping rules
2
What Regulations Govern What Regulations Govern Preclinical Testing? Preclinical Testing?
Pharmacologic & Toxicologic StudiesPharmacologic & Toxicologic Studies“…“…adequate information about the adequate information about the
pharmacological and toxicological pharmacological and toxicological studies…on the basis of which the studies…on the basis of which the sponsor has concluded that it is sponsor has concluded that it is reasonably safe to conduct the proposed reasonably safe to conduct the proposed clinical investigations. clinical investigations. The kind, The kind, duration, and scope of animal and other duration, and scope of animal and other tests required varies with the duration tests required varies with the duration and nature of the proposed clinical and nature of the proposed clinical investigations.”investigations.”
IND Regulations [21 CFR 312.23 (a)(8) - Pharmacology and Toxicology]IND Regulations [21 CFR 312.23 (a)(8) - Pharmacology and Toxicology]3
Preclinical Testing Strategy: FDA / CBER Guidance
4
5
Preclinical Testing Program:Preclinical Testing Program: Step-Wise and Science-Based Step-Wise and Science-Based
Proof-of-concept (POC) Proof-of-concept (POC) studies to studies to support the feasibility and activity of support the feasibility and activity of the product and associated study the product and associated study procedures for a specific indication procedures for a specific indication
PilotPilot studies to explore key studies to explore key parameters to guide definitive parameters to guide definitive preclinical study designpreclinical study design
DefinitiveDefinitive safety studies to support safety studies to support the proposed clinical trialthe proposed clinical trial
6
Preclinical Study Design Preclinical Study Design Considerations Considerations
Use of relevant animal species / Use of relevant animal species / modelsmodels
Application of the 3 R’s (Reduce, Application of the 3 R’s (Reduce, Refine, Replace) Refine, Replace)
Nonbiased designs (randomization, Nonbiased designs (randomization, blinded assessment)blinded assessment)
Adequate numbers of animals / groupAdequate numbers of animals / group Mimic the proposed clinical trial Mimic the proposed clinical trial
design as closely as possibledesign as closely as possible Adequate safety and / or activity Adequate safety and / or activity
endpointsendpoints Sufficient study durationSufficient study duration
Cellular, Tissue, and Gene Therapies Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Advisory Committee (CTGTAC)
Meeting Meeting Oocyte and embryo modification to prevent Oocyte and embryo modification to prevent
transmission of mitochondrial disease (February transmission of mitochondrial disease (February 25-26, 2014)25-26, 2014) To discuss available To discuss available
animal models animal models and/or in vitro and/or in vitro methods to address methods to address the safety and the safety and prospect of benefit of prospect of benefit of mitochondrial mitochondrial manipulation manipulation technologiestechnologies
7
Cellular, Tissue, and Gene Therapies Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Advisory Committee (CTGTAC)
Meeting Meeting
Preclinical issues raised by FDA / CBER:Preclinical issues raised by FDA / CBER: The possibility of inadvertent damage to the The possibility of inadvertent damage to the
manipulated oocyte or embryomanipulated oocyte or embryo The long-term risks associated with the The long-term risks associated with the
carryover of abnormal mtDNA to the offspringcarryover of abnormal mtDNA to the offspring The potential for abnormal embryo / fetal The potential for abnormal embryo / fetal
growth, resulting in offspring with significant growth, resulting in offspring with significant defectsdefects
8
Cellular, Tissue, and Gene Therapies Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Advisory Committee (CTGTAC)
Meeting Meeting General considerations cited by the Committee General considerations cited by the Committee
members:members: There is not sufficient animal data to support the use There is not sufficient animal data to support the use
of mitochondrial manipulation technologies in first-in-of mitochondrial manipulation technologies in first-in-human clinical trialshuman clinical trials
Multiple animal species / models will probably be Multiple animal species / models will probably be necessary to assess overall safety concernsnecessary to assess overall safety concerns
Sufficient numbers of animals (mothers and offspring) Sufficient numbers of animals (mothers and offspring) are needed to adequately evaluate the safety are needed to adequately evaluate the safety concernsconcerns
Long-term follow-up of offspring through all Long-term follow-up of offspring through all developmental stages will be necessary, with possible developmental stages will be necessary, with possible multi-generational evaluationmulti-generational evaluation
9
What Regulations Govern What Regulations Govern Preclinical Testing? Preclinical Testing?
Pharmacologic & Toxicologic StudiesPharmacologic & Toxicologic Studies“…“…adequate information about the adequate information about the
pharmacological and toxicological pharmacological and toxicological studies…on the basis of which the studies…on the basis of which the sponsor has concluded that it is sponsor has concluded that it is reasonably safe to conduct the proposed reasonably safe to conduct the proposed clinical investigationsclinical investigations. The kind, . The kind, duration, and scope of animal and other duration, and scope of animal and other tests required varies with the duration tests required varies with the duration and nature of the proposed clinical and nature of the proposed clinical investigations.”investigations.”
IND Regulations [21 CFR 312.23 (a)(8) - Pharmacology and Toxicology]IND Regulations [21 CFR 312.23 (a)(8) - Pharmacology and Toxicology]10
When to Engage CBER / OCTGT Pre-pre-IND interactionsPre-pre-IND interactions
Non-binding, Non-binding, informalinformal scientific discussions scientific discussions between CBER/OCTGT nonclinical review between CBER/OCTGT nonclinical review disciplines (Pharmacology / Toxicology and disciplines (Pharmacology / Toxicology and product / CMC) and the sponsorproduct / CMC) and the sponsor
Initial targeted discussion of specific issuesInitial targeted discussion of specific issues Pre-IND meetingsPre-IND meetings
Non-binding, Non-binding, formalformal scientific discussions with scientific discussions with clinical and nonclinical review disciplines clinical and nonclinical review disciplines (minutes generated)(minutes generated)
Meeting package should include summary data Meeting package should include summary data and sound scientific principles to support use of and sound scientific principles to support use of a specific product in a specific patient populationa specific product in a specific patient population
11
Contact Information for CBER / Contact Information for CBER / OCTGTOCTGT
Wei Liang, PhDWei Liang, PhD [email protected]@fda.hhs.gov 240-402-8323240-402-8323
Regulatory Questions: Regulatory Questions: Contact the Regulatory Management Staff in Contact the Regulatory Management Staff in OCTGT at [email protected] at [email protected] [email protected] [email protected] by calling 240-402-8361or by calling 240-402-8361
OCTGT Learn Webinar Series:OCTGT Learn Webinar Series: http://www.fda.gov/BiologicsBloodVaccines/Newshttp://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm Events/ucm232821.htm
12
Public Access to CBERPublic Access to CBERCBER website:CBER website:http://www.fda.gov/BiologicsBloodVaccines/http://www.fda.gov/BiologicsBloodVaccines/default.htmdefault.htmPhone: 1-800-835-4709 or 240-402-8010Phone: 1-800-835-4709 or 240-402-8010
Consumer Affairs Branch (CAB) Consumer Affairs Branch (CAB) Email: [email protected]: [email protected]: 240-402-7800Phone: 240-402-7800
Manufacturers Assistance and Technical Manufacturers Assistance and Technical Training Branch (MATTB)Training Branch (MATTB)Email: [email protected]: [email protected]: 240-402-8020Phone: 240-402-8020
Follow us on Twitter: Follow us on Twitter: https://www.twitter.com/fdacberhttps://www.twitter.com/fdacber 13
Thank you!Thank you!
14