1 Drug Safety, Animal Use, and Critical Path Opportunities FDA Science Board Advisory Committee Meeting March 31, 2005 Sadhana Dhruvakumar Director, Medical Testing Issues People for the Ethical Treatment of Animals (PETA) (617)

2 “It is important that we strengthen our postmarketing surveillance of adverse events, but our ultimate goal should be to prevent adverse events from occurring in the first place. We need to build safety into products from the ground up.” – CP Opportunities Report, 3/06 92% of drugs that pass preclinical testing, currently almost all animal-based, now fail during the clinical trial phase. – CP White Paper 3/04 Critical Path Initiative Reports: Drug Safety Preclinical Devt, Safety, & Efficacy Testing of Human Medical Products Clinical Trials in Limited Numbers of Patients Post-Marketing Surveillance

3 March 2006 UK clinical trial tragedy: TGN1412 Ab

4 “The relevance of these animal models in predicting effects in humans is uncertain…Although animal data have not been consistent…these findings have raised the possibility that COX-2 inhibitors could actually decrease the incidence of acute thrombotic events…” Weir MR, Sperling RS, Reicin A, Gertz BJ. Am Heart J 2003;146:591–604 (Merck publication) Vioxx and Cardiac Deaths

5 Animals in the FDA’s “critical path” The problems (Critical Path White Paper, 3/04) Animal toxicology is “laborious, time-consuming, requires large quantities of product, and may fail to predict the specific safety problem that ultimately halts development.” “Currently available animal models… have limited predictive value in many disease states.” The current drug discovery process, based as it is on in vitro screening techniques and animal models of (often) poorly understood clinical relevance, is fundamentally unable to identify candidates with a high probability of effectiveness. The solution? (Critical Path Opportunities List, 3/06) List has many more Opportunities calling for animal model/method development than calling for non-animal methods/human tissue models/cellular systems development Animal biomarkers only improve ability to predict (potentially irrelevant) animal toxicity results; List should prioritize focusing directly on human biomarker identification List calls for improving extrapolation from animals to humans but omits encouragement of cutting-edge human biology-based methods, e.g. microfluidic biochips lined with human cells CP Opportunities an exciting approach but List should encourage not incremental improvements but a paradigm shift away from reliance on animal surrogacy towards next-generation human-relevant methods

6 Rabies Vaccine Potency Testing Catch-22: Highly variable, painful, and widely criticized animal NIH test developed in 1960s cannot be replaced because it is so inconsistent that the reproducible, mechanistic, antigen quantification ELISA test developed in the 1970s cannot replicate its results (currently a requirement for validation) Science and public health are unduly compromised due to the limitations of the entrenched animal test and of the regulatory response

7 Identify top 10 worst lab safety tests (e.g., rabies potency, carcinogenicity, abnormal toxicity, etc.) –Survey stakeholders for their input regarding widely mistrusted tests –Analyze safety problems of recent drug withdrawals –“FDA's files constitute the world's largest repository of in vitro and animal results that are linked with actual human outcomes data. Further datamining efforts that effectively protect proprietary data could form the basis for useful predictive safety models.” – CP White Paper, 3/04 Establish and prioritize collaborative efforts to replace/eliminate worst tests –Rather than reacting to public product failures, proactively address the most flawed safety tests in order to prevent tragedies Possible mechanisms/venues –Science Board peer reviews, review of agency’s science programs –Drug Safety Oversight Board –Non-FDA body (e.g., C-Path Institute) working with FDA involvement + input –Through FDA Office of Critical Path Programs + placement on Opportunities List –Creation of a new FDA division, board, or committee tasked with assessing quality of preclinical tests (test method validation and invalidation) Addressing the Problem

8 The Interagency Coordinating Committee on Validation of Alternative Methods (ICCVAM) is meant to address cross- agency methods, but the most recent submissions (pyrogenicity testing and Botox LD50 potency testing) have been FDA-specific tests due to lack of an FDA forum or procedure for validating and incorporating new safety tests When novel tests are validated by others for replacement of outdated tests (e.g., by ICCVAM or European ECVAM), no clear or triggered process to incorporate into FDA regulations C-Path Institute is working with pharmaceutical Predictive Safety Testing Consortium to pool data on, “qualify”, and validate animal toxicity biomarkers – could this construct be turned to or extended to validation of novel (non-animal) test methods? FDA Test Method Validation