Jean Mulinde, M.D. Thomas Smith, M.D. April 12, 2007

1. Regulatory Pathways for Products for the Prevention or Treatment of Disease Caused by Shiga Toxin-Producing Bacteria Jean Mulinde, M.D. Thomas Smith, M.D. April 12, 2007

2. Meeting Overview • Biologic products for prevention or treatment of disease caused by Shiga toxin-producing bacteria • FDA presentations • Regulatory pathways for approval of drugs and biologics • Animal models of infection • Trial design issues • Topic experts • Epidemiology of Shiga toxin-producing E. coli infections • Clinical course and consequences of infections with E. coli O157:H7 and other Shiga toxin-producing bacteria • Scoring system • Industry presentations

3. Meeting Overview Points for discussion • Role of animal data • Primary endpoint for clinical studies • Trial enrollment strategies

4. Drugs and Biologics: Regulatory Background • Topics • The FDC Act and the PHS Act • Requirements for “adequate and well-controlled studies” • Accelerated approval regulations • “Animal Efficacy Rule” • References • Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products • 21 CFR

5. Drug Product Approval • Approved under authority of the Federal Food Drug and Cosmetic Act (the FDC Act) • 1962: FDC Act amended to add requirement for demonstration of effectiveness by “substantial evidence”

6. Drug Product Approval • “Substantial evidence” defined by 505(d) of the FDC Act as: “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”

7. Drug Product Approval • FDA’s position is that Congress generally intended to require at least two adequate and well-controlled studies, each convincing on its own, to establish effectiveness. • Section 115(a) of the 1997 Modernization Act amended section 505(d) of the Act stating the Agency may consider “data from one adequate and well-controlled clinical investigation and confirmatory evidence” to constitute substantial evidence if FDA determines that such data and evidence are sufficient to establish effectiveness.

8. Biologic Product Licensure • Approved under authority of the Public Health Service Act (PHS Act) • Section 351 of the PHS Act requires that licenses for biologics be issued only upon demonstration that products meet standards to ensure the “continued safety, purity, and potency” of the products. • “Potency” has been interpreted to include effectiveness (21 CFR 600.3(s)).

9. Biologic Product Licensure • 1972: FDA review of safety and effectiveness of all previously licensed biologics initiated The Agency determined then that proof of effectiveness for biological products would consist of controlled clinical investigations as defined in the provision for “adequate and well-controlled studies” for new drugs (21 CFR 314.126), unless waived as not applicable to the biological product or essential to the validity of the study when an alternate method is adequate to substantiate effectiveness (21 CFR 601.25(d)(2)).

10. Substantial Evidence of Safety and Effectiveness - Biologics • 21 CFR 601.25(d)(2) “Alternate methods, such as serological response evaluation in clinical studies and appropriate animal and other laboratory assay evaluations may be adequate to substantiate effectiveness where a previously accepted correlation between data generated in this way and clinical effectiveness already exists.”

11. Biologic Product Licensure • 1997 Modernization Act • Section 123(a) amended section 351 of the PHS Act • Single license for product and establishment • Did not change evidentiary standard (safe, pure, and potent) • Section 123(f) • FDA directed to take measures to “minimize differences in the review and approval” of products required to have approved BLAs under section 351 of the PHS Act and products required to have approved NDAs under section 505(b)(1) of the FDC Act.

12. Drug or Biologic Product - Substantial Evidence of Safety and Effectiveness • 21 CFR 314.126 Adequate and well-controlled studies • Defines the characteristics of an investigation that are needed to consider it “adequate and well-controlled” for purposes of section 505 of the FDC Act and to demonstrate “potency” or effectiveness for purposes of section 351 of the PHS Act

13. Drug or Biologic Product - Substantial Evidence of Safety and Effectiveness • 21 CFR 314.126 Adequate and well-controlled studies • Generally interpreted to mean at least two adequate and well-controlled studies • Need for independent substantiation of experimental results; a single experimental finding of efficacy, unsupported by other independent evidence, has not usually been considered adequate support for conclusion of effectiveness • Unconscious or conscious biases that may lead to flawed conclusions • Positive trial result by chance alone • Results at single center are dependent on site or investigator specific factors and results not generalizable to intended population • Rarely, scientific fraud

14. Can A Single Adequate and Well-Controlled Study Support Approval? • Single study for specific new use is supported by information from other related adequate and well-controlled studies • Other phases of disease process • Different population • Closely related disease • Different dose, duration of use, regimen • Different dosage form

15. Can A Single Adequate and Well-Controlled Study Support Approval? • A single multicenter study, of excellent design, that provides highly reliable and statistically strong evidence of important clinical benefit, such as effect on survival, and confirmatory study would be difficult to conduct on ethical grounds.

16. Can A Single Adequate and Well-Controlled Study Support Approval? • Caveats • Study clearly meets the requirements for adequate and well-controlled studies set forth in 21 CFR 314.126(b) • A single favorable study among several similar attempts that failed to support a finding of effectiveness does not constitute persuasive support for finding of effectiveness

17. Regulatory Mechanisms for Serious Conditions • Accelerated Approval • “Animal Efficacy Rule”

18. Accelerated Approval • Applies to certain products for treatment of serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments • Drugs - Subpart H in Section 314 of CFR • Biologics - Subpart E in Section 601 of CFR

19. Accelerated Approval 1. Approval with restrictions to assure safe use • Distribution restricted to certain facilities or physicians with special training or experience • Distribution conditioned on the performance of specified medical procedures

20. Accelerated Approval 2. Approval based on surrogate endpoint or on effect on clinical endpoint other than survival or irreversible morbidity • Surrogate endpoint must be reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit • When uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome, the applicant must study the product further to verify results in additional postmarketing studies that are adequate and well-controlled

21. Surrogate Endpoint • A biomarker that is used to predict clinical benefit (a direct measurement of how a patient feels, functions, or survives) • Detected earlier, or more readily, than corresponding clinical endpoint • To be considered acceptable, must have confidence that changes in the marker reliably predict the desired clinical endpoints

22. “Animal Efficacy Rule” • Applies to certain products that have been studied for their safety and efficacy in ameliorating or preventing serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances. • Drugs - Subpart I in Section 314 of CFR • Biologics - Subpart H in Section 601 of CFR

23. “Animal Efficacy Rule” • Applies only to new products for which definitive human efficacy studies cannot be conducted • unethical to deliberately expose healthy human volunteers to a lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substance • field trials to study the product's efficacy after an accidental or hostile exposure have not been feasible • Does not apply to products that can be approved based on efficacy standards described elsewhere in FDA's regulations (e.g., accelerated approval based on surrogate markers or clinical endpoints other than survival or irreversible morbidity) • Does not address the safety evaluation for the products to which it does apply

24. “Animal Efficacy Rule” • Approval based on evidence of effectiveness provided from adequate and well-controlled animal studies that establish that the product is reasonably likely to produce clinical benefit in humans

25. “Animal Efficacy Rule” Conditions • There is a reasonably well-understood pathophysiological mechanism of the toxicity of the agent and its prevention or substantial reduction by the product. • The effect is demonstrated in more than one animal species expected to react with a response predictive for humans • unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans.

26. “Animal Efficacy Rule” Conditions • The animal study endpoint is clearly related to the desired benefit in humans. • the enhancement of survival • prevention of major morbidity • The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans.

27. “Animal Efficacy Rule” • Three additional requirements: • A post-marketing study to verify the drug’s clinical benefit must be performed when these studies are feasible and can be done ethically. • The distribution of the drug can be restricted to ensure safe use, if necessary. • The sponsor must draft and distribute to patients information that explains that the approval is based on studies in animals, as well as other information that will permit the drug to be used safely.

28. Summary • Evidentiary standards for approval of drugs and biologics • Accelerated approval regulations • “Animal Efficacy Rule”

29. Points for Discussion • Role of animal data • Primary endpoint for clinical studies • Trial enrollment strategies