1. General Regulatory Issues in the Development of Drugs Intended for Treatment of Chronic Illness Sharon Hertz, M.D. Medical Officer Division of Anesthetic, Critical Care and Addiction Drug Products, FDA

2. Hypothesis: Drug A is capable of treating Symptom Complex Z in a safe and effective manner. Proof: At least two adequate and well-controlled trials demonstrating the hypothesis to be true, additional safety monitoring as needed. Results: Approval of Drug A with label. Promotion of Drug A based on findings of efficacy

3. What is the regulatory basis for studies used to support a finding of efficacy in an application? What is the regulatory basis for the requirements of the safety database? How are these findings, the product label, and product promotion related?

4. Efficacy Requirement for demonstration of efficacy based on amendments to the Food, Drug and Cosmetic Act, 1962. Section 505(a) of 21 U.S.C. 355 states that "No person shall introduce or delivery for introduction into interstate commerce any new drug, unless an approval of a an application filed pursuant to subsection (b) or (j) is effective with respect to such drug.”

5. Efficacy Section 505(b)(1)(A): “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use” shall be submitted as part of the application.

6. Efficacy Section 505(d)(5): a finding of “substantial evidence 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 proposed labeling…” is needed for approval of the application.

7. Efficacy The term “substantial evidence” is defined in 505(d) as “evidence consisting of adequate and well-controlled 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 …”

8. Efficacy 21 CFR 314.126 The essential characteristics of an adequate and well-controlled trial, including the required documentation of planning, conduct, data handling and record keeping.

9. Efficacy “The Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products (May 1998)”.

10. Safety ICH E1A Guideline for Industry The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions

11. Label 21 CFR 201.57(c)(2) “All indications shall be supported by substantial evidence of effectiveness based on adequate and well-controlled studies as defined in §314.126(b) of this chapter unless this requirement is waived under §201.58 or §314.126(b) of this chapter.”

12. Label The Contraindications, Warnings, and Adverse Reactions Sections 201.57(d), (e), and (g) will be based initially on information from clinical trials and may have based on postmarketing reports.

13. Advertising Section 202.1(e)(3)(ii) “The information relating to effectiveness shall include specific indications for use of the drug for purposes claimed in the advertisement … for which the drug is effective clinically as specifically as required, approved, or permitted in the drug package labeling.”

14. Advertising 1. It is necessary to set a level playing field. 2. A product used for more than one indication may have different dosing requirements for those indications. 3. Different indications - different patient populations - different safety profiles. Age, co-morbidity, concomitant medications /potential drug-drug interactions. Safety data needed for fair balance.

15. Clinical Trials Efficacy Safety Product Label Product Advertising