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Biomarkers and Subparts Rules and Exceptions

Biomarkers and Subparts Rules and Exceptions. James Witter MD, PhD Analgesic, Anti-inflammatory, and Ophthalmologic Drug Products HFD-550/ODEV/CDER/FDA. FDA and Medical Care. The FDA approves drug and biologic therapeutics for interstate commerce The FDA does not regulate medical care

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Biomarkers and Subparts Rules and Exceptions

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  1. Biomarkers and SubpartsRules and Exceptions James Witter MD, PhD Analgesic, Anti-inflammatory, and Ophthalmologic Drug Products HFD-550/ODEV/CDER/FDA

  2. FDA and Medical Care • The FDA approves drug and biologic therapeutics for interstate commerce • The FDA does not regulate medical care • Thus FDA-approved therapies may be used in ways that are deemed “standard-of-care” by any specific community • “off label” use

  3. Drug Development & Regulations • Pre-1938 • FDA existed (established 1906) • Only responded to problems • No requirement for testing or approval • Public Health Disasters • DNP for weight loss • 1 % cataracts (women), deaths (1930’s) • Elixir sulfanilamide for “all conditions in which the hemolytic streptococci appear” (1937) • Killed 107 (many children) • From diethylene glycol poisoning • Food, Drug and Cosmetic Act (1938)

  4. Food Drug & Cosmetic Act -1938- • Established requirement for safe therapies • Marketing required “NDA” but passive approval i.e. only if FDA did not object • Application refused if: • Investigations did not establish safety under proposed label • Tests show unsafe, or not safe • Insufficient information to establish safety • Label false or misleading

  5. 1962 Amendments to FD&C • Requirement for efficacy • Mechanism to conduct clinical studies • Goal to predict safety and efficacy when the product is marketed • Accomplished through carrying out adequate and well controlled trials

  6. FD& C Act: Section 505-2003- • Requires substantial evidence of safety and efficacy as the basis of approval • FDA must give positive approval • Permits the FDA to grant exemptions from the FD&C Act to study new drug products • IND for drugs and biologics

  7. Application to Market a New Drug, Biologic, or an Antibiotic Drug for Human Use (Form FDA 356H) • Section 505 (b) (1): application has full reports of investigations to show whether drug is safe and effective and has details about components, composition, methods and controls

  8. CFRCode of Federal Regulations • Codification of rules published in Federal Register by Executive department of the Federal Government • Divided into 50 titles • Represent broad areas subject to Federal regulation • Titles divided into chapters • Often bears name of issuing agency • Chapters divided into parts and subparts

  9. Title 21:Food and Drug Laws • Composed of 9 volumes with parts • Parts 1-1299 (first 8 volumes = Chapter 1) • Comprises Food and Drug Administration • Part 1300-end (single volume) includes: • Chapter 2 (Drug Enforcement Agency-Justice) • Chapter 3 (Office of National Drug Policy)

  10. Part 314 (Subparts)Application to Market New Drug • A-General Provisions • B-Applications • C-Abbreviated Applications • D-FDA action on B or C above • E-Hearing Procedures • F-Administrative Procedures for Antibiotics • G-Miscellaneous • H-Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses

  11. 21 CFR-Subparts H and E • Subpart H: 314.500 • Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses • 21 CFR 314: NDA regulations • Subpart E:312.80 • Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses • 21 CFR 312: IND regulations

  12. CFR definitions • Life-threatening: 314.81(a) • (1) Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted: and • (2) Diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival. • Severely Debilitating: 314.81(b) • Diseases or conditions that cause major irreversible morbidity

  13. “Surrogate” ApprovalSubpart H21 CFR 314.510 FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible mortality.

  14. Subpart HApproval Caveats 314.510 • Requirement that applicant study the drug further to verify and describe its clinical benefit where there is uncertainty • of the surrogate to clinical benefit • of observed clinical benefit ultimate outcome • Post-marketing studies usually underway • must be adequate and well controlled • must be carried out with due diligence

  15. Subpart HWithdrawal Caveats 314.530 • FDA may withdraw approval, following a hearing if: • Postmarketing clinical study fails to verify clinical benefit • Applicant fails to perform the required postmarketing study with due diligence • The promotional materials are false or misleading • Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use

  16. Subpart ECaveats 312.80 • FDA can exercise flexibility in applying standards while preserving safety and effectiveness • Procedures reflect recognition that physicians and patients are generally willing to accept greater risks of side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products to treat less serious illnesses

  17. Subpart ECaveats • 312.84Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and severely-debilitating illnesses • not approvable (drug) or deficiency (biologic) letter may be issued after review of data • 312.85Phase 4 studies • FDA may seek agreement from the sponsor to conduct certain phase 4 studies to delineate additional information about the drug’s risks, benefits,and optimal use

  18. Biomarkers and Surrogate EndpointsNIH/FDA sponsored meetingApril 15-16, 1999definitionsconceptual modelpossible relationships

  19. Conceptual modelBiomarker and Surrogate Endpoints - 1999 • Biomarkers include the measurements considered directly related to clinical outcomes, but are not the outcomes themselves • Biomarkers can evaluate the safety or efficacy (or both) of therapeutic intervention • Some biomarkers may achieve the status of a surrogate endpoint in a clinical trial • difficult due to disease complexity and single marker limitations

  20. Possible relationshipsBiomarker and Surrogate Endpoints - 1999 • Biomarker of no value as surrogate endpoint • intervention affects disease, not marker • Biomarker measures unfavorable outcome • intervention worsens clinical outcome • Biomarker has partial value • intervention’s positives and negatives not fully measured (most current surrogate endpoints) • Biomarker is ideal surrogate endpoint • full effect of intervention measured

  21. Biomarkers in SLE may: • be useful in exploratory studies • help identify or prioritize new therapies • help assess safety • help identify “at risk” or “resistant” patients • help compare therapies • help patients and doctors to select and monitor therapies • help assess efficacy (? surrogate endpoint)

  22. Surrogate Endpoint: Definition • A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions, or survives • Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint • Only valid if the effect on the surrogate leads to a clinical benefit

  23. Surrogates vs. Biomarkers • Surrogate endpoints are candidates for drug approval • Biomarkers do not have the same regulatory implication • Surrogates may be biomarkers, but not all biomarkers are surrogates.

  24. Clinically Meaningful Outcome Surrogate marker Biomarker

  25. Current State: Surrogates • Blood pressure • Lipid lowering agents • Blood sugar/HBA1c • Bone mineral density • HIV load

  26. Surrogates: Problems • Do not always account for adverse effect which may cancel out part or all of the apparent treatment benefit: • Cardiac Arrhythmia Suppression Trial (CAST) • NEJM 324: 781-788 (1991) • Anti-arrhythmics with worse survival • Deaths and cardiac arrests • Encainide/Flecainide: 63/755 (8.3%) • Placebo: 26/743 (3.5%)

  27. Subparts H and E • Potential advantage • accelerated approval • Potential disadvantage • accelerated withdrawal

  28. Uric acid: Biomarker or Surrogate • Serum uric acid is a laboratory measure • Elevated levels can correlate with gout attacks, tophaceous disease or renal disease in the right patient • Does lowering in serum uric acid • Decrease incidence of ESRD or stone formation? • Decrease gouty arthritis or size of tophi? • How much is enough? • Lower uric acid to < 6.0 mg/dl or more than placebo? • In all patients or only a proportion?

  29. Surrogate Approval-Example? • DS-DNA hypothetically proposed as surrogate for trial in SLE (renal disease?) • Responder approach to analysis • Endpoints in phase 2/3 trials to address short-term benefit • renal • ? quality of life outcome • Post-marketing commitment to verify long-term clinical benefit • ? preservation of renal function

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