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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 SubpartsRules and Exceptions

James Witter MD, PhD

Analgesic, Anti-inflammatory, and Ophthalmologic Drug Products


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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

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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)

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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

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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

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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

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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

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CFR Drug for Human Use (Form FDA 356H)Code 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

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Title 21: Drug for Human Use (Form FDA 356H)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)

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Part 314 (Subparts) Drug for Human Use (Form FDA 356H)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

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21 CFR-Subparts H and E Drug for Human Use (Form FDA 356H)

  • 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

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CFR definitions Drug for Human Use (Form FDA 356H)

  • 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

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Drug for Human Use (Form FDA 356H)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.

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Subpart H Drug for Human Use (Form FDA 356H)Approval 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

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Subpart H Drug for Human Use (Form FDA 356H)Withdrawal 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

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Subpart E Drug for Human Use (Form FDA 356H)Caveats 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

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Subpart E Drug for Human Use (Form FDA 356H)Caveats

  • 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

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Biomarkers and Surrogate Endpoints Drug for Human Use (Form FDA 356H)NIH/FDA sponsored meetingApril 15-16, 1999definitionsconceptual modelpossible relationships

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Conceptual model Drug for Human Use (Form FDA 356H)Biomarker 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

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Possible relationships Drug for Human Use (Form FDA 356H)Biomarker 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

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Biomarkers in SLE may: Drug for Human Use (Form FDA 356H)

  • 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)

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Surrogate Endpoint: Definition Drug for Human Use (Form FDA 356H)

  • 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

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Surrogates vs. Biomarkers Drug for Human Use (Form FDA 356H)

  • 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.

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Clinically Meaningful Outcome Drug for Human Use (Form FDA 356H)

Surrogate marker


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Current State: Surrogates Drug for Human Use (Form FDA 356H)

  • Blood pressure

  • Lipid lowering agents

  • Blood sugar/HBA1c

  • Bone mineral density

  • HIV load

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Surrogates: Problems Drug for Human Use (Form FDA 356H)

  • 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%)

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Subparts H and E Drug for Human Use (Form FDA 356H)

  • Potential advantage

    • accelerated approval

  • Potential disadvantage

    • accelerated withdrawal

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Uric acid: Biomarker or Surrogate Drug for Human Use (Form FDA 356H)

  • 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?

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Surrogate Approval-Example? Drug for Human Use (Form FDA 356H)

  • 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