Postmarketing Studies and Clinical Trials—Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act Guidance for Industry

PharmacovigilanceRisk Evaluation and Mitigation Strategy

Description

This guidance provides information on the implementation of section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 355(o)(3)), which authorizes FDA to require certain postmarketing studies and clinical trials for prescription drugs approved under section 505(c) of the FD&C Act and biological products approved under section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262).

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

Prescription Drug

Early-phase randomized, double-blind, parallel assignment clinical study

Biological Product

Regulated under section 351(i) of the PHS Act; Virus, therapeutic serum, toxin, vaccine, or protein applicable to prevention or treatment; Alternative regulation category for products meeting device definition

Gene Therapy

A type of ATMP involving recombinant nucleic acids or viral vectors.

Stakeholders

Applicant

Entity submitting development data and knowledge; Entity performing the work process for change

Regulatory Context

Regulatory Activities

Postmarketing Requirements

PMRs required by FDA; Studies or clinical trials conducted by the applicant after FDA approval

IND

Investigational New Drug submissions

BLA

Biologics License Application

REMS Assessment

Periodic evaluation of the REMS submitted to FDA

Postmarketing Commitments

PMCs agreed upon in writing; Studies or clinical trials agreed upon in writing by FDA and the applicant

REMS

Risk evaluation and mitigation strategy submission

NDA

New Drug Application

Accelerated Approval

Pathway for drugs and biologics for serious conditions; Regulatory pathway supported by surrogate or intermediate endpoints; Regulatory pathway based on surrogate or intermediate endpoints; Pathway for products based on surrogate or intermediate clinical endpoints

PMR

Postmarketing requirement for postapproval studies

PMC

Postmarketing commitment for collecting postapproval data

Document Types

REMS Assessment

Proposed REMS modifications no longer require submission of a REMS assessment; evaluation of whether the REMS is meeting its goals; Required assessment included with the supplement as adequate rationale

Annual Report

Reporting category for minor changes like removing a color additive

Protocol

Defines the standard of veterinary practice and limits for anesthetic regimens

Annual Status Report

Report on the status of PMRs and PMCs

Attributes

Timetable for Completion

Set of milestone dates to measure progress

New Safety Information

Information that triggers the authority to require PMRs

Final protocol submission

The first milestone generally used to measure progress of studies.

Technical Details

Testing Methods

Observational Pharmacoepidemiologic Study

Study designed to assess a serious risk associated with drug exposure

Meta-analysis

Random effects analysis using the DerSimonian and Laird method to estimate pooled resolution rates.

Processes

Pharmacoepidemiologic study

Observational studies used to estimate risks of serious adverse events.

Clinical Concepts

Serious adverse event

Critical safety outcome in clinical trials

Adverse Drug Experience

Reports of adverse events occurring in treated animals.

Q-T prolongation

A specific safety concern evaluated in thorough Q-T clinical trials.

Identified Hazards

Hazards

Serious Safety Risks

The target of PMRs, REMS, and SLCs

Serious Risk

Associated with the use of a drug that FDA becomes aware of post-approval

Unexpected Serious Risk

A risk not previously identified or expected based on the drug's profile

Standards & References

External Standards

ICH S1A

See the ICH guidance for industry S1A The Need for Long-Term Rodent Carcinogenicity Studies

Specifications

Drug substance specification standards

Updated based on optical rotation test data

View on FDA.gov Download PDF

Related CFR Sections (10)

21CFR601.91§ 601.91 Approval based on evidence of effectiveness from studies in animals.
(a) FDA may grant marketing approval for a biological product for which safety has been established and for which the requirements of § 601.90 are met based on adequate and well-controlled animal studies when the results of those animal studies establish that the biological product is reasonably likRead full regulation →
21CFR314.610§ 314.610 Approval based on evidence of effectiveness from studies in animals.
(a) FDA may grant marketing approval for a new drug product for which safety has been established and for which the requirements of § 314.600 are met based on adequate and well-controlled animal studies when the results of those animal studies establish that the drug product is reasonably likely to Read full regulation →
21CFR312.85§ 312.85 Phase 4 studies.
Concurrent with marketing approval, FDA may seek agreement from the sponsor to conduct certain postmarketing (phase 4) studies to delineate additional information about the drug's risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or Read full regulation →
21CFR601.27§ 601.27 Pediatric studies.
(a) Required assessment. Except as provided in paragraphs (b) , (c) , and (d) of this section, each application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration shall contain data that are adequate to assess the safety and effectivenessRead full regulation →
21CFR314.55§ 314.55 Pediatric use information.
(a) Required assessment. Except as provided in paragraphs (b) , (c) , and (d) of this section, each application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration shall contain data that are adequate to assess the safety and effectivenessRead full regulation →
21CFR314.510§ 314.510 Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.
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 predicRead full regulation →
21CFR601.41§ 601.41 Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.
FDA may grant marketing approval for a biological product on the basis of adequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, tRead full regulation →
21CFR314.81§ 314.81 Other postmarketing reports.
(a) Applicability. Each applicant shall make the reports for each of its approved applications and abbreviated applications required under this section and section 505(k) of the act.Read full regulation →
21CFR312.3§ 312.3 Definitions and interpretations.
(a) The definitions and interpretations of terms contained in section 201 of the Act apply to those terms when used in this part:Read full regulation →
21CFR601.70§ 601.70 Annual progress reports of postmarketing studies.
(a) General requirements. This section applies to all required postmarketing studies (e.g., accelerated approval clinical benefit studies, pediatric studies) and postmarketing studies that an applicant has committed, in writing, to conduct either at the time of approval of an application or a suppleRead full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

False or misleading risk presentation

Failure to submit under Form FDA-2253

Failure to submit promotional materials

Omission of material facts

False or misleading claims about efficacy and risks

False or misleading promotional communication

Failure to submit promotional materials at time of initial dissemination

False or Misleading Risk Presentation

Omission of Material Facts

Failure to Submit Under Form FDA-2253