Description
This guidance describes best practices pertaining to conducting and reporting on pharmacoepidemiologic safety studies2 that use electronic healthcare data, which include administrative claims data and electronic medical record (EMR) data.3 The guidance includes recommendations for documenting the design, analysis, and results of pharmacoepidemiologic safety studies to optimize FDA’s review of protocols and final reports that are submitted to the Agency. For purposes of this guidance, the term pharmacoepidemiologic safety study refers to an observational study designed to assess the risk associated with a drug exposure and to test prespecified hypotheses. For ease of reference, this guidance uses the term drug to refer to drug and biological products regulated by CDER or CBER. Medical devices are not within the scope of this guidance.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
4Defined in section 201(g) of the FD&C Act; Articles intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease; Product classification based on chemical action or specific intended uses like altering pH
Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.
Class of medicinal products where lack of efficacy may require ICSR reporting
development program for drug and biological products
Stakeholders
4Guidance for Industry
Entities maintaining electronic healthcare data responsible for QA/QC
Entity responsible for submitting applications under section 524B
Entity submitting development data and knowledge; Entity performing the work process for change
Regulatory Context
Regulatory Activities
7FDA's evaluation of submitted study designs
Observational studies using electronic healthcare data
The credibility assessment report may be included as part of a regulatory submission.
Submission process applicable to optical imaging drugs.
Submission process applicable to optical imaging drugs.
Submission process applicable to optical imaging drugs.
FDA has determined that a class-wide REMS is necessary for all opioid analgesic drugs.
Document Types
9RWD source typically collected for billing or payment; Partially curated data source such as administrative claims
Standards for Data Management and Analytic Processes in the Office of Surveillance and Epidemiology.
Determining cause of death may call for information from death certificates
Document defining the design and conduct of the trial
EMR data are generated in the course of routine clinical care provision
EMR data used in pharmacoepidemiologic safety studies
Defines the standard of veterinary practice and limits for anesthetic regimens
Reports of study results submitted to the Agency
required as part of the premarket submission
Attributes
10statistically justified calculation required in the plan
The time of a patient's actual date of service to the date when the adjudicated claim first appears.
Interval of exposure time relevant in design or analysis
Analysis by sex of clinical performance measures such as sensitivity
Performance metric achieved by the model
investigators should provide information about the churn rate; Proportion of enrollees that disenroll from a health plan
investigators should address continuity of coverage (enrollment and disenrollment)
adequate statistical power and accounting for planned analyses
Element 1 of the fundamental elements approach; Element 1 of a vulnerability assessment; The scale of harm resulting from contamination; actionable process step because of the public health impact that would occur if the tank were contaminated.; Measured by potential deaths (e.g., 10,000 deaths) if a step is contaminated.
sponsors should include confidence intervals on all reported results
Technical Details
Substances
2over-the-counter (OTC) medications and dietary supplements are not captured systematically; OTC medications and dietary supplements are not generally captured in insurance-based data sources.
Uncaptured prescriptions might include low cost generics and drugs obtained through programs.
Testing Methods
9Statistical considerations in clinical trials
Verification activity often required for preventive controls
An analysis that was not anticipated or described in the analysis plan or study protocol.
Analyses conducted before the development of the protocol and analysis plan to determine if a study is feasible.
Alternative to clinical trials for examining cessation behaviors.; Alternative study design to support a marketing order.
Used to obtain a pooled estimate from multiple data sources
Statistical approach to address confounding in pharmacoepidemiologic studies; Methods for bias reduction in the comparison of a treatment to a nonrandomized control group.
study design (e.g., cohort, case-control) employed
study design (e.g., cohort, case-control) employed
Processes
4Observational studies designed to assess risk associated with drug exposure
Information gathered in the outcome validation process should be incorporated into the analysis plan.
A framework for industry to use when submitting pharmacoepidemiologic safety study protocols; indicates the type of pharmacoepidemiologic safety study design; An observational study designed to assess the risk associated with a drug exposure and test prespecified hypotheses.
FDAAA provides the specific circumstances when FDA can require the conduct of postmarketing studies
Clinical Concepts
4Covariate ascertainment and validation
Confounding issue specific to vaccine studies
Other topics related to drug interaction studies
Safety monitoring concept defined in the protocol
Identified Hazards
Hazards
7mitigate potential unwanted bias in learning or performance estimation
A confounder variable whose values change over the study time frame.
A specific type of selection bias arising from differences in competing risks or loss to follow-up.
Results might be biased because of unmeasured confounding
Bias where the indication is an independent risk factor for the outcome; Type of channeling bias where indication is an independent risk factor
Bias where drugs are prescribed based on factors prognostic of patient outcomes; Drugs prescribed differently based on prognostic factors
A factor to be managed in the analysis of real-world data; considering sources of potential bias and confounding; Studies must address two sources of error: systematic error (bias, confounding).
Standards & References
External Standards
52008 ISPE guidelines highlight importance of describing data management; Guidelines for good pharmacoepidemiology practices (GPP).
Determination of the positive predictive value of a code-based (e.g., ICD) operational outcome definition.
ISPE guidelines 2008
CONSORT statement exemplifies how basic reporting standards can improve quality
STROBE statement provides guidelines for reporting observational studies
Specifications
1The investigators should describe the reasons for their choices of analysis plan; The plan should specify planned statistical techniques and diagnostic methods; Plan describing anticipated analyses for the study.
Related CFR Sections (3)
- 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 →
- 21CFR314.98§ 314.98 Postmarketing reports.
(a) Each applicant having an approved abbreviated new drug application under § 314.94 that is effective must comply with the requirements of § 314.80 regarding the reporting and recordkeeping of adverse drug experiences.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 →
See Also (8)
- CPG Sec 120.500 Health Fraud - Factors in Considering Regulatory Action (Status: Final)
- Format and Content for the CMC Section of an Annual Report (Status: Final)
- Evaluating the Risks of Drug Exposure in Human Pregnancies (Status: Final)
- How to Comply with the Pediatric Research Equity Act (Status: Draft)
- Reports on the Status of Postmarketing Study Commitments — Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 (Status: Final)
- Postmarketing Studies and Clinical Trials—Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act Guidance for Industry (Status: Final)
- Benefit-Risk Considerations for Product Quality Assessments (Status: Draft)
- Pediatric Drug Development: Regulatory Considerations — Complying With the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act (Status: Draft)