Postmarketing Adverse Drug Experience (PADE) Inspections - Part I
Legal Framework of PADE Inspections
- LAW: Federal Food, Drug and Cosmetic Act (FDCA)
- Title 21 of the Code of Federal Regulations (CFR)
- FDA’s Current Thinking
PADE Statutory Provisions / Regulations: Prescription Drug Products for Human Use
| # | FD&C Act, subchapter V, part A, section 505 (21 U.S.C. 355) | Comments |
|---|---|---|
| 1 | 21 CFR 310.305 | New Drugs: Records and reports concerning adverse drug experiences (ADEs) for marketed prescription drugs for human use without an approved new drug application |
| 2 | 21 CFR 314.80 | New drug applications: Postmarketing reporting of ADEs |
| 3 | 21 CFR 314.81(b)(2) | New drug applications: Annual reports |
| 4 | 21 CFR 314.90 | New drug applications: Waivers |
| 5 | 21 CFR 314.98 | Abbreviated applications: Postmarketing reports |
| 6 | 21 CFR 314.540 | Accelerated approval of new drugs for serious or life-threatening illnesses: Postmarketing safety reporting |
| 7 | 21 CFR 314.630 | Approval of new drugs when human efficacy studies are not ethical or feasible: Postmarketing safety reporting |
| 8 | 21 CFR part 4, subpart B | Postmarketing safety reporting for combination products |
Approval vs. Marketing
Once a drug is approved, applicant holders MUST receive, evaluate, and report adverse drug experiences (ADEs) to FDA, even if the drug is not marketed.
PADE Inspection - Scope
- Written procedures
- Product list (approval date, status, etc.)
- Late or Missing Periodic Reports or Annual Reports
- Late, missing, incomplete, or inaccurate 15-day reports
- ADEs from all sources
- Root cause analyses and corrective actions for deviations
- Confirmations for electronic submissions
- Training Documents
- Safety Contracts, Agreements, and Business Partners
- Organization, roles, and responsibilities
- Waivers
Who can be inspected for PADE Compliance?
- Application holders: Applicants with approved drugs and therapeutic biologics (prescription and non-prescription)
- New Drug Application (NDA)
- Abbreviated New Drug Application (ANDA)
- Biologics License Application (BLA)
- Non- Applicants: Manufacturers, packers, distributors, retailers, and certain others named on product labels (responsibilities vary based on product type)
- Approved prescription and non- prescription drugs and therapeutic biologics (NDA, ANDA, BLA)
- Unapproved prescription drugs
- Unapproved non-prescription drugs
- Third parties: Contractors, vendors, and other third parties
- Pharmacovigilance activities conducted on behalf of application holders or non-applicants
Risk Based Selection for PADE Inspection
- Inspection History:
- Compliance and inspection history
- Never inspected for PADE compliance
- Inspection findings from other program areas
- Firm’s written responses to previous PADE inspections
- Compliance and inspection history
- Firm Information:
- Corporate changes
- Portfolio (type and number of products)
- Complaints
- Internal FDA information
- Information from other health authorities
- Product Portfolio:
- New molecular entities
- High-risk
- Patient exposure
- Recalls Submissions to FDA
- Individual Case Safety Reports (ICSRs)
- Annual reports
- Periodic report
Conclusion
- DILI is a key concern for regulators, drug developers, and physicians, and is difficult to predict during drug development process.
- As severe DILI is generally rare, finding a single case may require treatment of thousands of people from varied patient populations.
- The clinical trials present an exclusive opportunity to detect hepatotoxicity and cases of potential DILI with a study drug prior to its use in general population.
- Monitoring the liver test abnormalities is useful for assessing trends over time and to analyze imbalance between study drug and placebo/comparator groups.
- Due to the limited number of subjects in a clinical trial, monitoring the standard serum liver tests to detect milder liver injury can be considered a predominant approach to predict the risk of possible DILI in clinical trials.
- Considering that there may be varied mechanisms of DILI and different clinicopathological phenotypes, a systematic collection of adequate diagnostic datasets along with a focused causality assessment performed by clinical experts is required for evaluation of each potential case of DILI in clinical trials.
Selected References
- https://www.fda.gov/
- Number of 483 issued from the System* Inspections ending between 10/1/2022 and 9/30/2023 https://www.fda.gov/inspections-compliance-enforcement-and- criminal-investigations/inspection-references/inspection-observations
- Postmarketing Drug Safety Compliance: 2019 Inspection Findings April 29, 2020 (Live Webinar) Center for Drug Evaluation and Research – Small Business and Industry Assistance, Center for Drug Evaluation and Research, US Food and Drug Administration
- Postmarketing Drug Safety and Inspection Readiness June 19, 2018 Center for Drug Evaluation and Research (CDER) Small Business and Industry Assistance (SBIA) Webinar
- Postmarketing Drug Safety and Inspection Readiness June 19, 2018 Center for Drug Evaluation and Research (CDER) Small Business and Industry Assistance (SBIA) Webinar
- CHAPTER 53 – Postmarketing Surveillance and Epidemiology: Human Drug and Therapeutic Biological Products, fda.gov
Author
DR. SUMIT VERMA
President Operations Management, CSPV
Dr. Sumit Verma is a medical graduate with specialization in anesthesiology and has more than 15 years of experience in the pharmaceutical industry, clinical medicine, clinical research, and pharmacovigilance. He has built teams that have consistently delivered and exceeded customer expectations across pharmacovigilance domains such as case processing, signal management, risk management, aggregate reports, and clinical safety. He has co-authored two books – one on pharmacovigilance and another on pharmacology.
About Soterius
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