Tag: FDA

Legal Framework of PADE Inspections

Good Corrective Action Plan – Four Reasons to Submit a Complete and Timely

Written Response

1. May be considered in an FDA compliance decision.
2. Demonstrates your acknowledgment and understanding of the observations to the FDA
3. Demonstrates your commitment to correct the observations to the FDA
4. Establishes credibility with the FDA

Points to Consider for Written Responses to the FDA

(SUBMIT THE REPORT WITHIN 15 WORKING DAYS)

Inspection Reporting: FORM FDA 483, Inspectional Observations

Inspection Classifications

No Actions Indicated (NAI)	Voluntary Action Indicated (VAI)	Official Action Indicated (OAI)
No Objectionable conditions or practices were found during an inspection (or the objectionable conditions found do not justify further regulatory action).	Objectionable conditions or practices were found, but do not rise to the level warranting OAI classification.	Objectionable conditions or practices were found, whose scope, severity, or pattern warrants the recommendation for a regulatory action.

a) Warning Letters

The issuance of a Warning Letter (WL) may be warranted when the inspection uncovers significant objectionable conditions related to noncompliance with PADE requirements. The CDER PVC Team and OSI management will evaluate all inspections classified as OAI by OBIMO on a case-by-case basis.

b) Untitled Letters

An Untitled Letter (UL) may be warranted when the deficiencies found at the firm are severe enough to justify a formal letter to the firm, but do not meet the threshold of regulatory significance for a WL.

Factors that influence the issuance of a WL or UL include the nature and extent of the violations (for example, if they are repeated or deliberate), the compliance history of the inspected firm, and the corrective actions implemented by the firm.

c) Enforcement Actions

1. Injunction: Injunction should be considered when follow-up inspection(s) show that the firm has a continuing pattern of significant and substantial deviations, despite previous attempts by FDA to obtain compliance. 1.
2. Seizure: Seizure for failure to comply with post marketing adverse drug experience reporting regulations would be possible only if the approval of the application for the product has first been withdrawn (FD&C Act, section 304(a)(1)). Seizure would then be based on distribution of an unapproved drug product. 2.
3. Prosecution: Evidence that a firm is submitting false information, not submitting required reports for serious post marketing adverse events, or withholding important information, the submission of which may have resulted in the Agency requiring labelling changes or withdrawing an application, should be referred to the Office of Criminal Investigations (OCI) for consideration of prosecution.

 

Legal Framework of PADE Inspections

PADE Statutory Provisions / Regulations: Prescription Drug Products for Human Use

S.no	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: Post marketing 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: Post marketing reports
6	21 CFR 314.540	Accelerated approval of new drugs for serious or life-threatening illnesses: Post marketing safety reporting
7	21 CFR 314.630	Approval of new drugs when human efficacy studies are not ethical or feasible: Post marketing safety reporting
8	21 CFR part 4, subpart B	Post marketing 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

1. Written procedures
2. Product list (approval date, status, etc.)
3. Late or Missing Periodic Reports or Annual Reports
4. Late, missing, incomplete, or inaccurate 15-day reports
5. ADEs from all sources
6. Root cause analyses and corrective actions for deviations
7. Confirmations for electronic submissions
8. Training Documents
9. Safety Contracts, Agreements, and Business Partners
10. Organization, roles, and responsibilities
11. Waivers

Who can be inspected for PADE Compliance?

1. 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)

2. 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

3. 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

1. Inspection History:

   • Compliance and inspection history

1. • • Never inspected for PADE compliance
     • Inspection findings from other program areas

1. • Firm’s written responses to previous PADE inspections

2. Firm Information:

   • Corporate changes
   • Portfolio (type and number of products)
   • Complaints
   • Internal FDA information
   • Information from other health authorities

3. Product Portfolio:

   • New molecular entities
   • High-risk
   • Patient exposure
   • Recalls Submissions to FDA

1. • • Individual Case Safety Reports (ICSRs)
     • Annual reports
     • Periodic report