It gives the basic understating regarding FDA warning letter-Prepared by Kaarkki

1. FDA Warning Letter-
Clinical Trials
Presented by……………Kaarkki.K
Quick Review

2. Overview:
• What is FDA…
• Indian FDA
• Why India?
• What is inspection?
• Who they will inspect?
• Type of Inspection
• Notice of Inspection
• Document to be Reviewed
• FDA 483 letter mean?
• What is an FDA Warning Letter?
• Classification of the inspection
• Most Common IRB Deficiencies
• Most Common CI Deficiencies
• Most common GLP deficiencies
• Most Common Sponsor-CRO-Monitor
Deficiencies
• FDA Inspections
• After Inspection
• Any enforcement in India? – Table Discussion

3. What is FDA…
• Food and Drug administration
• developed BIMO Program
• To help ensure the protection of the rights, safety, and welfare of human
research subjects
• FDA-regulated clinical trials, to verify the accuracy and reliability of clinical
trial data submitted to FDA in support of research or marketing
applications, and to assess compliance with statutory requirements and
FDA's regulations governing the conduct of clinical trials.

4. Indian FDA
• FDA opened the India Office in New Delhi in 2008, to ensure that
food and medical products exported from India to the U.S. are
safe, are of good quality, and are effective.
• 75th meeting of DTAB held on January 3, 2017, the Board’s
approval to rename ‘CDSCO’ as ‘IDA’ to make it simple and
befitting to its activities is the best that could happen to India’s
regulatory office

5. Why India?
• India is home to 135 FDA-approved manufacturing units and its Rs.1.1 trillion drug industry,
which largely makes generics, exported around Rs.40,000 cr. of drugs in 2012.
• 30% of this value being exported to the US alone.
• "FDA wants to ensure that Generic Cos. understand the risks associated with their product's
processes and ensure compliance to FDA's regulations.“
• "The FDA is confident that many companies understand and have implemented Good
Manufacturing Practices (GMPs)”.
• FDA interactions with industry, will take the necessary steps to self-correct.
• 241 inspections in(2012) India
•

6. • FDA investigator typically verifies compliance with the regulations
governing the use of investigational products and human subject
protections at 21 CFR parts 50, 56, 312, and/or 812.
What is inspection?

7. Who they will inspect?
• FDA BIMO Program involves site Visits to
• Clinical Investigator
• Sponsor
• Monitor
• Contract Research Organization
• Institutional Review Board
• Non Clinical (animal) laboratories
• bioequivalence analytical laboratories.

8. Type of Inspection
• FDA conducts both announced and unannounced inspections, typically under
the following circumstances:
• to verify the accuracy and reliability of data that has been submitted to the
agency;
• as a result of a complaint to the agency about the conduct of the study at a
particular investigational site;
• in response to sponsor concerns;
• upon termination of the clinical site;
• during ongoing clinical trials to provide real-time assessment of the investigator’s
conduct of the trial and protection of human subjects;
• at the request of an FDA review division; and
• related to certain classes of investigational products that FDA has identified as
products of special interest in its current work plan (i.e., targeted inspections
based on current public health concerns).

9. Notice of Inspection
• FDA investigator will display his/her FDA credentials
• issue a completed Form FDA 482 (Notice of Inspection)
Reference: Federal Food, Drug, and Cosmetic Act (21 USC 374), 21 CFR 312.68, and 21 CFR
812.145

10. Document to be Reviewed
• FDA is authorized at reasonable times to access, inspect, and copy
any required records related to the clinical investigation.
• Conclusion/Exit meeting

11. FDA 483 letter mean?
• Warning Letter is considered to be “prior notice”
• Respond within 15 days
• Your response to the FDA 483 may have been deficient
• FDA will initiate necessary action if no response is received
• Time is CRITICAL – you have to organize, understand, resolve and
respond to the FDA

12. What is an FDA Warning Letter?
• The United States Food and Drug Administration defines a Warning Letter as
"...a correspondence that notifies regulated industry about violations that FDA has
documented during its inspections or investigations. Typically, a Warning Letter notifies a
responsible individual or firm that the Agency considers one or more products, practices,
processes, or other activities to be in violation of the Federal Food, Drug, and Cosmetic
Act (the Act), its implementing regulations and other federal statutes.

13. Classification of the inspection
• based on the observations noted during the inspection, the investigator’s
report, and FDA District Office supervisory personnel review.
• the final classification of the inspection is made by the FDA District
Office.
• The conclusions of the inspection are reported as
• Official Action Indicated (OAI),
• Voluntary Action Indicated (VAI),
• No Action Indicated (NAI).
• Memo to File (MTF)

14. • An OAI inspection classification occurs when significant objectionable
conditions or practices were found and regulatory action is warranted to
address the establishment's lack of compliance with statute(s) or regulation(s).
• A VAI inspection classification occurs when objectionable conditions or
practices were found that do not meet the threshold of regulatory significance.
Inspections classified with VAI violations are typically more technical violations
of the FDCA.
• An NAI inspection classification occurs when no objectionable conditions or
practices were found during the inspection or the significance of the
documented objectionable conditions found does not justify further actions.

15. What Does FDA’s Decision to Issue a Warning
Letter Really Mean
• FDA perceives violations to be of regulatory significance.
• FDA likely thought the 483 response was inadequate.
• FDA does not trust the company to correct problems sufficiently on its
own.
• By issuing a warning letter, FDA requires the Company to pay more attention to
the issues.
• By issuing a warning letter, FDA requires the manufacturer to explain how it
plans to address the deficiencies.
• FDA requires the company to deal aggressively with the issues by suspending
product reviews and export certificates until corrections are made.

16. What Does FDA’s Decision to Issue a Warning
Letter Really Mean
• Warning Letters typically represent the first step if an inspection
was classified as official action indicated (OAI).
• Warning Letter is often the last warning that failure to achieve
prompt corrective action may result in enforcement action.
• FDA is not required to issue a warning letter before taking further
legal action (e.g., injunction, seizure, criminal investigation).

17. Most Common IRB Deficiencies
• Inadequate initial and/or continuing review
• Inadequate SOPs
• Inadequate membership rosters
• Inadequate meeting minutes
• Quorum issues
• Inadequate communication with CI/institution
• Subpart D issue. Additional Protections for Children Involved as
Subjects in Research

18. Most Common CI Deficiencies
• Failure to follow the investigational plan and/or regulations
• Protocol deviations
• Inadequate recordkeeping
• Inadequate accountability for the investigational product
• Inadequate communication with the IRB
• Inadequate subject protection – failure to report AEs and informed
consent issues

19. Most common GLP deficiencies
• Organizational and/or Personnel inadequacies
• Incomplete/inadequate/no study records
• Inadequate archiving
• Inadequate/no standard operating procedures (SOPs)
• Protocol deviations
United States Food and Drug Administration (USFDA) had conducted an inspection
from 10th April, 2017 to 18th April, 2017 - Aurobindo Pharma
At the end of the inspection, we have been issued a Form 483 with 6
observations.

20. Most Common Sponsor-CRO-Monitor Deficiencies
• Inadequate monitoring
• Failure to bring investigators into compliance
• Inadequate accountability for the investigational product
• Failure to obtain FDA and/or IRB approval prior to study initiation

21. FDA Inspections
2015 2014 2013 2012 2011
CI 822 803 664 697 576
IRB 138 152 174 158 187
Sponsor/CRO/
Monitor 117 138 120 109 141
GLP 36 43 61 60 45
Total 1113 1136 1019 1024 949

22. After Inspection
• FDA investigator who conducted the inspection prepares a written
Establishment Inspection Report (EIR).
• FDA Centre - evaluation and final classification of the inspection
outcome
• types of letters is typically sent from
(1) A letter that generally states that FDA observed basic compliance with
pertinent regulations. Note that a letter is not always sent when FDA
observes no significant deviations.
See FDA’s CPGM, Program 7348.811, “Clinical Investigators and Sponsor-
Investigators.”

23. • (2) An Informational or Untitled Letter that identifies deviations
from statutes and regulations that do not meet the threshold of
regulatory significance for a Warning Letter. Generally, such
letters may request a written response from the clinical
investigator.
• See FDA’s procedures regarding initiation of Untitled Letter
procedures, found in the Regulatory Procedures Manual (RPM)

24. • (3) A Warning Letter that identifies serious deviations from applicable
statutes and regulations. A Warning Letter is issued for violations of
regulatory significance
• Significant violations are those violations that may lead to enforcement
action if not promptly and adequately corrected. Warning Letters are
issued to achieve voluntary compliance, and include a request for
correction and a written response to the agency.
• See FDA’s procedures regarding initiation of disqualification proceedings,
found in the RPM

25. • (4) A Notice of Initiation of Disqualification Proceedings and Opportunity to
Explain (NIDPOE).
• FDA may initiate a process to disqualify the clinical investigator from receiving
investigational new drugs and/or biologics if disqualified under part 312, or
investigational devices if disqualified under part 812, if the investigator has
repeatedly or deliberately failed to comply with applicable regulatory
requirements or has deliberately or repeatedly submitted false information to
the sponsor or FDA in any required report. See 21 CFR 312.70 and 812.119. The
NIDPOE identifies alleged violations and provides the investigator with an
opportunity to explain the matter at an informal conference or in writing. If, in
response to the NIDPOE, the investigator provides an explanation that is
accepted by the agency and the disqualification is not warranted, alternatives
such as a detailed corrective action plan may be considered. If the investigator’s
explanation is not accepted by the agency, the agency may issue a Notice of
Opportunity for Hearing (NOOH) under 21 CFR part 16.

26. Any enforcement in India? – Table Discussion
• BILL NO. LVIII OF 2013- introduced in the Rajya Sabha on 29th
August, 2013

27. Thank you