FDA Issues New Guidance for Sponsor & CRO Inspections


FDA guidance sponsor CRO inspections

FDA Issues Updated Guidance on Sponsor & CRO Inspections

FDA is increasing their emphasis on Sponosr and CRO inspections with the release of an updated version of the Compliance Program Guidance Manual, CP 7348.810, Sponsors, Contract Research Organizations, and Monitors (CPGM). This FDA guidance document gives instructions to FDA personnel on how to conduct an inspection of a sponsor or CRO involved in FDA regulated research.

It significantly modernizes the previous CPGM, released over 10 years ago, introducing new sections and deleting sections that were obsolete or irrelevant.

There are new sections on the Registration of Studies on ClinicalTrials.gov; Review of Site Records; Financial Disclosure; Electronic Records and Electronic Signatures; Emergency Research; International Data; and GLP Studies. Other sections, such as Medical Devices, are substantially updated and clearer. The new CPGM should professionalize FDA’s approach to sponsor and CRO inspections and ensure closer review of a sponsor’s regulatory responsibilities. It is long overdue. I have done a brief analysis of Section III, Inspectional, of the new CPGM. There are also some helpful links to documents in Section VI, References and Contacts including several documents that I had never heard of before.

FDA inspection guidance on sponsors and CROs

Sponsor and CRO Inspections Usually Will be Scheduled

The first significant change is right at the beginning of Section III, Inspections, “under this program will be pre-announced unless otherwise instructed in the inspection assignment.” This formalizes a policy that began a few years ago under the Medical Devices Initiative. In addition, the new CPGM makes a point of emphasizing a statement routinely included in FDA inspection documents: Approaches that differ from those described in FDA’s Guidance documents should not be listed on the (Form FDA) 483 (Inspectional Observations) unless they constitute deviations from the regulations.” There are also instructions that the new CPGM “provides only the minimum scope of the inspection” for the field investigator to “expand the inspection as the circumstances warrant.” There are also specific instructions on how to document a violation:

“Any deviations from regulations should be thoroughly documented. For example, if the sponsor failed to review monitoring reports in a timely fashion and/or failed to bring non- compliant clinical investigators into compliance, monitoring reports, report review dates, and evidence of clinical investigator continued non-compliance should be documented and copied.” (original emphasis)

There are specific instructions that stem from FDA’s increased vigilance regarding falsification of data:

FDA sponsor inspection

Increased Emphasis on Falsification of Data

“Discuss potential violations involving fraud subject to Title 18 of the United States Code (18 U.S.C.) with your supervisor, District Compliance Officer, and assigning Center contact for appropriate referral to the Office of Criminal Investigations (OCI).” Reader’s should note that Title 18 violations are the ones that can put you into prison. Here are the new sections of the CPGM:

D. REGISTRATION OF STUDIES ON CLINICALTRIALS.GOV

“ClinicalTrials.gov is a website maintained by the National Library of Medicine (NLM). Its establishment was mandated by the 1997 FDA Modernization Act (FDAMA) to provide a public resource for information on studies of drugs, including biological drug products. The FDA Amendments Act of 2007 (FDAAA) mandated expansion of this data bank and included enforcement provisions to help ensure compliance.” There are specific guidance instructions in this section including a discussion of the Form FDA 3674, which we all will be paying closer attention to. Among the additional instructions to FDA field investigators are:

“6. Determine whether primary and secondary outcomes measures are listed on ClinicalTrials.govfor the study/studies. Determine if the outcome measures, if any, listed on ClinicalTrials.gov are generally consistent with the primary and secondary outcomes in the sponsor’s study protocol(s).

7. When examining informed consent documents related to an applicable clinical trial registered on ClinicalTrials.gov, determine if the appropriate required statement referencing ClinicalTrials.gov is included6. 21 CFR 50.25(c). The statement is:

‘’A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.’’’

For the section on Monitoring Procedures and Activities there is one significant change in recognition of the changes in the conduct of clinical trials: “With the prevalence of multisite clinical trials, traditional monitoring techniques – early and frequent on-site visits at all clinical sites – have become resource intensive. Regulations do not prescribe a specific monitoring technique, simply stating that sponsors are required to select monitors qualified by training and experience to monitor the investigational study (21 CFR 312.53(d), 511.1(b)(8)(ii), and 812.43(d)).”

FDA sponsor CRO inspections guidance

Monitoring of Clinical Trials is Evolving

In part, this statement recognizes that 100% source/CRF verification might not be practical or necessary, that sponsors may need to adapt new techniques, sometimes described as “Compliance Monitoring,” where monitoring records and reports are reviewed to determine outlier data. This could include no adverse events reported at a specific site. The CPGM goes on to state: “Determine if all CRFs are verified during monitoring visits. If a representative sample was selected, determine how the size and composition of the sample were selected.”

Financial Disclosure is discussed for the first time by FDA in a CPGM. Financial disclosure violations are very rarely cited by FDA during sponsor/CRO inspections. This may change with these instructions:

“1. Determine if the sponsor obtained financial disclosure information from each investigatorbefore his/her participation in the clinical trial, as required by 21 CFR Part 54 and 21 CFR 312.53(c)(4) and 812.2(b)(5) and 812.43(c)(5).

2. Determine if the sponsor received prompt updates regarding relevant changes in financialdisclosure information from investigators during the study and for one year after study completion.

3. Determine if the sponsor reported to FDA (on Form FDA 3454 and 3455, respectively), allpertinent investigator disclosures and certifications of financial information as required by 21 CFR 54.6.

4. Determine if the sponsor retained the documentation to support the certifications anddisclosures of investigators’ financial information that was reported to FDA.”

FDA inspection of sponsor

Updated Section on
Part 11

There is an updated section on Electronic Records and Electronic Signatures. The FDA guidance document, “Guidance for Industry Part 11, Electronic Records; Electronic Signatures – Scope and Application” (Part 11 Guidance) is discussed at length confirming that this document currently represents FDA’s enforcement policy regarding Part 11.

The CPGM emphasizes issues including the Scope of Electronic Records & Signatures; Procedures; Data Collection; & Security.

Finally there are new sections on Emergency Research; International Data; & Nonclinical Laboratories reflecting new regulations, guidance documents, or inspection policies. It is important to note that although FDA will not inspect GLP studies at every sponsor/CRO inspection, the possibility exists. The new CPGM gives the field investigator specific instructions on what to look for in non-clinical studies. (UPDATE: Read the recent Sponsor Warning Letter on Preclinical Studies on the link below.)

The new CPGM will significantly change how Sponsor/Contract Research Organizations, and Monitor inspections are conducted. It confirms a shift to review of sponsor responsibilities by FDA’s Bioresearch Monitoring program managers. It is a very important document for sponsors and CROs to review.

Read the New CPGM

Guidance for Industry on Financial Disclosure

Guidance on Certifications Required By FDAAA (including clinicaltrials.gov)

Compliance Policy Guide on Fraud and Untrue Statements…

Part 11: Scope & Application Guidance

Sponsor Warning Letter on Preclinical Studies from CDRH

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