If you’re just joining us, take a look at parts one and two.


There aren’t many examples to draw on to demonstrate the issues with enforcement when a clinical service provider isn’t a CRO.

Why is that?

When FDA conducts an inspection, they must link findings directly back to predicate rule requirements (e.g., 21 CFR Part 312). If the actor and activity cannot be linked to the predicate rule because of the way obligations have been transferred, writing a finding becomes very difficult.

Take the 25-day inspection of CoreLab Partners, Inc. in July and August 2010 as an example (483 issued 2 September 2010, FEI number 3008410340). Because the company was not a CRO, multiple observations were written as if the company was a sponsor and its radiologists were clinical investigators. From a data integrity and availability perspective, Observations 1 and 4 are the most interesting.

Observation 1 dealt with computer systems used to blind image files, store and version image files, and read and annotate image files. Perceived inadequacies in audit trails resulted in FDA citing the company for “Failure to prepare or maintain accurate case histories with respect to observations and data pertinent to the investigation.” (An investigator responsibility under 312.62(b).)

Observation 4 dealt with copies of original source documents, which were used in the image adjudication process. These copies, which were important to determine if readers had been “truly blinded,” had been discarded. This led FDA to conclude “Records and reports were not retained for two years after marketing application approval.” (An investigator responsibility under see 312.62(c).)

Observation 2 cited the provider for failing “to select qualified investigators” and ensuring “the study is conducted in accordance with the protocol and/or investigational plan.” (A sponsor responsibility under 312.53(a).) Similarly, Observation 3 stated, “Investigators who were not qualified by training and experience as appropriate experts were selected to investigate a drug.” (See also 312.53(a).) And finally, Observation 5 cited the provider for failing “to obtain from an investigator a commitment to update financial information, to allow complete and accurate certification or disclosure statements.” (A sponsor responsibility under 312.53(c)(4).)

Well-written observations, but somehow they feel awkward.

They feel awkward because the regulations, as currently written, don’t support business as it’s conducted today.

Do we need to revise Part 312? Of course we do. What are the obligations associated with clinical trials? Who is responsible for them? Can the responsible party delegate the obligations? If not, and the obligations are delegated or transferred anyway, how can FDA effectively enforce the regulations to protect clinical trial subjects and the larger population of patients, once a drug is approved? (Too big to blog!)

For Discussion

Here are some questions for you. Enter a comment below to answer – I can’t wait to hear what you think!

  • Can you explain why the other 3 examples listed at the beginning are not CROs?
  • What about IWRS providers? Where do you think they fall and why?
  • Is it different in other parts of the world? If so, how? And why do you think that is?
  • What do you think needs to change?

About the Author

Jamie Colgin is Govzilla’s GCP Product Manager and is the recipient of the prestigious Charles H. Butler Excellence in Teaching Award.  She joins Govzilla from Colgin Consulting, Inc.

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