Overview of the Medical Research & Ethics Committee’s (MREC) Industry Sponsored Research (ISR) Performance Statistics, 2014 – 2016

Gurpreet K*, Asha T*, Sharina MN*
*Medical Research Ethics Unit, NIH Secretariat, Ministry of Health Malaysia

MREC was formally established in 2002, with the purpose of safe guarding the rights, welfare and safety of subjects participating in research in Ministry of Health (MOH) facilities. It is the sole ethics committee for Ministry of Health facilities and may act as an Independent Ethics Committee for facilities outside the MOH. Read more

Investigator’s Corrective Action Plan Fails to Satisfy FDA

Following an FDA inspection, the agency lists identified deficiencies in a Form FDA 483, Inspectional Observations, and in the FDA Establishment Inspection Report. There is no regulatory requirement for the inspected party to respond to the Form FDA 483. Nevertheless, a well-reasoned, complete and timely response is generally in the inspected party’s best interests, not least because it may mitigate a decision for further action and demonstrates commitment and intent to comply, which will establish credibility with the FDA. When the inspected party chooses to provide a written response, any subsequent FDA warning letter is likely to include a judgement on the appropriateness of that response. From a review of even a small number of FDA warning letters, it is evident that the agency often finds that the corrective and preventive actions (CAPAs) proposed by inspected parties are inadequate. One such case is described below.

MISSED LABORATORY EVALUATIONS

An investigator participating in two oncology trials failed to perform a large number of protocol-required laboratory tests, including coagulation profile laboratory tests for four out of five subjects on up to 15 occasions. In addition he failed to perform liver function tests for all five subjects on at least three occasions. In his written response to these violations, the investigator confirmed that the protocol-required laboratory tests were missed for subjects enrolled in the two studies. He indicated that, as a part of his corrective action plan (CAP), he had added a “clinical trials link” to the site’s electronic medical record (EMR) to provide study staff with access to study information. He further stated that he will review the process of accessing study information and the importance of following the study calendar with his staff. The FDA replied that the response was inadequate because it did not include sufficient information to enable the agency to evaluate the adequacy of the CAP for use in any future clinical research. In particular, the FDA stated that it was unclear how adding a “clinical trials link” to the site’s EMR would ensure that protocol requirements would be met for studies at the site. The response did not provide details of a CAP to prevent similar violations from occurring in the future, or sufficient details to implement additional measures and procedures to address the inspection findings. The FDA was therefore unable to determine whether the CAP was sufficient to prevent similar violations in the future.

LESSONS LEARNED

A corrective action can be defined as any action designed to eliminate the cause of a detected nonconformity or other undesirable situation. A preventive action is one intended to eliminate the cause of a potential non-conformity or other undesirable potential situation. Thus preventive action is taken to prevent occurrence, whereas corrective action is taken to prevent recurrence. A CAPA should describe the implementation of actions taken to detect and eliminate the cause of an area of non-compliance; it should also prevent the recurrence of non-compliance. As evidenced by the FDA’s reaction to many proposed CAPAs, it is important that the CAPA is written correctly, with those responsible following a defined process, typically taking in the following:

  • stating the problem, including the root cause
  • breaking the solution into discrete measurable actions
  • identifying the person accountable for each action
  • setting achievable deadlines
  • monitoring progress. (Regulatory agencies will expect a CAPA to address each observed inspection deficiency or violation in a complete and transparent way, ie. it should)
  • address the specifics of the inspection findings but also consider potential system-wide or global implications
  • reflect the outcome of the root cause analysis and include, where appropriate, plans to achieve immediate, short and long-term corrections within stated timeframes
  • provide a way to verify and/or monitor the effectiveness of the planned corrective actions
  • include copies of any referenced supporting documents.

Read more contents from CRM Bulletin Issue 8. Download here!

Depending on the extent of the observed deficiencies and their potential to impact upon the study, it may also be necessary to report the inspection findings to other entities such as the affected ethics committee(s)/ institutional review board(s). Again, depending on the nature of the observations, this may require several communications (eg. an immediate report followed by updates as and when more information becomes available and corrective actions are implemented and monitored).

As highlighted above, FDA warning letters usually evaluate the CAPA proposed in response to the Form FDA 483. Common deficiencies in proposed plans include:

  • insufficient detail or inadequate documentation on the specific corrective actions to be taken
  • not addressing why a specific problem occurred or not describing the extent of the problem; quantifying the number of affected studies/subjects may be helpful
  • not describing the preventive measures to be taken
  • not describing the extent/pervasiveness of the problem (ie. how many subjects were affected in the current study and whether the problem extended to other studies)
  • not providing the timeframe in which corrective actions have been or will be undertaken and/or completed.

Source: Clinical Research Advisor/Clinical Quality Assurance – November 23, 2015