Regulatory Inspection

Generally, scope and type of monitoring depends on a study risk profile and complexity, but interim monitoring visits (IMVs) usually occur with 4 to 8 weeks intervals (with the first IM to be performed at each study site soon after the inclusion of the first subject in order to avoid possible systematic mistakes).

As a CRA, I should state that it is a very unusual situation when a CRA responsible for the site has no concerns about the unusual recruitment rate (whether too low or high) at a particular site. If we consider the questions regarding this site’s performance from this week’s DQ assignment, the following can be highlighted:

Even if the first IMV occurred in 3or 4 weeks after the first subject’s randomization and the number of the enrolled subjects at this site was on average for the study at the time of the IMV, the CRA/project management should have earlier paid attention to the facts that:

  • Too many subjects have been enrolled since the first IMV (MS is a relatively rare pathology, and 47 enrolled subjects means that the site is able to identify and include approximately 1 subject each day into the study!). Even in-house the CRA should review copies of screening logs, contact the sites for follow-up, etc. (Cooley, S., 2008).
  • Absence of screen failures alone does not necessarily mean fraud (rather careful pre-screening activities and experience of the site staff), but in conjunction with the high recruitment rate it is suspicious.
  • No documented AEs or SAEs is also a very suspicious, especially if a particular AE is foreseen in the IB and the protocol. It is possible that there have been no SAEs at the site, but taking into account the number of the enrolled patients, some of them should be on investigational drug and experience the expected AEs.
  • Fraud with subjects’ informed consents (especially taking into account the number of consents in question) is a very serious suspicion. The CRA should have described it in the monitoring report and discuss with the Lead CRA (Project Team) his/her concerns. Depending on a CRO/Sponsor’s SOPs a decision to perform additional IMV or internal QA audit may be made.

The following must be clarified and the next steps would be then:

  1. Average enrollment/screen failure/AE and SAE rates at the other study sites.
  2. Performance of Dr. Westbrook’s site in previous studies (if known).
  3. Whether or not study management team deems the site’s performance suspicious.

ACTIONS:

a)      Prompt discussion of the concerns and the upcoming FDA inspection with the LCRA/Team Lead;

b)      Scheduling the IM / QA audit depending on management/Sponsor’s decision;

c)      Notifying the regulatory authorities about the suspected/ confirmed problems (according to MHRA regulations [n.d.] is obligatory within 7 days from the moment when Sponsor was notified,  whereas FDA may conduct inspection upon receipt of a complaint about particular site’s performance or as a response to Sponsor’s concerns, [FDA, 2010]).

CONSEQUENCES (Khosla, R. et al., 2000; MHRA, n.d.):

-        Site’s exclusion from the study;

-        Inspection of site’s performance in all other studies ever conducted by the site;

-        Exclusion of the data generated by the site from the final analysis;

-        A temporary of forever debarment of the PI/site from participation in clinical trials;

-        Legal proceedings;

-        Study statistical power may be significantly affected, and study rescue will require additional time and money expenditures.

 

References:

 

  1. Cooley, S. (2008) Monitoring for Quality: Innovative and Traditional Resources in a Risk-based Monitoring Program [Online]. Available from: http://www.quintiles.com/elements/media/white-papers/white-paper-monitoring-quality.pdf (Accessed: 05 November 2010).
  2. FDA (2010) Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors. FDA Inspections of Clinical Investigators [Online]. Available from: www.fda.gov/downloads/RegulatoryInformation/…/UCM126553.pdf (Accessed: 06 November 2010).
  3. Khosla, R., Verma, D.D., Kapur, A., Khosla, S. (2000) ‘Efficient Source Data Verification’, Indian Journal of Pharmacology, 32, pp.180-186, [Online]. Available from: http://medind.nic.in/ibi/t00/i3/ibit00i3p180.pdf (Accessed: 06 November 2010).
  4. MHRA ( n.d.) New guidance on reporting breaches of Good Clinical Practice (GCP) or the trial protocol [Online]. Available from: http://www.mhra.gov.uk/NewsCentre/CON2030355 (Accessed: 05 November 2010).