Jul 28 2011

Imaginary patients, Imaginary data, et Cetero, et Cetero…

Cetero Research

Image via www.cetero.com

The FDA recently issued a letter to a CRO based in Cary, NC, outlining serious violations at one of their facilities including “widespread falsification of dates and times in laboratory records… and the apparent manipulation of equilibration samples to meet predetermined acceptance criteria.”  This letter is a follow-up to two on-site audits, conducted as a result of a whistleblower complaint, in December 2010 and May 2011 that each resulted in a 483.  Basically, the FDA feels that the CRO’s response to the allegations is inadequate and suggests that the data from multiple studies is irrevocably tainted.  Not only will this cost the sponsors of those trials significant time and money, there are cases where negligence or misconduct could impact patient safety.

Both study sponsors and CROs owe it to everyone involved to be vigilant in all aspects of their business for any suspected fraud or other ethical violation.  We shouldn’t just pay lip service to these issues by creating SOPs — we should actively use them to ensure that clinical data is of the highest integrity.  While I recognize that there is a continual trade-off between cost, time and quality, there are some obvious steps that we can take to minimize the risk of problems.

Before selecting any investigator (or if there’s an investigator change), spend a few minutes with the FDA’s list of the audits they have performed and their lists of restricted/disqualified/debarred investigators.   You can also easily search for FDA warning letters sent to CROs, investigators or other vendor companies (see my colleague’s post for more on warning letters).  Don’t forget to check on your IRB as well, and to verify any medical licenses or other certifications.

Before selecting your CRO (any CRO, including your pre-clinical CRO), your Phase 1 unit, or any study site, I recommend an audit.  You want to see some of their SOPs, check on how they implement them, and review some training records for key staff.  You’ll also want to think about taking a closer look at your CTM-related  vendors, your central lab, and your EDC vendor.  Alternatively, if you are using a CRO that has preferred vendors for some services, you can ask them about the last time they audited their providers.

In my experience, it seems that many ‘anomalies’ found at sites are minor protocol violations, documentation mistakes or errors due to lack of experience and training by site personnel.  Training – CRA training, investigator meeting training, and on-site training – is a direct investment in data quality and patient safety but too often nominated for the chopping block when something has to go to reduce costs.

During the conduct of non-clinical studies, having a non-clinical expert at the nonclinical laboratory monitor the study is critical to getting good data.  Ensuring that the CTM is mixed properly, the dosing protocol is followed, etc. is much easier done in person and in real time, rather than after a study is completed.  The little time and money saved when not having a nonclinical expert on site at the beginning of a study can cost much more time and effort trying to figure out how to analyze and explain bad data.

During study conduct, clinical sites should be visited regularly by qualified monitors to verify data, review informed consents and other regulatory documents, and perform drug accountability.  In addition to regular monitoring visits, occasional co-monitoring with an experienced lead CRA can help identify and resolve potential issues.  There are many examples where thorough monitoring has uncovered fraud such as the enrollment of imaginary patients or falsification of informed consent forms or medical record.

One of the most well-known trial misconduct cases is that of a late stage study evaluating an antibiotic where a physician enrolled 400 or so imaginary patients and reported an unheard of 0% drop-out rate.  When a monitor reviewed the data, she was alarmed by the obvious discrepancies and promptly reported her findings.  The warning letter sent to the study sponsor is still available on the FDA website.  It describes findings such as an overall lack of source documentation, missing or modification of data such as dates, times, and adverse events, multiple IVRS randomization calls at odd times, and informed consent issues, among others.  This case clearly illustrates the importance of regular site monitoring visits for all clinical trials, and vigilance throughout the clinical development process.

I don’t believe that fraud is widespread in our industry but it can damage the perception of drug development as well as directly impact patient safety.  We owe it to everyone to stay aware.

This is a post by Annabel Bower, M.B.A.  Annabel is the Director of Business Development Strategy and Operations at Cato Research.