From The Editor | April 26, 2017

Unintended Con$equences Of FDA Form 483s

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By Bob Marshall, Chief Editor

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Having campaigned for elimination of the front-room/back-room strategy for routine FDA inspections in a recent column, I now think that my regulatory optimism may have been a bit too hasty. I talked with Sandra Maddock, president and CEO of IMARC Research, about trends in clinical research for medical devices, and she opened my eyes to a few very sticky situations with the FDA.

Maddock began her career as a critical care nurse and moved on to become a cardiovascular research coordinator. This latter role provided the spark that spawned IMARC. “I started IMARC in 1999 as a direct result of being a research coordinator at a clinical site. I thought there was likely a better way to monitor a clinical study than what I was experiencing. Seeing the potential for significant improvement was my opportunity,” Maddock explained. Over the past 18 years, she has built an organization that is focused on monitoring and auditing medical device clinical trials.

I asked Maddock about the priorities of IMARC, to which she quickly replied, “making sure that patients are protected and that clinical data has integrity.” Given her experience and the focus of her company, I also wanted to know what she sees as current trends in medical device clinical trials.

“I see a lot more expectation of clinical data for studies that, maybe, in the past, wouldn’t have required so much clinical data. There also is definitely more emphasis on the oversight of clinical trials, and specifically on the monitoring of clinical trials. The industry seems to be taking that very seriously. They are, as an industry, being more conservative in how they approach monitoring and auditing,” Maddock offered. “Interestingly enough, the FDA put a guidance document out on a risk-based approach to monitoring clinical investigations several years ago, and it was meant to help companies prioritize their monitoring efforts. Prioritizing and minimizing the monitoring effort is important, because it’s such an expensive part of running a clinical trial.”

FDA Seems To Be Saying One Thing, But Expecting Another

An article written for one of Med Device Online’s sister sites, Clinical Leader, describes the guidance document Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring as a fundamental shift in clinical trials. But, in Maddock’s opinion, the inspectors and investigators from FDA’s bioresearch monitoring program (BIMO) still are expecting data to be 100-percent monitored. This expectation clearly is not consistent with the guidance document’s intent.

There are several possibilities for this disconnect. Perhaps sponsors and/or contract research organizations (CROs) have not done a good enough job of implementing their risk-based monitoring programs to justify a reduction of the monitoring effort. Perhaps the inspectors and investigators are not on board with the concept of using a risk analysis to reduce the amount of monitoring necessary, or maybe BIMO just didn’t get the memo. This will be a difficult situation to rectify until FDA and BIMO are on the same page. The site under inspection has little leverage to change this.

Unintended Consequences of 483s

Another concern I discussed with Maddock is the number of FDA form 483s being issued to clinical sites, and the questionable nature of many of the associated observations.  When the FDA inspects a clinical site, just as when they inspect a medical device manufacturer, their own manual and training instruct them to record any significant observations on a 483. Further, the FDA website states that “FDA Form 483 does not constitute a final agency determination of whether any condition is in violation of the Food, Drug & Cosmetic Act or any of its relevant regulations.” The disturbing trend that Maddock has noticed is that issuing a 483 seems to be the norm, rather than the exception. She also has observed that many of the findings seem insignificant and, in some cases, the findings are not really even findings, once reviewed in context.

An example of this would be if, during a routine monitoring visit, a patient record was observed indicating a creatinine level of 2.1, when it should have been 1.2. The monitor communicates that the creatinine level was transcribed incorrectly and requests that it be corrected, which it is. Later, during an inspection, a 483 is issued to the site stating that the original data was erroneous and needed to be corrected during a monitoring visit. The data had been corrected prior to the inspection, and the need for the correction had been discovered during a monitoring visit. The process worked. In this type of situation, how would this be a significant observation?

This is a concern for the medical device industry, and especially for CROs. If more 483s are being issued to clinical sites, and the observations reported at those sites are not significant (or they are outright incorrect), this practice can have unintended consequences for the CRO and the medical device company sponsoring the research.

A 483 issued to a site can result in the loss of business for the site or for CROs. In one instance that Maddock shared with me, a clinical site that had a long-standing relationship with a sponsor organization received a letter indicating, “Due to the Form FDA 483 that was issued to your site this year, we have decided to not move forward with your site.” If there were true and significant observations related to the site’s execution and documentation of a clinical trial involving human subjects, the FDA should, by all means, take action. Any consequential loss of business or damage to the site’s reputation would be justified.

In this case though, Maddock, who assisted this site with their 483 letter, indicated that the 483 issued to this site was a compilation of erroneous findings that painted a highly inaccurate picture of the site's abilities to conduct clinical research. The site submitted a response letter with concrete evidence negating each observation, but in the meantime, the site had little recourse to amend this situation.

The expectation of 100-percent monitoring — in light of the risk-based monitoring guidance document and the asserted prevalence of 483s for inspections of clinical sites — has me curious to learn more from our broader audience. Please share in the Comments section below your recent experiences with medical device clinical trials.