Coast IRB, an independent institutional review board (IRB) based in Colorado Springs, Colo., received a Warning Letter from the U.S. Food and Drug Administration (FDA) concerning the company’s improper expedited review of a phase I study being conducted in northern California. In an unusual move, the agency has temporarily suspended the IRB’s ability to do expedited reviews.

An FDA Warning Letter is quite rare among independent or central IRBs with perhaps one or two issued in a single year. Warning letters to institutional review boards in hospitals or academic settings are more numerous, with the FDA issuing six per year on average.

Coast’s warning letter stemmed from an FDA audit conducted between July 10 and 18, 2007. IRBs are subject to such standard audits every five years. The FDA subsequently reported its inspection findings to the company in a standard Form FDA 483.

“We were surprised to get it. We thought we had adequately responded to the FDA. Obviously the FDA had a different view on that,” said Gary King, general counsel for Coast.

Although Coast stated it has taken steps to minimize any disruption in its business, by adding review boards and holding more frequent meetings, not having the ability to do expedited reviews will no doubt put stress on the company.

“That is going to be a tremendous burden because there is a huge amount of work that is done via expedited review. And these can be as minor as a change of a comma to a semicolon on a consent form,” said David Vulcano, vice-chairman, board of trustees of the Association of Clinical Research Professionals (ACRP). Vulcano has researched IRB issues extensively, including warning letters.

Coast’s responses to that inspection letter were submitted in August and November 2007; however, they have not been made publicly available. According to the FDA, the company failed to address its concerns in their responses, prompting the agency’s action.

“Obviously at the time we believed it was adequate, or we wouldn’t have submitted it to the FDA. The FDA disagreed, and we’ve taken their comments to heart,” said King.

According to the warning letter, Coast approved a recruitment advertisement that the IRB board had rejected, deeming it “coercive in nature.” Coast confirmed that the issue with the advertisement centered on the language used to

describe patient compensation to enroll in the study. Coast’s board rejected the sponsor’s ad on three separate occasions and attempted to change its language in such a way that both parties would find it acceptable.

In addition, the warning letter stated that Coast’s chief executive officer, Darren McDaniel, then appointed a new member to the company’s board and instructed him to conduct the expedited review independently from the rest of its members. It stated that not only did the ad’s approval fail to qualify for expedited review based on FDA criteria but also that the unidentified member “lacked the requisite relevant experience to conduct expedited review on behalf of the IRB.” According to FDA regulations [21 CFR 56.11O (b)], McDaniel lacked the authority to designate anyone to conduct an expedited review. That ability is only permissible by the IRB’s chairperson.

A particularly troublesome issue is that according to the FDA, none of the other board members interviewed were aware of the ad’s expedited review and that McDaniel stated he was unaware of the board’s previous rejections.

“Despite the full board’s consideration of this matter at three previous meetings, documentation of the disapprovals in the minutes of both March 8 and 15, and e-mails that indicate otherwise, you stated that you were unaware of the Board’s decisions on this matter,” the FDA Warning Letter stated.

Vulcano keeps a close eye on the IRB sector and has researched and presented extensively on various IRB issues. He recently analyzed 32 IRB warning letters issued from 2000 to 2006. Vulcano found that only 28% of IRB warning letters contained violations concerning expedited review.

“In and of itself, an improper expedited review on an advertisement is usually not warning [letter] material, maybe a Form 483 but not a warning letter. But if the FDA is not happy with your response to their 483, then you’ll likely get a warning letter. That is an overall theme when analyzing warning letters,” explained Vulcano.

Given the recent clamor for more oversight of clinical trials and on drug safety in general, some may see the FDA’s recent actions as a trend towards increased IRB scrutiny.

Vulcano disagrees. “I think the FDA is going to follow through with its audit responsibilities, as it has always done. It may just be the case where more and more work is being done by central IRBs and so therefore your chances of getting an audit that isn’t going to go well go up, a simple matter of statistics,” said Vulcano.

Coast’s written response to its warning letter will not be submitted to the FDA until April 16, but King said, “Frankly I believe that, between some missteps and miscommunications, we instituted an expedited review that really wasn’t a well advised move on the part of Coast. In hindsight, I would tell you that we shouldn’t have done it and everyone acknowledges that we should not have done it,” said King.

King stated that the company is complying with the terms of the warning letter and is also making some procedural changes “above and beyond” what is required by the FDA to prevent future violations.

“We want to make sure that we are taking this opportunity to learn from this and make sure that we are communicating that to the FDA. This is an industry that absolutely has to have the public’s trust and the FDA has a very difficult and very important job in making sure that trust is justified,” said King.