Dispute with FDA Over Binding Protocol Agreement Has Medical Device Maker All Tied Up

 Is it fair for CDRH to ignore, at will, a binding protocol agreement (BPA) with a device maker about a pivotal clinical study? A citizen petition filed with FDA in May is alleging that the agency did just that. Mela Sciences (Irvington, NY) is claiming CDRH reviewers changed their minds about a study after reviewing the company’s premarket approval (PMA) submission for a new, potentially life-saving product.

Mela Sciences asks in the petition that the agency honor the BPA, as well as other laws and regulations, in its review of the MelaFind, a skin cancer–detecting device. The move is intended to free the submission from a prolonged review that, despite its so-called expedited status with FDA, has lasted 23 months and counting, according to the company.

“Mela Sciences took extraordinary steps to ensure that the MelaFind PMA would be reviewed in a transparent and efficient manner,” Joseph Gulfo, MD, the company’s president and CEO, said in a statement. “We enrolled more patients into our pivotal study than any prospective trial ever conducted in melanoma detection. We believe we satisfied all of the clinical requirements laid out in the protocol agreement. Even with an expedited review and an urgent unmet medical need for better tools to detect melanoma at its earliest, most curable stages, the FDA’s review of our PMA has extended nearly two years.”

The 34-page petition represents the latest chapter in Mela Sciences’ struggles with CDRH. In March 2011, the company submitted an amendment to its MelaFind PMA that would limit the indication for detecting skin cancer to dermatologists only. The decision to limit the device’s use was in response to comments made at a meeting of FDA’s General and Plastic Surgery Devices advisory panel in November 2010. The panel voted, 8–7, that the benefits of using the device outweighed the risks. The company says it requested a meeting with FDA after the panel meeting, but has not heard back from the agency.

In briefing documents released before the panel meeting, FDA device reviewers indicated that they had significant concerns about MelaFind, especially regarding its indications for use. The reviewers questioned the adequacy of the data submitted, noting that the two protocols involved were observational studies that did not include data about clinical decisions made using MelaFind. The reviewers cited other flaws, including a lack of data about the risks and benefits of MelaFind as compared with standard lesion management of care. The reviewers wanted more studies testing its capabilities when used by doctors on an atypical lesion and more data demonstrating that doctors are able to properly identify atypical lesions that can be diagnosed by MelaFind.

The company describes MelaFind as a noninvasive, objective, multispectral computer vision system. Doctors would use it to evaluate nonacral, nonulcerated, and nonbleeding pigmented cutaneous lesions. The lesions would have to be between 2 and 22 mm in diameter and demonstrate one or more atypical characteristics, such as asymmetry, border irregularity, color variegation, and regression or evolution.

The petition charges that CDRH “repeatedly abrogated” the BPA after Mela Sciences “conducted its pivotal clinical trial in accordance with the agreement.” According to the complaint, the trial revealed that the device had a sensitivity level of 98.3% in detecting possible cases of melanoma. This met the BPA’s sensitivity endpoint of 95% and, according to the complaint, proved the device was capable of providing “statistically significantly greater specificity than clinicians.”

The PMA was submitted in June 2009, and FDA granted it expedited review, according to the complaint, “because MelaFind is a breakthrough technology intended to affect a condition that is life-threatening and irreversibly debilitating.” However, CDRH then changed its mind and abrogated the BPA. The center sent a “not approvable” letter to the company, contending that the study protocol to which it had bound itself did not adequately demonstrate safety and effectiveness. The agency said a new prospective study of a different design was necessary.

The petition contends that this was an illegal departure from the BPA. The company also says it was denied the opportunity to request a PMA review by an advisory panel before FDA sent the action letter. It protested to CDRH director Jeffrey Shuren and was granted an after-the-fact panel hearing, at which the agency “revised the standards for determining safety and effectiveness in an attempt to undermine the statistically significant results of the MelaFind pivotal study.”

According to the petition, FDA was also wrong to claim the company deviated from protocol by failing to include a three-month follow-up group in its study because the BPA stated that including such a group was optional. The company takes issue with FDA’s implied assertion that physician sensitivity should have been measured in the pivotal study because doing so would have required biopsies of all lesions on all patients, which would have likely been “considered unethical and would not be acceptable to institutional review boards.”

The Mela Sciences petition alleges FDA violated other provisions and regulations specified by the Food, Drug, and Cosmetics Act during the PMA review. The company claims FDA did not provide timely feedback based on the center’s interim review of the PMA, thus prejudicing the company in the 100-day meeting. FDA also allegedly failed to provide Mela Sciences with equal access to information submitted to the panel, including a prejudicial letter, and denied the company access to information in advance of the panel meeting.

Reached for comment, FDA press officer Erica Jefferson said the agency had not yet reviewed the petition, adding, “Please note, the company’s application is currently under premarket review with a decision anticipated in the near future.”

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