An MD&DI May 1998 Column
CDRH's demand for a PMA instead of a 510(k) for a grandfathered indication raises questions about the center's statutory authority.
Is FDA's Center for Devices and Radiological Health exceeding its authority by setting a new standard for a device's grandfathered, pre-1976 indication? Former CDRH Office of Device Evaluation director Robert L. Sheridan, now vice president for marketing submissions at C. L. McIntosh & Associates (Rockville, MD), believes the center has gratuitously and illegally raised the scientific evidence requirements for his client, CryoGen Corp. (San Diego), manufacturer of a cryosurgical probe.
CDRH insists that CryoGen file a premarket approval (PMA) application instead of a 510(k) for permission to label the device for a pre-1976, grandfathered indicationendometrial ablation of the uterusalthough the probe is already labeled for soft-tissue ablation in the uterus and for ablation to treat arrhythmias in the heart. Sheridan argues that this new demand represents an extrastatutory assertion of a new standard for the device on the part of FDA, with echoes of the Myo-tronics case (see "A Troubled Affair" on p. 60 in the January 1998 MD&DI).
FDA officials point out, however, that they have a responsibility to ensure that public safety isn't harmed by the perpetuation of old, grandfathered, and largely undocumented technologies like cryosurgery when newerand by implication safertechnologies have gone through the scientifically rigorous PMA process. As for the CryoGen device's grandfathered endometrial ablation indication, FDA claims the indication was only investigational before 1976, not commercial. CDRH's review management maintains that the new demand for a PMA will put the device's patient outcomes through a strenuous proof of safety and effectiveness to protect public health.
But FDA doesn't have the statutory authority to demand a PMA for a grandfathered indication, counters Sheridan. CryoGen isn't trying to get its advanced, high-tech version of cryosurgery into the market through a back door, he argues; the company is conducting a 200-patient clinical trial under an investigational device exemption (IDE) and will provide FDA with the clinical reassurance the agency says it can't find in the literature for this device. Thus, says Sheridan, the device shouldn't be disqualified from the quicker, easier 510(k) route to market.
The central issue under contention is disarmingly simple. The CryoGen device is approved for general soft-tissue ablation and as an intrauterine probe but not for intrauterine endometrial ablation, a market thought to amount to 700,000 procedures annually in women with menorrhagia (excessive menstrual bleeding). Sheridan and CryoGen say the process falls within the definition of soft-tissue ablation. However, FDA's October 1, 1997, letter of 510(k) approval states, "The use of cryosurgery for endometrial ablation raises new types of safety and effectiveness questions when compared to currently identified predicate devices used for this purpose and therefore will require approval of a PMA for this indication."
CryoGen has failed to convince FDA of the merits of its proposed endometrial indicationmerits which, if the clinical data bear them out, would make the device at least four times as effective as its new, premarket-approved competitors in treating menorrhagia in women who have finished child bearing. CryoGen CEO David Murray claims his company's technologically improved intrauterine probe has superior ablation accuracy because the ice used in cryosurgery can be viewed in real time by sonograph and because it operates under 400 psi of system pressure, compared with 3000 psi for competing argon-gas cryosurgery devicesmaking the CryoGen device much safer in the rare event of product failure.
Far from exciting the staff of CDRH's Division of Reproductive, Abdominal, Ear, Throat, and Radiology Devices, however, CryoGenlike Myo-tronics and several less-celebrated predecessorssays it ran into a wall of bureaucratic indifference, followed by pressure to abandon the 510(k) course in favor of a PMA or a product-development protocol. CryoGen's efforts to overcome this indifference did not meet the open hostility that beset Myo-tronics, but CryoGen still took the avenues of protest that Myo-tronics and others had already traveledletters to Congress and meetings up the chain of command.
Unlike those companies, however, Sheridan took another, innovative, step as well. Instead of seeking a congressional oversight hearing, he decided to work within the system under 21 CFR 10.75, and wrote to FDA interim commissioner Michael Friedman, MD, to request supervisory oversight. His reason was CDRH's refusal during a six-month period "to discuss, or answer correspondence concerning the regulatory issue" of why a PMA is required for a pre-1976 device indication. Friedman passed Sheridan's letter back down to CDRH director Bruce Burlington for response.
On January 23, Burlington wrote to CryoGen saying he had "independently determined that for use in endometrial ablation it is unlikely the CryoGen system can be shown to be substantially equivalent to predicate cryosurgical devices." He did note that the "option of submitting a 510(k) premarket notification for this intended use is not foreclosed to you. If you submit such a notice, we will evaluate its completeness and if found complete will conduct a substantive review of it."
That possibility was the only light in Burlington's letter, which then proceeded to raise new legal, safety, and effectiveness issues. Burlington argued that the grandfathered, pre-1976 endometrial use of the predicate device was only investigational, and that, further, since 1990 the law has demanded that grandfather status be restricted to showing the predicate device manufacturer's intended use.
CryoGen's enlistment of ultrasonographic monitoring for greater ablation accuracy "raises new types of questions of safety and effectiveness," Burlington wrote, without specifying the questions. "These new questions, if not appropriately answered, would deny prospective patients an independent evaluation by FDA of the safety and effectiveness of these devices when used for endometrial ablation. Based on our analysis, the use of this product to achieve endometrial ablation remains investigational, certainly is a significant-risk procedure, and any clinical investigation of this use should be conducted under an IDE approved by FDA."
Noting that such an IDE had been "conditionally approved" a week earlier, Burlington warned the company not to "promote this specific use until you have obtained appropriate premarket authorization from FDA."
On February 23, CryoGen founder and R&D vice president John Dobak, MD, and his vice president for regulatory affairs and quality assurance, Cheryl Shea, met for two hours with a CDRH review team led by supervisory biomedical engineer Colin Pollard to discuss IDE clinical study requirements. They came away more encouraged and hopeful than they had been before, sensing more interest in their product and position.
The law prohibits public discussion of pending applications, so FDA will probably deny that it has had a change of heart. Rather, it will probably say that the company became more compliant or more cooperative. Perhaps CryoGen did. But at the higher levels of FDA, the stony face of the bureaucracy still has not flinched. CryoGen's request for supervisory oversight has not been granted, and its question about FDA's statutory authority to raise the scientific evidence requirement remains unanswered.