What is it about CDRH that — notwithstanding Congressional orders to pursue “least burdensome” approaches — so often causes it to bend or break its own rules? The agency often deals roughly with small companies that have unusual products that don’t easily fit cookie-cutter regulatory approaches.

In the lengthening stream of earlier examples (think neuromuscular dental device maker Myo-Tronics (Kent, WA), external automatic defibrillator maker Laerdal (Wappingers Falls, NY), and neonatal and gynecological monitoring devices maker Utah Medical Products (Midvale, UT), and Bio-Clinical Systems (Anyang City, Korea), all of whom defeated the Center at huge legal cost) now add cranial electrotherapy stimulator maker Electromedical Products International (Mineral Wells, TX), which is still fighting.

There are many others that did not win (think TMJ Implants, driven into bankruptcy over CDRH’s refusal/inability to explain the scientific basis of its decision that its jaw implants caused injuries that must be reported under MDR regulations — or think device gas sterilizer maker Andersen Products (Haw River, NC) driven almost to bankruptcy — or others that gave up just to protect their reputations).

All had one thing in common: they were small (less than 50 employees) and consequently had too much at stake to give in without a fight.

In Electromedical Products International’s (EPI) case, the fight is about whether its only product line, Alpha-Stim, a noninvasive, non-life supporting medical device that’s been on the market for more than 30 years without any serious complaints and is sold over-the-counter everywhere else in the world, should be a Class III device.

CDRH has been bumbling around on this question since 1978, but now shows signs of getting serious. Confronting EPI with the prospect of having to conduct rigorous, well-designed, double-blind clinical studies in more than 50 patients or leave the market, CDRH convened a 14-member meeting of its Neurological Devices Panel in February to consider whether CES devices like Alpha-Stim should stay in Class III or go into Class II as this and other companies have petitioned for.

The devices’ Class III status has been in contention since 1978, CDRH always backing off in a funk, sometimes for a decade or more, when challenged.

Little wonder. Consider the usual and customary characteristics of a Class III device: supports or sustains human life, or is of substantial importance in preventing impairment of human health, or presents a potential, unreasonable risk of illness or injury. CES devices don’t conform to either criterion.

But the 1976 Medical Device Amendments apparently foresaw such situations because they gave the Secretary the non-mandatory option (delegated down in this case to CDRH) to “conduct such activities as may be necessary to develop or obtain” sufficient information to establish a device’s safety and effectiveness.

EPI says CDRH has selectively rejected nearly all of its safety and effectiveness information on Alpha-Stim because the data involved studies in fewer than 50 patients, were not presented in English, were unpublished, or conducted in animals — leaving it reliant on “questionable” 1970s data to which CDRH has applied 2012 review standards.
But the Food, Drug & Cosmetic Act contains an alternative standard for Class III device evaluation: “valid scientific evidence” which the act says “the Secretary may” elect to consider: human experience with a marketed device (more about this in a moment).

A pressingly obvious question at this point is why expend taxpayer resources on demanding Class III for these devices in the first place, given their lack of medical controversy?

CES Devices and Device Classification

A classification panel in 1978 had given as a reason for putting CES devices in Class III its belief that “it is not possible to establish an adequate performance standard for this device because the characteristics of the electrical current necessary for effectiveness are not known. The panel believes that general controls will not provide sufficient control over these characteristics.” It further went on to opine the devices present “a potential unreasonable risk of illness or injury to the patient if the practitioner relies on the device, and it is ineffective in treating the patient's illness.”

CDRH promptly went to sleep on the matter for 15 years. In 1993, it proposed a rule requiring a PMA for the devices, reiterating the classification panel members’ views and presenting no new data about harmful effects or safety. Simultaneously, CDRH rejected imperfect studies presented by sponsors.

The rule was finalized in 1995, but revoked two years later after EPI sued the agency, causing it to briefly convert to full flexibility and admit in the Federal Register that it had “become aware of additional information relevant to the possible reclassification of the CES device from Class III to Class II or Class I.” It then announced that it believed it was “more appropriate” to invoke the procedures under section 515(i) of the Food Drug & Cosmetic Act and issue an order requiring manufacturers of CES devices to submit information on their devices’ safety and effectiveness.

It took CDRH another 14 years to get serious about that. In April, 2009 it published a 515(i) notice that applied to all of the 25 remaining devices, including EPI’s Alpha-Stim, that still held Class III preamendments status “as the first step in the process of final rule-making.” Letters went out giving their makers four months to respond. The Center then slumbered on the issue for another four years until last August, when it snapped back to its original 1978 position, proposing to require PMAs for the CES devices. That’s when EPI and two other CES makers petitioned CDRH for Class II status.

In addition to those petitions, CDRH received over 200 comments, most of which the agency implied were in favor of Class II (FDA as a matter of policy does not discuss comments to its dockets in a vote-counting or popularity contest kind of way, thereby preserving its flexibility to decide against the majority if it should elect to do so).

Lacking its own expertise to evaluate the sponsor petitions, CDRH convened the Neurological Devices Panel (NDP) to consider them. None of the members disclosed “qualified expert status” in CES devices, but they were provided with what EPI calls a biased 83-page CDRH executive summary that argued for Class III status on the same vague grounds the Center had used in 1993.

In an apparent effort to ensure the panel’s acquiescence, CDRH failed to instruct it on the regulatory standard of “valid scientific evidence” they were to apply to the information being considered. At 21 CFR 860.7(c)(2), this is described as “evidence from well-controlled investigation, partially controlled studies and objective trials without match controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use.” (Emphasis added.) This omission by CDRH was deliberate, EPI counsel Larry R. Pilot says, and it misled panel members into thinking that valid scientific evidence did not include marketing experience. This degraded the quality of EPI’s evidence, with one panel member even disparaging it as “testimonials.”

Asked by CDRH whether, based on the available scientific evidence, the probable benefits to health from use of CES for these indications (treatment of insomnia, depression and anxiety) and conditions of use, outweighed the probable risks, most panel members said they did not — although chairman Robert W. Hurst (Hospital of the University of Pennsylvania) qualified that in his summary by observing that several members expressed “reservations due primarily to what appears to be complete lack of safety concerns. Don’t see any safety problems.”

Despite this, the panel voted to keep CES in Class III because there was no showing of effectiveness. EPI vice president Scott Elder attributes that to CDRH’s prejudicial rejection of most of the company’s studies.

As for CDRH’s compilation of CES risks as suggested by unverifiable MAUDE database reports — Worsening of the condition being treated as a result of ineffective treatment, potential adverse effects from electrical stimulation of the brain, potential risk of seizure, skin irritation, headaches, blurred vision — the panel unanimously rejected it as inaccurate and incomplete, agreeing only with skin irritation and headaches and in two cases wanting to add dizziness. CDRH introduced “potential risk of seizure” (a consequence that can be fatal) from MAUDE while admitting that the only reports there involved seizures that occurred before CES was used.

“Roughly eight and one quarter million CES treatment were administered in the past five year by Alpha-Stim alone,” Elder says, “and no one during its 31 years of experience ever reported a seizure.” Of course, that doesn’t mean no one ever will, and CDRH accordingly remains open to that hypothetical possibility.

As in too many other episodes targeting small companies with unusual devices in this most dysfunctional of FDA Centers over the years, here appears another instance of CDRH serial malfeasance. This non-life-sustaining product clearly does not conform to the usual Class III criteria, so the Center seems to have distorted those criteria again and again since 1978 to contrive a fit, and in the process to have broken its own rules for fair conduct in advisory panel consultation.

CDRH does have one friend in its treatment of CES devices. Public Citizen Health Research Group director Sidney Wolfe, who can usually be relied upon to oppose any corporate position, has strongly urged Center director Jeffrey Shuren after the NDP meeting to hold fast to the Center’s Class III decision. When attorney Pilot pointed out the flaws and legal failings in that decision, Wolfe declined to alter HRG’s position, saying it was based on “publicly available material.”

So like so many small companies before it when confronted with CDRH wrong-headedness, EPI faces significant and unnecessary hardship on the road ahead — in its case, the expense of conducting — as Wolfe expressed it — “rigorous, well-designed, controlled, double-blind” clinical trials if it wants to keep Alpha-Stim on the U.S. market.
Whatever became of the 12-year-old statutory requirement for CDRH to pursue the “least burdensome” approach mandated by Congress to regulating device companies?

In the aftermath of last year’s uproar over the dysfunctional 510(k) program at CDRH, to say nothing of its incapacity to curb marketing abuses by the out-of-control LASIK eye surgery industry or to protect consumers from mercury exposure in dental amalgams, it’s past time for a top-to-bottom rebuild there, with a top priority on its internal culture.