Public censure of FDA's device center is escalating, but former Office of Device Evaluation staffers who spoke to "The Gray Sheet" paint a different picture of the review process than the corrupt image that has surfaced in recent months.

"It does not reflect the reality of the office that I know," said Miriam Provost, former ODE deputy director for science and engineering review.

Nine current CDRH staffers (who remain anonymous, though it is believed at least some work or worked in the radiological devices review branch), are calling for the removal of all center managers.

Their allegations were detailed in an ¹ October 2008 letter to Rep. John Dingell, D-Mich., and a ² Jan. 7 communication to President Obama's transition team; the letters followed what the writers feel was an insufficient response from just-departed FDA Commissioner Andrew von Eschenbach (³ Also see "CDRH Staffers To Obama: House Cleaning Urgent At Device Center" - Medtech Insight, 12 January, 2009., p. 7).

The whistleblowers charge ODE and center leadership with ordering or intimidating staff reviewers to modify scientific evaluations, conclusions and recommendations. They also say mangers have accepted data that is not scientifically valid, ordered scientists to ignore FDA guidance documents, and allowed false statements in agency documents, among other complaints.

On Jan. 27, the New York Times wrote an editorial criticizing CDRH and calling for a "major overhaul" of FDA.

Staffers inside CDRH are not talking about the matter publicly. FDA's press office says the agency takes the charges seriously and is investigating.

Proper Dispute Process Followed - Former Staffers

But two scientists who recently left CDRH for the consulting world are perplexed by the allegations, which they say don't jive with their experience of the review process.

Provost left FDA in 2007 after 13 years and is now with Alexandria, Va.-based Biologics Consulting Group. She previously served as an ODE division director, branch chief and reviewer.

"There is no reason for an ODE manager to coerce or intimidate, or any of those words the letter writers used," she said. "There is no need to do that, because the process allows for managers to overturn. It is the way the process works."

Glenn Stiegman, VP of regulatory affairs for Musculoskeletal Clinical Regulatory Advisers, agrees. "I think this is an isolated event," said the former ODE orthopedic devices branch chief and reviewer. He left the agency in 2006 after six years with CDRH.

"The level of frustration being voiced by this isolated group of employees can't be generalized across the whole ODE because I never experienced anything of that nature whatsoever," he said.

Both Provost and Stiegman point to a 1993 ⁴ Blue Book memo, an internal ODE guidance for documenting and resolving differences of opinion on product evaluation, as an accurate reflection of how things work in practice.

"Reviewers are never told that they have to change their mind or change their view or change their opinion," Provost stressed. "They are always allowed to document whatever their recommendation is, but it is just a recommendation. That is the way the process works. The decision is finally made by people higher than the reviewer level."

The Blue Book memo stresses the importance of consensus development among reviewers, supervisors and management so that an "institutional position on the application can be reached." If there is no consensus, "resolution of differences by management is necessary," it says.

The memo states that the lead reviewer for an application has final responsibility for the initial review, though he or she is encouraged to consult with a supervisor and other colleagues. "In the event of a disagreement, however, the supervisor may not order a draft review to be changed," the memo says.

Following the review, it is up to the branch chief to concur with the conclusions - which can then get sign-off by a division director for a final decision - or to disagree.

If the branch chief can't concur, he or she "must discuss this with the reviewer," the memo says. If differences cannot be bridged, the matter must be forwarded to the division director, who is instructed to meet with the reviewer and the supervisor and to evaluate the entire review package.

It falls to the division head to make a final decision. If the issues to be resolved do not involve "substantive scientific aspects" of the review, the director "may render a decision and merely make an appropriate supporting notation," the memo says.

But if the director ultimately elects to not accept or to act against the reviewer's recommendations on substantive scientific matters, he or she must write a memo overturning the reviewer recommendation and explaining his rationale.

Provost said it is rare for disputes to get to this level or higher, but it happens.

One notable example involves Cyberonics' PMA for its VNS Therapy neurostimulation device for treatment-resistant depression, approved in 2005. In that case, as detailed in an investigation by the Senate Finance Committee, Center Director Dan Schultz approved the product after overruling more than 20 FDA staff members who had concluded that the company's data did not meet reasonable standards for safety and effectiveness (⁵ Also see "Schultz’ Controversial Approval Of Cyberonics Device Has Little Precedent" - Medtech Insight, 27 February, 2006., p. 4).

But Provost said it would be wrong to conclude that because there is a formal dispute or overturned decision, that it means reviewers' input was not taken seriously.

"We would have meetings and everyone would sit around and talk about it," she said. "And people had their opinions and some people had strong opinions. So there is definitely an environment where discussion is accepted and, in fact, is expected."

Dissent May Include Displeasure With 510(k)s

Neither Provost nor Stiegman know who the letter writers are and they did not perceive during their time at the agency the level of discontent portrayed in the communications.

"Things seemed to run fairly smoothly across the whole office," Stiegman said. "Certainly a scenario like this was never seen or heard about."

Provost believes the issue relates in part to disagreements over proper use of the 510(k) process. "When I read between the lines in these letters, that is a lot of what this sounds like to me: somebody who does not like the 510(k) program."

In other words, she suggests, reviewers may favor requiring additional studies beyond what was employed in prior instances to prove substantial equivalence.

She worries that some scientists are trying to change the standards on an application-by-application basis, rather than through rulemaking and guidance.

"Individual reviewers can't decide on their own what the review standards are for each submission," Provost said. "That is just not the way the program works. It has to be administered in a fair way. Otherwise, as a regulatory agency, FDA would be arbitrary and capricious."

Provost believes strongly that the 510(k) process is working well to ensure that products reaching the market are safe. "Working at FDA and knowing the people at FDA like I do, I can tell you that they would not approve a device if they had evidence that it was not safe," she said.

Reform Momentum Picking Up

Nonetheless, the scientists' allegations make it more likely that a new FDA commissioner, yet to be named, will make changes at CDRH.

"One of the first priorities of the new FDA commissioner I think should be to set a tone that the scientific standards will be rigorous, and that coercion within the agency will be unacceptable," said Peter Lurie of Public Citizen's Health Research Group.

The whistleblower charges are also fueling congressional interest in legislating reforms, particularly to the 510(k) program.

On Jan. 28, Rep. Frank Pallone, D-N.J., chairman of the House Energy and Commerce Subcommittee on Health, announced he will hold hearings on "glaring inadequacies" at FDA, "starting with medical devices."

Critics of the 510(k) program point to a recent Government Accountability Office ⁶ report to buttress claims that high-risk, complex devices are going to market without sufficient reviews of effectiveness and safety.

In the report, GAO urges FDA to quickly review and definitively classify the 20 types of pre-amendments devices that are still listed as Class III (high risk) products but reviewed via 510(k).

GAO did not find, however, that products with new intended uses or new technological features were, by and large, being inappropriately reviewed as 510(k)s, nor did it recommend fundamental changes to the 510(k) program (⁷ Also see "GAO Report On 510(k) Program Calls For Regulations On 20 Device Types" - Medtech Insight, 19 January, 2009., p. 3).

But Diana Zuckerman, president of the National Research Center for Women & Families and a vocal critic of CDRH, looks skeptically at the GAO report in the context of the whistleblowers' letters.

The Jan. 7 letter says managers coerced "FDA experts to modify scientific evaluations, conclusions and recommendations in violation of the laws." It also charges ODE Director Donna Bea Tillman with "knowingly allow[ing] her subordinates to issue written threats of disciplinary action if physicians and scientists failed to change their scientific opinions and recommendations to conform to those of management."

Zuckerman reads this as alleging that scientists were pressured to actually change the written contents of their reviews, which, she says, could call into question the findings of the GAO report, which relied on FDA pre-market review documents.

"What I have heard, and what would certainly be consistent with the letter from the scientists, is that you can't necessarily assume that just because any written documentation says that 'this is not a new technology,' that that is true," she said in an interview.

"It is one thing if the scientists write down what they believe and the supervisors disagree with them," Zuckerman notes. "It is another thing when their supervisors say, 'You have to change what you wrote down because I don't like it.'"

- David Filmore (d.filmore@elsevier.com)

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