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Top management at FDA is being accused of corruption by scientists in a letter. It says that managers interfered with scientists responsibilities to ensure the safety and efficacy of medical devices. According to the letter, “misconduct reaches the highest levels of CDRH management including the Center Director and Director of the ODE.”

The accusations of coercion and intimidation have led Representatives John Dingell (D-MI) and Bart Stupak (D-MI) of the House Energy and Commerce Committee to begin a congressional investigation. They believe FDA experts were “ordered, intimidated, and coerced” to modify scientific reviews, conclusions, and recommendations on devices. The scientists claim they were forced to accept data that wasn’t scientifically valid.

Bloomberg News says that the scientists reported their concerns to von Eschenbach in May. While the agency’s assistant commissioner for integrity and accountability, William McConagha, found “convincing” evidence to support the allegations, no action has been taken, according to Dingell and Stupak.

Look for more on this developing story in the Washington Wrap-Up section of MD&DI’s January issue.

Story from devicelink.com.

With the advent of the Obama administration and a newly recharged Democrat-run Congress, The Gray Sheet is predicting an increase in user fees and a more active FDA. Industry experts speculate on how and why such changes may come about. The full article is reprinted below:

The general expectation is that health care reform under the new administration will hinge around controlling costs and increasing access to care. A continued push for comparative-effective research is almost certain to be part of the picture.

On the regulatory front, the next four years could mean a better funded and more active FDA, with a strong focus on product safety.

“There has certainly been consensus among Democrats and Democratic policy-makers that FDA has failed to live up to expectations and hasn’t aggressively addressed laws on the books on the pre-market side and post-market side,” said John Manthei, a partner at the law firm Latham & Watkins and former majority counsel to the House Energy and Commerce Committee.

“We should fully expect to see a much more aggressive FDA as we move into 2009.”

The next Congress will likely look to new device and drug industry user fees as a way to increase FDA funding, Manthei predicted. Democratic lawmakers agree that FDA needs more resources, but given other Obama administration priorities and the huge federal sums already poured into the financial bailout plan, increased FDA appropriations could be hard to come by, he noted.

“There’s going to be a lot of competition for those funds, which makes the user fee much more appealing,” Manthei said.

For device companies, new fees are likely to come in the form of a user fee for manufacturing inspections (1″The Gray Sheet” May 12, 2008, p. 4).

The idea appeared earlier this year in House and Senate import safety bills that would have imposed an annual registration fee on device companies with foreign facilities; the fees would have been used to support more frequent FDA inspections of overseas manufacturing operations.

Those bills didn’t gain momentum this year, but the proposal could be revived in the 111 Congress. A House Energy and Commerce Committee aide said Nov. 6 that committee leaders plan to introduce their version of the import bill “as quickly as possible” next year.

But new user fees would face industry opposition, particularly from smaller device companies, noted Manthei, who serves as outside counsel for the Medical Device Manufacturers Association (MDMA).

“The industry agreed to double its user fee contribution under the second installment of user fees under the 2007 FDA Amendments Act,” MDMA Executive Director Mark Leahey said. “To expect the device industry to fund more of the agency is unrealistic,” he added. “We can’t afford to subsidize more of the FDA in fees.”

MDMA supports expanded FDA authority overseas, but opposes any additional fees, Leahey said. “Any additional resources must come from congressional appropriations.”

Improving FDA’s foreign inspections program has also been flagged as a priority by the Government Accountability Office. GAO launched a new 2Web site Nov. 6 designed to inform the incoming administration: “3GAO Transition Site” of urgent issues needing to be addressed.

Congressional Oversight Will Shift To Industry

Manthei also predicted that the aggressive oversight seen in the recent Congress will shift from FDA to industry, with a Democratic Congress uninterested in calling Obama appointees to task.

“I think oversight of FDA is going to come to an immediate halt this January,” he said. “This time, industry will be in the congressional crosshairs.”

In particular, industry will be scrutinized for its performance on product safety issues, and its willingness to be “forthcoming” with FDA with safety data, Manthei suggested.

Device firms should also expect to see more FDA-related legislation, attorney Manthei said.

“Industry kind of fell within a comfort zone that amendments to the FDA authorizing statute would largely occur about once every five years, in conjunction with the reauthorization of the prescription drug user fee act and the medical device user fee act,” he said. “Those days are over.”

“Industry should fully expect and be prepared that FDA legislation now may become an annual event.”

Off-label promotion issues are also likely to receive attention in the coming Congress. House Oversight and Government Reform Committee Chair Henry Waxman, D-Calif., vigorously opposes FDA draft guidance on industry distribution of journal articles that describe off-label product uses, charging that the guidance gives industry a free pass to promote products for off-label uses (4″The Gray Sheet” Sept. 15, 2008, p. 8).

“I would not be surprised for Congressman Waxman to make that a priority, and for that guidance document to potentially be pulled,” Manthei said.

Waxman has also fought against federal pre-emption defenses in product liability lawsuits, and could push legislation to overturn the industry-backed policy of PMA pre-emption affirmed for medical devices in a Supreme Court case earlier this year (5″The Gray Sheet” March 24, 2008, p. 19).

Waxman’s work on these and other device post-market issues is expected to continue regardless of whether he stays at the top of the oversight panel or succeeds in wresting control of the Energy and Commerce Committee from fellow FDA reformer John Dingell, D-Mich..

Stronger FDA, But Under Whose Leadership?

While industry observers began speculating last week on who might be the next FDA commissioner, that nomination will probably not come until after key Cabinet appointments are announced.

Nevertheless, “it’s too important of a position, and I would expect the nomination process to happen shortly after the beginning of 2009,” Manthei said.

Among the names being bandied about are Cleveland Clinic’s Steve Nissen, Harvard` University’s David Blumenthal, George Washington University’s Susan Wood, Duke University’s Robert Califf, and Medtronic’s Susan Alpert.

Nissen, chair of Cleveland Clinic’s department of cardiovascular medicine and a sometimes aggressive critic of drug and device companies and FDA, periodically serves on FDA advisory committees and is already an official adviser to the Obama campaign. Blumenthal, director of Massachusetts General Hospital’s Institute for Health Policy, was a major contributor to the Obama health plan. Wood, former head of FDA’s Office of Women’s Health, is now a research professor at GW’s School of Public Health.

Califf is co-chair of the public/private Clinical Trials Transformation Initiative and also has advised FDA panels, but has close ties to the drug industry. Alpert joined Medtronic as chief quality and regulatory officer after decades at FDA, including six years as director of the Office of Device Evaluation. But Senate HELP Committee Chairman Edward Kennedy, D-Mass., has in the past voiced opposition to having an industry person atop FDA.

“That obviously is going to eliminate a number of potentially very qualified candidates,” Manthei said.

Comparative Effectiveness Comparatively Likely

President-elect Obama championed comparative-effectiveness research during his campaign, and the idea is likely to be thoroughly debated as Congress gets serious about health care reform next year.

Obama said that, as president, he would create an institute to guide reviews and research on the comparative effectiveness of alternative diagnostic and therapeutic interventions “The Gray Sheet” Oct. 20, 2008, p. 3). The findings would be incorporated into practice guidelines, standards and other evidence-based tools for doctors and patients.

The device industry supports creating a branch within the Agency for Healthcare Research and Quality to conduct comparative-effectiveness research, AdvaMed Senior Executive VP David Nexon told “The Gray Sheet” in a Sept. 2 interview.

“But we’d be concerned if it became a device for denying people coverage of cost-effective treatment,” Nexon added. “That’s something we’d want to watch.”

The House Ways and Means Committee sees comparative effectiveness legislation as “a big ticket item coming through the committee” next year, said Dan Elling, Republican staff director for Ranking Member Jim McCrery, R-La.

“There’s a lot of interest in it on both sides of the aisle, because we need to get a better handle on how we are getting our money’s worth out of the Medicare program,” Elling said Nov. 5.

“We [have to have] a good idea about what is going to be the most effective form of treatment - i.e., if it is going to be drug versus drug, or a device versus a drug, or a device versus some other sort of surgery - and looking at those sorts of things is something that both parties are interested in,” Elling added.

Meanwhile, in the Senate, Max Baucus, D-Mont., said Nov. 7 that he will unveil a new white paper, entitled “Call To Action: Health Reform 2009,” detailing goals and policy options for comprehensive health care reform. The paper is likely to include comparative effectiveness as a way to “reform the delivery of health care for efficiency and quality,” Baucus said.

In August, Baucus co-sponsored with Budget Committee Chairman Kent Conrad, D-N.D., the Comparative Effectiveness Research Act of 2008 to create a $300 million institute to review evidence and produce information on treatments to achieve the best clinical outcome for patients.

- Jessica Bylander and Sue Darcey

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FDA has selected Jonathan Sackner-Bernstein, MD, chief medical officer of contract research organization Clinilabs, as CDRH’s new associate director for postmarket operations. Since Sept. 2, he has been overseeing the center’s recently created matrix structure, which comprises 13 networks each responsible for a specific product category or activity.

“Each network brings together experts from various functional areas within the center, spanning premarket review to compliance and postmarket surveillance, forming cohesive groups focusing a wide variety of expertise on identifying, analyzing, and acting on specific postmarket issues,” an agency statement said.

“Dr. Sackner-Bernstein will supervise the work of the networks by providing clear direction and priorities, fostering the development of a common vision, and clarifying roles and responsibilities. As a member of the center’s senior leadership team, he will also act as a liaison between the networks and senior center management.”

Sackner-Bernstein previously served on CDER’s Cardiovascular and Renal Drugs Advisory Panel and CDRH’s Dispute Resolution Panel.

—James G. Dickinson

As you might expect, ever since the Vioxx and Guidant issues, FDA Commissioner Andrew von Eschenbach often gets asked whether FDA has tightened its approval standards. In a column on FDA’s Web site, he provides his answer: no. “FDA has not changed its philosophy or its standards for medical product approval, and is in fact engaged in a rigorous process improvement effort to make the regulatory pathway more efficient, transparent and, yes, more rapid,” he writes. But, he adds, FDA realizes that no drug or medical device can ever be 100% risk-free, so the agency has put and continues to put systems in place, both at the premarket and postmarket stages, that allow it to better understand and identify the risks. Its mission, to both protect and promote the public health, and to make sure that new medical products get to the market as quickly as possible once it can be determined that they are safe and effective, remains.

CDRH has launched CDRH Learn, a Web site for online education of industry. It consists of a series of training modules describing many aspects of medical device and radiological health regulation, covering both premarket and postmarket issues. This tool is intended to provide the medical device and radiological health industry with an information resource that is comprehensive, interactive, and easily accessible.

The first two courses are an overview of medical device regulatory requirements and an introduction to the Quality System Regulation.

A 510(k) benchmarking survey on submission and clearance practices found that even as FDA transitions to electronic filing, most device firms have not relinquished paper-based systems.

The survey, conducted jointly by Compliance-Alliance LLC and Certified Compliance Solutions, found that an overwhelming majority (84%) had never filed a 510(k) submission electronically. Half the respondents who had used FDA’s automatic tools for electronic 510(k) submissions said that the tools made submission easier, while the other half said the tools made filing more complicated. Among the survey’s findings are the following:

* Most companies received clearance in 120 days or less.
* Most firms do not use a third-party reviewer for 510(k) submissions.
* FDA requests additional data for at least 89% of submissions.
* The majority of companies submit five or fewer 510(k)s annually.

Some companies do not market products subject to 510(k). But 31% of those respondents intended to use the cleared product as a predicate for a future submission.

In comparison with clearance methods used by other countries, 62% of respondents thought the FDA 510(k) process was more complex, but most said it also was appropriate to ensure safety. Firms generally thought that the agency’s review and the questions therein were appropriate. About one-third of respondents either thought that FDA asked for information beyond what is required or asked questions that were beyond the scope of equivalence.

In submitting a new 510(k) for a device modification, about two-thirds of respondents cited change in the indications for use as the primary reason. The other most common reason was evolution of the device’s functionality.

Conducted in June 2008, the survey had 235 respondents representing a variety of large, medium, and small device firms. For more information about the survey, visit www.compliance-alliance.com.

– Lawrence Lloyd

The 510(k) process has been used to clear about 90% of medical devices for U.S. marketing since its inception in 1976. Yet to many outside the medical device industry, and even to some within the industry, the process is not well understood. So in August, AdvaMed released a white paper explaining the history of the 510(k) process and how it works.

It concludes that the 510(k) process is “an appropriate and effective regulatory approach for the vast majority of medical devices” because it allows “patients to have access to essential lifesaving, life-enhancing, safe medical technology in a timely fashion.”

In the mainstream media, there is often commentary about how most medical devices do not undergo the same level of regulatory scrutiny as drugs, with the implication being that this is a bad thing. But, the report says, the 510(k) process “is of critical importance in ensuring that medical devices are neither underregulated nor overregulated.” This is not an easy thing to accomplish, considering that about 3500 products go through the 510(k) process each year.

Because the world of medical devices encompasses so many different products and technologies, it doesn’t make sense to have them all evaluated the same way, the report states. Rather, appropriate scientific evaluation methods differ depending on the type of device, and the level of risk it presents.

“Were every medical device subject to the rigorous PMA process, there would be very few new and innovative medical devices entering the market and few or no improvements to marketed devices,” the report states.

The report provides a history of how the Medical Device Amendments Act of 1976 was created and what the rationale was for setting up the 510(k) process as part of that law. In particular, those who shaped the law understood that it did not make sense to hold most devices to the same evidentiary standards for safety and effectiveness as drugs. Part of the reason was that they understood that the medical device innovation process was quite a bit different from that for drugs. Devices have much shorter life cycles, and their manufacturers frequently produce new versions based on feedback from users and real-world data.

The report also debunks four myths about the 510(k) process. The first myth is that “substantial equivalence” means showing a new device is similar to one on the market before May 1976. In fact, most of today’s 510(k) devices show equivalence to state-of-the-art products. And a device cannot be considered substantially equivalent to a product that has been removed from the market or found to be adulterated or misbranded.

The second myth is that the 510(k) program is just a “quick and easy way” for device makers to get their products on the market. In fact, it is not uncommon for review times to exceed 90 days, especially if the application includes significant changes in technology or in intended use. And only the simplest of devices are cleared based on a comparison of specifications. More devices are cleared based on nonclinical testing; about 8% of 510(k) clearances involve clinical data. All must have gone through the design control process, which includes risk analysis.

The third myth is that device malfunctions and patient injuries result from 510(k) devices. The reality, the report states, is that many of the products cited in those arguments were faulty because of manufacturing problems. Those problems cannot be detected in paper reviews, whether PMA or 510(k). Instead, they are detected when a firm’s quality system is inspected. Nor can premarket clinical evaluation, whether PMA or 510(k), predict every problem that might occur when a device hits the market.

The fourth myth is that the 510(k) third-party review program is just a means for manufacturers to avoid FDA review. In fact, third-party reviews are no less rigorous than those done by the Office of Device Evaluation (ODE). They are performed more quickly because they are not sitting in a queue at ODE. And FDA does not have to accept the third-party reviewer’s decision.

The full report can be seen at www.advamed.org

– Erik Swain

When it comes to enforcement actions against regulated industry, FDA has a “blank check” and keeps no records related to resource expenditures, either monetary or employee time. This is the conclusion to be drawn from three recent and uniform agency responses to Freedom of Information Act (FOIA) requests for documentation on resources expended in two controversial enforcement actions. They are the 2005 federal court QSR/GMP loss to Utah Medical Products (Midvale, UT), and its four-year-old ongoing MDR case against TMJI (see previous story).

The first response, reported here last month, came from Office of Chief Counsel deputy chief counsel for program review Ann Wion. She said her office had “no responsive record” to my request for “legal expense summary documents showing accumulative dollar amounts and full-time equivalent (FTE) employee resources expended in all regulatory enforcement activities and [civil money penalties] litigation against [company] …”

Subsequent inquiries revealed that, as in all other government agencies, such attorney work product records have been shielded forever from public access since a 1983 Supreme Court ruling. Nevertheless, I still await a Department of Justice response to my request for a cost accounting of its expenses in these cases.

Meanwhile, trying another tack, I broadened and revised my request at FDA to exclude attorney work product. It now encompasses “estimates of inspection time, investigation time, compliance officer time, center review time, and Office of Chief Counsel review time, expressed in both dollar and FTE terms, for FDA work performed in preparing compliance and enforcement action, exclusive of actual litigation expense, against” Utah Medical and TMJI.

In due course, I again received a neg-ative response from Wion, advising “we have no responsive records from the Office of Chief Counsel.” I also received one from CDRH Freedom of Information Branch officer Joy Lazaroff, saying that “we did not find the requested records.” She added that such information “is not maintained” by CDRH and that this was a partial response; other unnamed FDA components would separately respond. Presumably one of those was Wion’s office.

Another component might be FDA’s Denver district office, where the inspections of both Utah Medical and TMJI were based. Colleague John Scharmann, a former Denver district director himself, advised me that field investigators do make out time sheets regarding their inspections, and report travel and other inspection-related expenses that might be accessible under FOIA. I immediately submitted a request for those documents.

Scharmann doesn’t believe similar records are kept for employees in other parts of FDA. This impression is reinforced by a former FDA headquarters official who added that he believes FDA should adopt a cost-accounting approach for employee time, so that answers can be given for such questions as, “What is the cost of each action that FDA takes? For example, what is the cost of a warning letter or seizure or litigation from start to finish? I don’t think FDA exercises that kind of accountability at the present time. The question is, why not? How are they accounting for resources—especially when they continually say that the agency does not have enough resources?”

– James G. Dickinson

The convergence of medical devices, pharmaceuticals, and biologics has been under way for a few years now, and it is creating new challenges in these related but separate industries. Converging areas such as genomics, proteomics, and nanotechnology have created new diagnostic and therapeutic possibilities. Moreover, they have presented a new avenue for product innovation and an opportunity for the development of more personalized medicine.

That shift, of course, brings changes that are akin to starting a new company. Companies that venture into the converging world of combination products must take an integrated approach to defining their strategy, their development process, and their company’s organization, said Dennis Goldberg, president and CEO of Transport Pharma. Goldberg spoke at the BIOMEDevice conference in September. The company is a specialty pharmaceutical firm, with a dermal product pipeline based on the combination of medical electronics, materials engineering, formulation chemistry, and skin biology.

The development of combination products requires dedicated and collaborative efforts, open and flexible communication, and input from across multiple disciplines. Many times, development of such products won’t even fit into a company’s current business model. Goldberg suggests that companies developing such products need to have expertise in all of the relevant core competencies in order to provide guidance to vendors. Transport’s team, for example, is comprised of experienced engineers, chemists, biologists, and experts in clinical development regulatory affairs.

The advent of combination products has also meant changes at FDA, and will likely mean further evolution of the agency’s approach to convergent technologies. The Office of Combination Products (OCP) was established by FDA in 2003 to identify and assign these products to the lead FDA review center—CDRH, the Center for Drug Evaluation and Research (CDER), or the Center for Biologics Evaluation and Research (CBER). In 2007, FDA issued decisions on 57 combination products, 27 of which went through CDRH.

“In the current conservative FDA environment, the standard is very high,” Goldberg said. His company split its application into two parts: a new drug approval and a 510(k) submission. “We provided CDRH with a pullout of the 510(k) to make it easier for [the center] to review the portion that was applicable to the device.”

Many of the first products to be submitted to FDA involved combining diagnostics or devices with drugs, but this is shifting with the integration of diagnostics and devices with sophisticated instrumentation and information technologies. In that environment, he said, FDA looks for guidance from the company.

“[OCP] is only a gatekeeper,” Goldberg said, referring to OCP’s role in simply determining the appropriate center for a product based on its primary mode of action.

As life sciences companies begin to develop more products that cross boundaries, the regulatory landscape will also shift. It will be critical for you to provide input to FDA to ensure that the model that evolves is one that works for you.

The organization of a convergence company looks very different from a medical device company, and certainly the regulatory path is more complex. Combination products have the potential to offer greater therapeutic benefits than drugs, devices, or biologics on their own, and as such, will continue to drive the direction of new products that address the trend toward personalized medicine.

– Sherrie Conroy

FDA said it will spend as much as $2.5 billion over the next 10 years to upgrade its information technology systems, many of which are hopelessly out of date, reports the Associated Press. This will help the agency better track medical devices, drugs, food, and the other products it regulates. The funds will be awarded over the next decade to 10 contractors. FDA Commissioner Andrew von Eschenbach said the agency needs a “high-tech, efficient data management system” in order to carry out its mission.