FDA has faced intense criticism, as commentators have raised serious questions about its ability to protect the nation's medical drug and device supply. Less visibly, but just as strongly, manufacturers have identified the need for more certainty and greater efficiencies in regulatory interactions. Two recent developments reflect the potential that FDA will be increasing its muscle. Working groups from within FDA have proposed revisions to the way the agency evaluates medical devices. Although some streamlining would occur, the net effect would be increased regulatory engagement and heightened data requirements, which could be particularly hard for emerging companies to meet. In addition, legislation has been proposed that would materially increase FDA's power to regulate the substantial percentage of our country's active drug ingredients that are made outside the United States, while stepping up FDA's obligation to monitor them. Final action has not been taken with respect to either change, so the possibility for more modest revision remains.
CDRH Released Working Group Reports
In September 2009, FDA's Center for Devices and Radiologic Health (CDRH) established a task force to evaluate the use of science in regulatory decision making and a working group to consider the 510(k) process for clearing medical devices. In August 2010, reports containing their preliminary assessments and recommendations were released for public comment. The reports were accompanied by a Message from Center Director Dr. Jeffrey Shuren, indicating that CDRH seeks to foster medical device innovation, enhance regulatory predictability, and improve patient safety.
In total, the reports suggest steps to improve FDA's ability to address rapidly advancing scientific developments, to facilitate data sharing and utilization, and to bring greater transparency, consistency and predictability to CDRH decisions. Although many details are not provided, the reports also suggest that, overall, it will be predictably and consistently true that medium and higher-risk medical devices will require additional safety and effectiveness data, before and after they are marketed. In addition, the reports recommend heightened requirements for companies to submit to FDA the reasoning and data that support their own internal evaluations. Public oversight may increase as well, with a recommended database including ready access to device labeling and schematics. Companies have expressed concern that this public disclosure would destroy their intellectual property.
Why Evaluate the 510(k) Process?
The 510(k) review process was established in 1976, when the Food, Drug and Cosmetic Act was amended to provide for FDA oversight of medical devices. With certain exceptions for low-risk devices, devices first introduced to market after May 28, 1976 were required to undergo an in-depth premarket approval process, unless the devices could be cleared for marketing through the 510(k) review. Devices eligible for this review are substantially equivalent to devices that already were introduced to market before May 28, 1976.
This pathway is a critical one. In a recent letter to FDA Commissioner Dr. Margaret Hamburg, a group of legislators indicated that the 510(k) process is the pathway to market for more than 90 percent of the medical devices sold in the United States.
There has been a great deal of confusion however, within and outside CDRH, about the precise definitions that govern "substantial equivalence" determinations. In broad terms, the process was meant to allow some evolution in indicated uses and technological characteristics, if device safety and effectiveness were not diminished. Over time, however, statutory and regulatory revisions combined with advancing technology to make navigating the process vastly more complex. Concern arose about increasingly inconsistent and unpredictable regulatory determinations when these broad concepts were applied to specific devices. Uncertainty can inhibit device innovation, as investors are less comfortable supporting products with uncertain pathways to market. It also is difficult, especially for smaller companies, to respond to unexpected requests for data mid-process, particularly when the data requested is clinical data.
Separately, concern arose that too many new devices were cleared by comparison to predicate devices that did not adequately ensure ongoing safety and effectiveness. Concern also arose that FDA was not receiving or evaluating full safety data.
Clarity, and Burden, Increasing
In addressing these concerns, the 510(k) working group proposed that FDA strengthen and utilize a more streamlined de novo classification process, for lower-risk novel devices that cannot be cleared through the 510(k) process because there is no clear predicate device. The working group also recommended that CDRH clarify key terms within the substantial equivalence determination and train its reviewers about how to implement them. The science task force also recommended better training, shaped by a Center Science Council and supplemented by external networking with outside experts. It also suggested more frequent communications to industry about FDA's expectations, particularly as they change with new science. Together, these changes could well improve efficiencies, level the playing field, and promote innovation.
Many proposals, however, suggest an increase in data requirements and regulatory engagement. The 510(k) working group recommended that CDRH issue a guidance creating a new "class IIb" device subset for greater risk or more complex devices, for which clinical, manufacturing or postmarketing data typically will be necessary. These types of information are required now, for many devices, and greater predictability would help. In bringing a formal consistency to this decision, however, CDRH may require more frequent or in-depth data, overall. This move also is signaled by the science task force report, which recommended that CDRH continue its efforts to improve the quality of human clinical trial data to support device decisions.
The working group also cautioned against clearance of a new device by comparing it to devices no longer being marketed in the US, or to multiple predicate devices. It also suggested that CDRH consider disallowing the use of split predicates, which means a sponsor could not use one device to establish the indicated uses and another device to establish the technological characteristics. Constricting these uses would substantially impact the path forward for many devices.
Both groups targeted the "least burdensome provisions" of the Food and Drug Modernization Act of 1997, which directed FDA to consider the least burdensome means of demonstrating substantial equivalence. A 2002 guidance had interpreted these and other provisions broadly, indicating that "the least burdensome concept should be integrated into all premarket activities, as well as postmarket activities as they relate to the premarket arena." The current task force characterized the aim of the original statute as eliminating only unjustified burdens on industry. CDRH reviewers have expressed concern that the prevailing culture has made it difficult for them to seek needed information.
Information they will receive, and more of it, as proposed by both groups. The 510(k) working group, for example, recommended that sponsors submit more comprehensive data up-front with the application. It also proposed more frequent updates after clearance, with regular submissions outlining minor device modifications and safety experience. Both groups recommended increased capture and analysis of real-world postmarketing device experience, and the science task force outlined a formal signal evaluation process CDRH may use to decide when this experience warrants a regulatory change.
CDRH Seeks to Assure, but Holds Ground
Midway through the public comment period, in an August 31, 2010, webinar, representatives from CDRH fielded questions concerning the reports. Not surprisingly, some comments challenged the need for change or expressed concern that the proposed changes will make the process for clearing medical devices so difficult that device innovation will be impeded, or companies will move out, and U.S. patients will not have the benefit of new technology. Though affirming its support for innovation, CDRH representatives held their ground, defending the need for change and the proposals made.
In at least one instance, however, CDRH sought to reassure industry. At one point in the afternoon, Christy Foreman, the acting director of the Office of Device Evaluation, said it was not CDRH's intent to turn the world upside down for device makers. She offered assurance that the new proposed classification level IIb was designed primarily to bring greater transparency to CDRH's current practices and thinking, rather than to fundamentally change its view about what data are required. The devices for which clinical data would be required are those where CDRH is receiving clinical data already. Dr. Shuren also expressed this view. In addition, Ms. Foreman emphasized that a need for clinical data would not necessarily mean a company must conduct a randomized, controlled clinical trial. The term "clinical data" should be interpreted broadly to include a range of available information about experience in people.
Industry and Legislators Urge Caution
Despite these assurances, on October 4, the last day for public comment, the California Healthcare Institute (CHI) submitted a letter urging caution and asking that the more controversial provisions be delayed. CHI represents the broad biomedical sector of the California economy, including leading universities and research institutes, venture capital firms and life sciences companies. CHI sought detailed proposals, with new public comment periods, for any major change. CHI directly opposed several of the recommendations, including the creation of a new Class IIb. CHI sought the continued ability to use split and multiple predicate reference devices and indicated that many of the new data requirements outlined in the reports were both unnecessary and unduly burdensome.
On October 12, eight days after the close of the comment period, a bipartisan group of 12 House Energy and Commerce Committee members wrote a letter to Dr. Hamburg, echoing the CHI comments without referencing them specifically. The legislators emphasized the need to maintain a well-functioning, efficient system for device clearance if the U.S. medical technology industry is to maintain its global leadership. The group identified five proposals as being controversial, all having the potential to disrupt the device review process. The areas identified as controversial were those directly opposed by CHI. Although not expressing opposition to any recommendation, the House group urged that in these controversial areas, the FDA provide precise and detailed proposals with additional public comment periods before moving forward.
Proposal to Expand FDA's Role in Drug Safety Monitoring and Enforcement
In a similar vein, and reflecting growing awareness and concern over drug quality issues, Senator Michael Bennet (D-CO) introduced legislation on August 3, 2010, entitled Drug Safety and Accountability Act of 2010. The legislation focuses on improving safety of drugs and drug ingredients that are manufactured outside of the United States, where up to 80 percent of the United States' active drug ingredients originate.
According to the bill, recent drug recalls and warnings "have exposed gaps in quality systems to ensure drugs in the United States are safe and free from contamination." Examples in the Act include the 149 Americans who died in 2007 and 2008 from heparin contaminated in the manufacturing process in China and the 1,300,000 over-the-counter children's medicines that were recalled in 2010 for quality issues.
The bill is a reiteration of several measures in the Drug and Device Accountability Act of 2009, proposed last April by Sens. Ted Kennedy and Chuck Grassley. That proposal stalled in the Committee on Health, Education, Labor, and Pensions.
The Bill's Teeth
The Bennet bill would provide FDA with greater monitoring and enforcement power.
- Quality control would be expanded by requiring drug manufacturers to implement Quality Management Plans, to document the supply chain for drug ingredients, and to submit to inspections of factories and warehouses. The Secretary also would have authority to subpoena witnesses during investigations conducted under the Act.
- FDA has long sought the power to order recalls but has been rebuffed by courts, who characterized the power as an "additional arrow" in FDA's "already well-equipped bow." See, e.g., U.S. v. C.E.B. Prods., Inc., 380 F. Supp. 664, 671 (N.D. Ill. 1974) (denying government's request for "judicial sanction" to recall adulterated cosmetics). For the first time, under the proposed legislation, FDA would have the power to mandate a drug recall. FDA also would have the authority to order the "appropriate person (including the manufacturers, importers, distributors, or retailers of the drug)" to cease distribution and notify health professionals of the cessation order.
- The bill expands FDA's authority to assess civil penalties for violations of the Food, Drug, and Cosmetic Act. Presently, FDA may assess civil penalties for violations of regulations regarding risk evaluation and mediation strategies, clinical trials, direct-to-consumer advertising, and drug sample-related convictions. The bill adds the power to assess liabilities against "[a]ny manufacturer, distributor, importer, broker, or filer that violates a requirement of this Act that relates to drugs for human use," with limited exceptions for violations covered by pre-existing penalties. Each violation of the Act is subject to a maximum fine of $100,000. Further, manufacturers, distributors, importers, brokers, or filers that knowingly report or enter false or misleading data for drug importation documents would be liable for a maximum fine of $150,000 for each act of reporting or entering of false data.
- The bill would allow FDA to exchange information with other regulatory agencies.
- Whistleblowers would be protected from employer retaliation.
The bill also targets FDA, requiring FDA to do more to ensure quality control, including the creation of an updated system to "track and assess every establishment that is involved in the manufacturing, preparation, propagation, compounding, or processing of a drug or active ingredient of a drug."
Although the similar 2009 bill stalled in committee, Sen. Bennet's bill was introduced the same day the Pew Prescription Project released its March-April 2010 poll results, which reported on Americans' attitudes regarding prescription drug safety. The poll respondents largely agree that contamination of prescription drug ingredients is a serious but uncommon problem. The respondents also report little confidence in drugs from India and China, and they endorse measures that would give FDA more drug safety enforcement authority.
The bill has been referred to the Committee on Health, Education, Labor, and Pensions. With the Senate in recess and given the number of other bills pending before the committee, the Bennett bill's present legislative status is unclear. However, the Bennett bill may be aligned with the just right factors—a conducive regulatory atmosphere and public concern over foreign drug safety—for the bill at least to make it out of committee, this time around.