Medical Device & Diagnostic Industry Magazine
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An MD&DI April 1998 Column

FDA MODERNIZATION ACT

A subchapter on dissemination of information about off-label uses is among the new FDA reform law's important provisions.

Following a multiyear lobbying effort by the affected industries, the FDA Modernization Act was signed into law by President Clinton on November 21, 1997, amending many sections of the Federal Food, Drug, and Cosmetic Act (FD&C Act) governing the regulation of medical devices. To help members of the device industry understand and benefit from the new law, this two-part article provides section-by-section descriptions of its provisions. Last month's installment covered sections 201­210, areas such as investigational device exemptions, the review priority of certain devices, humanitarian device exemptions, declarations of conformity to accepted standards, the scope of FDA reviews, 510(k) requirements, automatic Class III designations, classification panels, review time frames, and third-party review of 510(k)s.¹ Twenty-three additional sections are described below. In the June issue of MD&DI, a follow-up article will discuss FDA's implementation of the act's provisions, focusing on the guidances and rules the agency was directed to issue by February 20.

SECTION 211. DEVICE TRACKING

Section 211 of the new law amends section 519(e) of the FD&C Act and repeals the mandatory tracking requirements for some high-risk devices imposed by the Safe Medical Devices Act of 1990 (SMDA). FDA's discretionary tracking authority as granted under SMDA has also been narrowed.

Pursuant to section 211, FDA may require a manufacturer to adopt a method of tracking a Class II or Class III device if the failure of that device would be reasonably likely to have serious adverse health consequences, if the device is intended to be implanted in the human body for more than one year, or if the device is life sustaining or life supporting and will be used outside a health-care facility. Any patient receiving a device subject to such tracking may refuse to release, or refuse permission for the device manufacturer to release, his or her name, address, social security number, or other identifying information for the purpose of tracking.

The medical device industry had complained that the device tracking requirements imposed by SMDA were costly, burdensome, and, in many cases, unnecessary. Congress responded by narrowing these requirements and deleting the requirement for automatic mandatory tracking of certain types of devices. The illustrative list of trackable devices included in 21 CFR 821 will be replaced with a new list of Class II and Class III devices that FDA will order to be tracked. FDA is in the process of informing manufacturers of devices that have previously required tracking about whether to continue doing so.

SECTION 212. POSTMARKET SURVEILLANCE

Section 212 of the Modernization Act amends section 522 of the FD&C Act. SMDA mandated postmarket surveillance for certain high-risk devices and gave FDA broad discretion to impose postmarket surveillance on manufacturers of other types of products as well. Under the new law, manufacturers will no longer automatically be required to conduct such follow-up studies for some types of devices. Instead, FDA may order postmarket surveillance for specific Class II and Class III devices when the failure of the device would be reasonably likely to have a serious adverse consequence, when the device is intended to be implanted in the human body for more than one year, or when the device is intended to be life sustaining or life supporting and will be used outside a health-care facility.

Upon receiving a postmarket surveillance order, a manufacturer must submit a surveillance plan within 30 days. FDA then has 60 days to evaluate the qualifications of the person designated to conduct the surveillance and determine whether the plan will result in the collection of useful data. The agency may require a study lasting up to 36 months; any longer study has to be mutually agreed upon by the manufacturer and FDA. If no agreement can be reached, then the manufacturer and FDA must follow the dispute resolution process outlined in section 404 of the Modernization Act.

As with tracking, FDA plans to contact manufacturers currently conducting postmarket surveillance studies, but companies with ongoing studies ordered under section 522 of the FD&C Act are directed to continue at this time.

SECTION 213. ADVERSE EVENT REPORTS

The major thrust of section 213 of the Modernization Act, which amends section 519 of the FD&C Act, is to abolish any requirements that medical device distributors submit adverse event reports to FDA or to device manufacturers. Distributors will still be required to maintain records of adverse events. However, the provisions of SMDA that required mandatory distributor reporting have been repealed, as have the FD&C Act stipulations that required distributors to submit to FDA periodic certifications of the number of adverse events reported. Similarly, distributors are not required to submit reports of corrections and removals to FDA, as device manufacturers are required to do under the new corrections and removals regulation.

Section 213 also amends the FD&C Act by exempting wholesale distributors that do not manufacture, repackage, process, or relabel devices from registering their facilities with FDA. The section also defines wholesale distributor as any person (other than the manufacturer or the initial importer) who distributes a device from the original place of manufacture to the person who makes the final delivery or sale of the device to the ultimate consumer user.

With regard to user facilities, section 213 modifies the reporting requirements of SMDA to require annual summaries of adverse event reports instead of the semiannual summaries previously required. FDA also is directed to draft regulations for a program (to be known as the Sentinel Program) under which the agency will limit user facility reporting to a subset of facilities that constitutes a representative profile of adverse event reports for device-related deaths, serious illnesses, and serious injuries. FDA has already instituted a similar pilot program as part of its internal reforms. During the implementation of the Sentinel Program, the present user facility reporting requirements will continue to apply. Finally, FDA is directed to submit a report to Congress by November 21, 1999, describing the Sentinel Program and the progress that has been made toward its implementation.

SECTION 214. PRACTICE OF MEDICINE

Whether FDA has the right to interfere in any way with a physician's practice of medicine is a long-standing controversy. Section 214 of the Modernization Act adds a provision to the FD&C Act that is designed to clarify the agency's role in this regard, although it is unlikely this new section will end the debate.

The new provision specifies that nothing in the FD&C Act shall be construed to limit or interfere with the authority of a health-care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate health-care practitioner-patient relationship. Notwithstanding this direction, Congress also specifically stated in this new provision that it should not be considered as limiting any existing FDA authority to establish or enforce restrictions on the sale or distribution, or in the labeling, of a device that are part of a determination of substantial equivalence, established as a condition of approval, or promulgated through regulations. It also stated that this section should not be considered to change any existing prohibition on the promotion of unapproved uses of legally marketed devices. In sum, rather than actually clarifying FDA's role in the practice of medicine, this provision has simply reaffirmed, to some extent, FDA's belief that under certain circumstances, delineated above, it has the authority to regulate how physicians use devices.

SECTION 215. NONINVASIVE BLOOD GLUCOSE METERS

Section 215 of the new act is essentially a congressional finding that noninvasive blood glucose meters may have an appropriate role in assisting in the treatment of diabetes. A sense of Congress is provided to the effect that the availability of safe, effective, noninvasive blood glucose meters would greatly enhance the health and well-being of all people with diabetes. Although this provision has no direct legal effect, it may assist manufacturers of noninvasive blood glucose meters in getting their products through the FDA review process with greater alacrity than would otherwise have been expected.

SECTION 216. USE OF DATA RELATING TO PREMARKET APPROVAL, PRODUCT DEVELOPMENT PROTOCOLS

Use of Data Relating to Premarket Approval. Under one provision of section 216, which amends section 520(h) of the FD&C Act, any information contained in a premarket approval (PMA) application (including information from clinical and preclinical tests or studies used to demonstrate the safety and effectiveness of a device, but excluding descriptions of methods of manufacture and product composition and other trade secrets) shall be available, six years after the PMA application has been approved by FDA, for use by the agency in the following ways: (1) in approving another device, (2) in determining whether a product development protocol for another device has been completed, (3) in establishing a performance standard or special control, or (4) in classifying or reclassifying another device.

This provision essentially replaces the "four of a kind" provision in SMDA, under which FDA was permitted to use safety and effectiveness information submitted in a PMA application after the fourth device "of a kind" has been approved by the agency. This SMDA provision was never implemented by FDA because the device industry threatened litigation over the exact meaning of a device "of a kind." The new provision is much clearer than that in SMDA and can be easily implemented. Just what value this provision will have to the device industry remains to be seen, however. Safety and efficacy data that are six years old typically relate to a generation of device that may no longer have commercial value to its manufacturer. Nevertheless, any time that FDA is able to rely upon one company's data to assist a competitor, concerns and controversy will arise.

Product Development Protocols. A second part of section 216 specifies that FDA may on its own initiative refer a proposed product development protocol (PDP) to a review panel for a recommendation regarding approval of the protocol. In addition, FDA is directed to refer such protocols to a panel upon request by the submitters unless the agency finds that the proposed protocol and accompanying data substantially duplicate another PDP previously reviewed by the panel.

SECTION 217. NUMBER OF CLINICAL INVESTIGATIONS REQUIRED FOR APPROVAL

Section 217 of the new act amends section 513(a) of the FD&C Act by making it clear that FDA may approve a PMA application based upon a single clinical investigation, if appropriate. As are several provisions described in the first part of this article, this provision is designed to encourage FDA to streamline the PMA application process and reduce the amount of data required of manufacturers.

SECTION 401. DISSEMINATION OF INFORMATION ON OFF-LABEL USES

Section 401 of the Modernization Act adds a subchapter D to the FD&C Act. Perhaps the most complicated and controversial of all of the new act's provisions, this subchapter was designed by Congress to respond to industry's complaints that FDA has been much too strict about the dissemination of off-label use information for approved drugs and devices. FDA has one year to issue regulations implementing section 401, which takes effect upon issuance of those regulations or one year from the date of passage of the Modernization Act, whichever is sooner. The new subchapter sunsets seven years after regulations are issued or in the year 2006, whichever is later.

Manufacturers of devices that are legally on the market can distribute copies or reprints of journal articles or reference texts discussing off-label uses of the devices. However, such distributions can only be made under certain conditions. Specifically, the unsolicited dissemination of off-label use information is permitted only if the following requirements are met:

1. The information to be disseminated is not derived from clinical research conducted by another manufacturer or, if it is derived from research conducted by another manufacturer, the manufacturer disseminating the information has the permission of that manufacturer to disseminate that information.

2. The material is published in peer-reviewed and reputable scientific/medical journals or reference texts. Where the material is derived from a reference text, the latter must be written and distributed in a manner independent of the manufacturer, as determined by other criteria set forth in the law.

3. The material must be about, or include information about, a clinical investigation regarding the device that appropriate experts would agree is scientifically sound.

4. The material must not be considered false or misleading or pose a significant risk to the public health.

5. The target audience is limited to health-care practitioners, pharmacy benefit managers, health insurance issuers, group health plans, or a federal or [other] government agency.

6. A copy of the material is submitted to FDA for review 60 days in advance and the materials are accompanied by summaries of clinical trial and clinical experience data relating to the new off-label use of the device.

7. The material is accompanied by a prominent statement disclosing the following points:

(a) that the information relates to a use of the device that has not been cleared or approved by FDA;

(b) an explanation of whether the information is being disseminated at the manufacturer's expense;

(c) an explanation of whether compensation has been received from the manufacturer by any of the authors or whether they hold a significant financial interest in the manufacturer;

(d) a description of the official labeling for the device and all updates with respect to the labeling;

(e) a statement of products, if any, already cleared or approved for the same use;

(f) identification of any person that has provided funding for the studies relating to the new use of the device for which the information is being disseminated;

(g) a bibliography of scientific/medical literature about the new off-label use;

(h) such other objective and scientifically sound information (or an objective and scientifically sound statement provided by FDA) that FDA determines is necessary to provide objectivity and balance to the disseminated information. FDA must provide the manufacturer with notice of such determination and an opportunity for a meeting.

In addition, before disseminating information about an off-label use, the manufacturer must submit a supplemental PMA application to FDA for that use or certify that either of the following conditions have been satisfied: the necessary studies to support a supplemental application for the new use have been completed, and the supplement will be submitted within six months of the initial dissemination of information about the new use; or a proposed protocol and schedule for conducting studies have been submitted to and agreed upon by FDA and that a supplemental application will be submitted within 36 months. However, manufacturers can apply for an exemption to the requirements for submission of a supplemental application on the grounds that it would be economically infeasible to submit such an application or that it would be unethical to conduct the necessary studies, e.g., the new use has become the standard of care. If FDA fails to act on a request for exemption within 60 days, it is deemed approved. On the other hand, FDA may terminate a "deemed approved" exemption at any time and order the manufacturer to cease disseminating the information.

Finally, the manufacturer must submit to FDA semiannual lists of materials disseminated pursuant to this provision. Each list must include all persons who received the materials in the previous six months and identify the categories of providers that received the material.

After dissemination has begun, FDA has the authority to order a manufacturer to cease distribution and/or order appropriate corrective action under the following conditions:

1. If FDA determines that the new use may not be effective or may present a significant risk to public health. The manufacturer is required to notify FDA upon learning about any additional clinical research or other data that relates to the safety or effectiveness of the new use.

2. If the manufacturer fails to comply with all of the requirements relating to permission to disseminate under this provision. The manufacturer must be given notice and an opportunity to meet with FDA and to correct minor violations before an order halting dissemination may be issued.

3. If FDA determines that the supplemental application is not approvable, or if the manufacturer fails to submit an application within the required six-month period or fails to pursue the required studies for the 36-month period with due diligence.

Finally, section 401 calls for two studies. The comptroller general is directed to conduct a study of the impact of this subchapter and report the results to Congress by January 1, 2002. In addition, HHS must study the scientific issues raised by this section relating to the effective dissemination of useful information to health-care practitioners, the quality of the disseminated information, the quality and usefulness of the information FDA requires to be provided, and the impact of the subchapter on research into new device uses. The results of this study must be reported to Congress by September 30, 2005.

As can be discerned from the detailed list of caveats and restrictions presented above, it will be very difficult for most medical device manufacturers to meet the requirements of section 401 and, thus, to disseminate information on new off-label uses of their approved medical devices. The implementing regulations that FDA will be publishing within a year will be crucial in determining how useful this section will be to the medical device industry.

SECTION 402. EXPANDED ACCESS TO INVESTIGATIONAL THERAPIES AND DIAGNOSTICS

Section 402 of the Modernization Act adds a new section 561 to the FD&C Act to provide patients with expanded access to unapproved therapeutic and diagnostic products outside of traditional clinical trials. Whether it will be widely relied upon to expand access to new devices will depend to a great extent on how FDA implements the provisions.

Under the new law, any person, through a licensed physician, may request a manufacturer or distributor to provide a device with an investigational device exemption (IDE) if the physician determines that the person has no comparable or satisfactory alternative and if the probable risk of harm from the investigational device is not greater than the risk from the disease. FDA must determine that there is sufficient evidence of the device's safety and effectiveness to allow its use and that its use in this instance will not interfere with the conduct of a clinical investigation. Sponsors of such an IDE device must submit a clinical protocol to FDA describing the device's use in a single patient or small group of patients.

This section also provides that a sponsor or physician can submit a protocol for widespread or "treatment" use of an investigational device under certain conditions: (1) if it is intended to diagnose, monitor, or treat a serious or immediately life-threatening disease or condition; (2) if no comparable or satisfactory alternative is available; (3) if the device is undergoing clinical trials or such studies have been completed; (4) if the sponsor is actively pursuing marketing approval; (5) if provision of the device will not interfere with an ongoing clinical trial; and (6) sufficient scientific support exists for use of the product. FDA may withdraw treatment use approval if it determines that the requirements specified above are not being met. The agency also may notify associations and other appropriate persons about the availability of such treatment protocols.

SECTION 403. APPROVAL OF SUPPLEMENTAL APPLICATIONS FOR APPROVED PRODUCTS

Under section 403, FDA is required, within 180 days after enactment of the Modernization Act, to publish procedures for the prompt review of PMA supplements. The agency also must publish final guidance documents that clarify the requirements for approval of PMA supplements. The final guidance must clarify the circumstances under which published information may serve as a basis for approval of a supplement, specify data requirements that will avoid duplication of previously submitted data by recognizing the availability of such data to support an application, and define which supplemental applications are eligible for priority review.

This section also requires FDA to designate a representative within CDRH who will encourage the prompt review of PMA supplements and work with device manufacturers to facilitate the development and submission of data in support of their supplements. In addition, FDA is instructed to develop programs and policies to facilitate collaboration with the National Institutes of Health (NIH); professional, medical, and scientific societies; and other appropriate persons to identify published and unpublished studies that may support supplemental applications and to encourage manufacturers to base their PMA supplements on such studies whenever possible.

These changes are intended to streamline the PMA supplement process and make it more consistent. This section complements the PMA supplement provisions of section 205 in seeking to reduce the burden of PMA supplemental filings.