The FDA Modernization Act of 1997: Part I

March 1, 1998

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The FDA Modernization Act of 1997: Part I

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


The device industry's efforts to reform FDA have resulted in a far-reaching new law, which is detailed in this series.

Capping several years of efforts by the pharmaceutical, medical device, food, and biologic products industries to reform FDA, on November 21, 1997, President Clinton signed into law the FDA Modernization Act of 1997. With certain exceptions noted in the act itself, most of the law's provisions became effective on February 19, 1998. Although the device industry had argued vigorously since the beginning of the decade that the regulatory process at FDA has been inefficient, in many cases unfair, and in need of drastic reform, the Modernization Act represents an evolutionary rather than revolutionary reform of medical device regulation. In fact, many of the changes are an outgrowth of the recent and ongoing reengineering efforts by FDA's Center for Devices and Radiological Health (CDRH) and Vice President Al Gore's Reinventing Government program.

This two-part article on the new law describes its requirements and their genesis, covering sections 201 through 210 in this month's installment and sections 211—217, 401—417, and 420—421 next month. A third article will focus on the act's implications and FDA's implementation of the new legislative requirements. The act directs FDA to have numerous regulations and guidances in place by February 20, and the third article will review those initiatives. As is always true, Congress can give direction to the agency, but how FDA interprets and implements a new law is often as critical to the regulated industry as the statutory language chosen by the legislators.


IDE Supplements. Under section 201 of the new law, FDA must promulgate regulations that will allow clinical study sponsors to make modifications to investigational devices and study protocols without submitting investigational device exemption (IDE) supplements to the agency. Specifically, section 201 amends section 520(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and gives FDA one year from the date of enactment to establish, by regulation, the procedures and conditions under which changes can be made in connection with investigational devices without FDA approval. The section also identifies several specific types of changes that will not require IDE supplements:

(i) developmental changes in the device (including manufacturing changes) that do not constitute a significant change in design, that do not constitute a significant change in device or in basic principles of operation and that are made in response to information gathered during the course of investigation; and

(ii) changes or modifications to clinical protocols that do not affect—

(I) the validity of data or information resulting from the completion of an approved protocol, or the relationship of likely patient risk to benefit relied upon to approve a protocol;

(II) the scientific soundness of an investigational plan submitted under paragraph (3)(A) [in the IDE application]; or

(III) the rights, safety, or welfare of the human subjects involved in the investigation.

The law further directs FDA to include provisions in its implementing regulations establishing that these types of changes can be made if the sponsor of the study determines, on the basis of credible information, that the change or modification meets the specified criteria, and submits to FDA, not later than five days after implementing it, a notice of the change or modification.

The intent of this reform is to permit study sponsors to determine initially whether a proposed change necessitates the filing of an IDE supplement. Of course, FDA has the option of disagreeing with a sponsor's determination and requiring an IDE supplement. As will be discussed in more detail in our later article on the implementation of the Modernization Act, this provision is a response to complaints by the medical device industry that the IDE process has been made overly complex, with CDRH requiring IDE supplements for even minor changes in manufacturing procedures, device designs, and study protocols.

Early Collaboration on Data Requirements for Clinical Studies. Another reform of the IDE process embodied in section 201 allows sponsors of clinical studies of any Class III device to submit an investigational plan (including the clinical protocol) for early FDA review. Such a plan can be submitted prior to the official submission of the IDE application or, in the case of a nonsignificant-risk device not requiring an IDE application, prior to seeking approval to conduct a study from an institutional review board (IRB). Any agreement reached by the sponsor and FDA regarding this plan must be made part of the administrative record and may be changed by FDA only in certain circumstances related to protecting the public health.

This provision is a response to criticism from industry that the FDA clinical review process has not been sufficiently interactive. Often, lack of communication and understanding between FDA and study sponsors has led to significant delays in conducting clinical studies and problems with the ultimate premarket approval reviews. The intent of the new provision is to slow down or stop the proverbial "moving target" in the conduct of clinical trials and resolve industry's concern that FDA often changes its mind with regard to appropriate study design and end points during the course of a study. To some extent, FDA has already sought to address this problem through internal guidances that promote pre-IDE meetings and communication with study sponsors. The new law, however, codifies this approach and specifies the direction FDA must take in interacting with study sponsors.

FDA now has 30 days after receiving a request for review of an investigational plan to meet with the study sponsor in order to reach agreement on the clinical plan, and the agreement reached by the applicant and FDA must be made part of the written administrative record in order to be binding on the agency. This provision is not unlike the provision in the current drug regulations at 21 CFR 312.47(b)(v), which provides that agreements between sponsors and FDA on end-of—Phase 2 studies are to be recorded in the meeting minutes and that, barring a significant scientific development that requires otherwise, studies conducted in accordance with such agreements shall be presumed to be sufficient in objective and design for the purpose of obtaining marketing approval for the drug. The medical device industry has been arguing for quite some time that similar language should be included in the device regulations; under this section 201 provision, that is likely to happen.

Section 201 also specifies that any agreement made part of the administrative record cannot be changed except with the written agreement of the sponsor or pursuant to a decision by the director of the FDA office in which the device is being reviewed that a substantial scientific issue essential to determining the safety or effectiveness of the device has been identified. If the director (presumably the director of the Office of Device Evaluation or an ODE division director) does make such a determination, it must be documented after the sponsor of the study has been provided an opportunity to meet with the director to discuss the scientific issues involved.

Review of Data Supporting PMA Applications. The final provision of section 201 relates to FDA's acceptance of data in premarket approval (PMA) applications and is intended to recognize statutorily that almost all medical devices undergo some modifications during the course of a clinical trial, especially during those trials lasting 24 months or longer. Under the new law, FDA must accept and review all statistically valid and reliable data and any other information from clinical investigations conducted under the IDE regulations if the following two conditions are met:

(I) the data or information is derived from investigations of an earlier version of the device, the device has been modified during or after the investigations (but prior to submission of an application under subsection (c)) and such a modification of the device does not constitute a significant change in the design or in the basic principles of operation of the device that would invalidate the data or information; or

(II) the data or information relates to a device approved under this section, is available for use under this Act, and is relevant to the design and intended use of the device for which the application is pending.

In the past, FDA has been extremely strict with respect to the pooling of data from the testing of modified versions of an investigational device and the device as originally designed and described in the IDE application. Under this new provision, FDA must accept the data from studies of modified versions of a device unless those modifications are considered a "significant change in design" or a change in the "basic principles of operation of the device." Of course, it will be up to FDA to define whether a change does in fact constitute a significant change in design or basic principle of operation.


Section 202 of the Modernization Act amends section 515(d) of the FD&C Act. Under this new provision, FDA is required to establish review priorities for certain types of devices: (1) those representing breakthrough technologies, (2) those for which no approved alternatives exist, (3) those that offer significant advantages over existing approved alternatives, and (4) those whose availability is in the interest of patients.

This provision codifies, to some extent, the expedited review policy that FDA announced on June 30, 1993. Under that policy, devices eligible for expedited review are classified into four similar categories: (1) devices to treat life-threatening or irreversibly debilitating conditions for which no alternatives are available, (2) devices to treat life-threatening or irreversibly debilitating conditions when approved device alternatives may not be as beneficial as the device under review, (3) devices that are revolutionary (i.e., breakthrough), and (4) devices offering a specific public health benefit. FDA may have to modify its existing policies to harmonize the existing expedited review procedures and categories with the new statutory language.


Section 203 of the new act amends section 520(m) of the FD&C Act to streamline and expand the humanitarian device provisions of the Safe Medical Devices Act of 1990 (SMDA). Under the section 203 provisions, a request for a humanitarian device exemption (HDE) submitted to FDA in the form of an application must be approved or denied by the agency within 75 days. Previously, the review-period timing was less certain.

Additionally, SMDA provided that devices that have HDE approval must be used only under IRB control. Under the new law, an HDE device can be used prior to IRB approval of a clinical study provided that a physician determines that such approval cannot be obtained in time to prevent serious harm or death to a patient. When a physician does use an HDE device without approval from an IRB, the physician must notify the chairperson of the IRB of that use and identify the patient involved, the date the device was used, and the reason for the use.

Finally, under the HDE provisions of SMDA, an exemption was effective for only 18 months; the Modernization Act repeals that limitation. Nevertheless, FDA may require the sponsor of an HDE device to demonstrate continued compliance with the HDE regulations if the agency believes that such a demonstration is necessary to protect the public health or if the agency has reason to believe that the criteria for the HDE are no longer being met. However, FDA can suspend or withdraw an HDE only after providing the holder of the exemption an opportunity for an informal hearing.


Section 204 of the Modernization Act amends section 514 of the FD&C Act by granting FDA authority to recognize, through publication in the Federal Register, all or part of a medical device standard developed by a nationally or internationally recognized standards development organization. The intent of this provision is to align FDA procedures more closely with the European Union's heavy reliance on standards in approving products for marketing. FDA has been exploring this approach for quite some time. In fact, the agency has partially integrated this concept into its reengineering initiatives, including the so-called new 510(k) paradigm.

Section 204 provides companies seeking premarket clearance from FDA with the option of submitting a Declaration of Conformity that certifies that the device under review conforms with a specified standard. This declaration can stand in lieu of data that FDA otherwise might have required in support of a 510(k) premarket notification or PMA application. FDA has the authority to request, at any time, the data or information relied on by the declarant; however, this provision of the act directs the agency to accept the Declaration of Conformity unless agency reviewers find that the data or information submitted in support of the declaration do not demonstrate that the device conforms with the specified standard or that the standard identified in the declaration is not applicable to the particular device under review. The declarant must maintain the data and information supporting conformity of the device to the standard for a period of two years after the date of the classification or approval of the device by FDA, or for a time equal to the expected design life of the device, whichever is longer.

The declaration procedure outlined in section 204 is a welcome addition to the existing premarket notification and approval procedures, which manufacturers can still use, if desired. As will be discussed in greater detail in our later article, reliance upon conformity with recognized standards can significantly lessen the paperwork burden in premarket submissions and significantly expedite approval of new medical technologies.

The Senate report on this provision specifically recommends that FDA provide an opportunity for public comment on decisions to recognize specific standards, where appropriate. The report states that notice-and-comment rule making is not required to recognize a standard because the use of the declaration procedure by manufacturers is voluntary.

Finally, FDA is given the option of withdrawing recognition of a standard by publishing a notice in the Federal Register if scientific or medical information becomes available indicating that the standard is not appropriate for ensuring the safety and efficacy of medical devices. This provision was effective February 19, 1998.


Section 205 of the Modernization Act amends sections 513 and 515 of the FD&C Act to reform some particularly unpopular aspects of FDA's 510(k) notification and PMA review procedures. Specifically, the new act gives manufacturers certain options for reducing the often burdensome data requirements for 510(k) notices, original PMA applications, and PMA supplements.

Reducing Data Requirements through Reliance on Postmarket Controls. The first major provision of section 205 relates to how FDA can expedite market clearances by using postmarket controls to assist in ensuring a device's safety and efficacy rather than relying solely on the data submitted in premarket filings. With regard to PMA applications, the new law states that FDA, in determining whether there is reasonable assurance of the effectiveness of a device, must consider whether the extent of the effectiveness data that would otherwise be required for approval of the PMA application can be reduced through reliance on postmarket controls. Similarly, to facilitate reviews of 510(k) filings, FDA is directed to consider the extent to which reliance on postmarket controls can expedite substantial equivalence findings.

This provision responds to the device industry's longstanding complaint that FDA has set unreasonably high standards for the data needed to support 510(k) and PMA submissions, resulting in inefficiency and unfairness in the device clearance and approval processes. Congress is seeking to persuade FDA to shift some of the premarket data requirements to postmarket review and controls. Whether this attempt at legislative persuasion is likely to be successful will be discussed in our later article.

Resolving PMA Effectiveness Data Requirement Issues. Section 205 also contains provisions relating to early agency-sponsor collaboration concerning the type of valid scientific evidence of effectiveness that is needed to support premarket approval of a device. Under the new law, companies intending to submit a PMA application have a right to meet with the agency even before submitting an IDE application to obtain an official FDA determination on the type of data necessary to demonstrate the device's effectiveness. The law provides that a manufacturer's written request for such a meeting must include: (1) a detailed description of the device; (2) the proposed conditions of use of the device; (3) a proposed plan for determining whether there is a reasonable assurance of effectiveness; and (4) information regarding the expected performance of the device, if available. Within 30 days after the meeting, FDA must specify, in writing, the type of scientific evidence that will be needed to provide a reasonable assurance that the device is effective under the conditions of use proposed by the applicant.

Thus, under the new law, FDA must work with applicants early in the premarket approval process to determine exactly what data are necessary to establish a device's effectiveness. This may sound easy to accomplish, but in fact obtaining agreement with FDA on efficacy end points and success criteria has been a difficult and time-consuming task for industry. In determining what data are needed, the agency must now consider, in consultation with the company, the "least burdensome appropriate means" of evaluating the device's effectiveness. In addition, the specification of the needed valid scientific evidence by FDA is binding upon the agency unless it is later determined that the decision "could be contrary to the public health."

This provision, like the IDE provisions of section 201, is designed to address the "moving target" complaint of industry and also to lower what many have considered to be the unreasonably high standards of scientific proof of efficacy required by FDA following the issuance of the Temple Report in 1993. (That report severely criticized CDRH's clinical review practices and led to heightened data requirements.)

Limiting the Information Needed to Support 510(k) Clearance. The Modernization Act also includes a provision in section 205 stating that whenever FDA requests information to support a 510(k) submission involving devices with differing technological characteristics, the agency must limit its request to information that is necessary to make a substantial equivalence determination. FDA also is directed to consider the "least burdensome means of demonstrating substantial equivalence" and tailor its information request accordingly.

This provision is intended to lessen the amount of data required to support 510(k) notices. FDA, of course, can still decide what is the "least burdensome means of demonstrating substantial equivalence"; nevertheless, Congress clearly wants the agency to step back from requesting significant amounts of data in support of 510(k) notifications.

Determinations of Intended Use. With respect to the scope of premarket reviews, section 205 also contains provisions that would prevent FDA from fully implementing what industry has called the agency's "implied intended use" policy. In the past, FDA has required certain PMA and 510(k) applicants to submit data supporting a use that is not included in the product's proposed labeling. FDA's justification for requesting such data has been that while the device in question is not labeled for that specific use, the manufacturer actually intends or anticipates that the device will be used for that application.

The new law specifically provides that FDA's review of PMA applications must generally consider only those conditions of use stated in the labeling when determining whether a device is safe and effective. The agency has some leeway in that it can decide that the labeling is false or misleading, but it must do so based upon a "fair evaluation."

With regard to 510(k) submissions, FDA is directed to limit its substantial equivalency review to the conditions of use identified on the device's proposed labeling. In some cases, the director of ODE can require specific labeling caveats, which could include information about an off-label or implied use. However, to order such labeling, the director must justify, in writing, that a reasonable likelihood exists that the device will be used for that off-label application and that such use could "cause harm." The ODE director's written determination that caveats are needed must be provided to the 510(k) applicant within 10 days of the date of the notification of the director's concerns about the proposed labeling. In addition, the director must specify the limitations on the implied use of the device. Section 205 also states that the ODE director cannot delegate this responsibility, and that the provision will sunset on November 21, 2002.

This provision is one of the more controversial in the new law. No longer can FDA freely require the submission of data concerning a use not included in the product's proposed labeling. However, if there is a potential for off-label use that could cause harm, ODE can still warn the public through a contraindication, warning, or other statement in the labeling about the potential off-label use.

Reducing the PMA Supplement Burden. The final provision of section 205 relates to reducing the necessity of submitting burdensome PMA supplements for certain modifications to previously approved Class III devices. Presently, under 21 CFR 814.39, FDA approval of a PMA supplement is required before a device manufacturer can make a change "affecting the safety or effectiveness of the device." FDA has interpreted that regulatory provision expansively, requiring PMA supplements for even minor changes in manufacturing procedures. Under the new law, PMA supplements are not required if a change is a modification in a manufacturing procedure or method and certain conditions are met; such a change may now be made 30 days after the manufacturer provides a written notice to FDA that describes the manufacturing change in detail and summarizes the data and information that support the change. However, during that 30-day period FDA may notify the manufacturer that the agency has determined that a PMA supplement will be required. In those cases in which a PMA supplement is deemed necessary, the law further provides that FDA has 135 days to review the supplement, but the time elapsed during the 30-day window is to be considered part of those 135 days.

Additionally, section 205 provides that when a PMA supplement is required for an incremental device design change that affects safety and effectiveness, the PMA supplement must be approved by FDA if the following two conditions are satisfied: (1) nonclinical data demonstrate that the design modification creates the intended additional capacity, function, or performance of the device; and (2) clinical data from the approved PMA application and any previous supplement or supplements provide a reasonable assurance of the safety and effectiveness of the modified device. However, FDA is allowed to require additional clinical data when it is necessary to evaluate a design modification's safety and effectiveness.

The device industry has complained for many years about the necessity of filing PMA supplements for minor manufacturing changes; this provision fully addresses these concerns. With regard to design changes, the new law does not quite go so far as to provide a 30-day review option, but it does direct FDA to approve PMA supplements for design changes in a more streamlined and efficient way.


Exemptions from 510(k) Requirements for Class I and Class II Devices. Section 206 of the new act amends section 510(k) of the FD&C Act with regard to premarket notification requirements in several ways. First, this section reinforces FDA's ongoing initiative to exempt Class I devices from 510(k) requirements by including a provision stating that all Class I devices will be considered exempt except those intended for a use that is of substantial importance in preventing the impairment of human health or those that present a potentially unreasonable risk of injury or illness. Under this provision, few Class I devices should be ineligible for exemption from 510(k) requirements.

Second, section 206 directs FDA to publish in the Federal Register, within 60 days of the passage of the new act, a list of Class II devices that can also be exempted from 510(k) requirements. FDA may also add other Class II devices to this list later, on its own initiative or in response to a petition from an interested person. Any additional listings proposed by FDA must be published in the Federal Register with a 30-day comment period. The agency then has 120 days to publish a final exemption order. The law also specifies that if FDA fails to respond to a petition for an exemption within 180 days after receipt, the petition is considered granted. The Class II exemption list was published on January 21 and exempted, effective immediately, 62 additional Class II devices.

Limitation on the Use of FDA's Reference List. Another significant change to the 510(k) requirements under section 206 provides that FDA cannot withhold a determination of substantial equivalence because of an applicant's failure to comply with any provision of the FD&C Act unrelated to a substantial equivalence decision, including a finding that the facility in which the device will be manufactured is not in compliance with GMP requirements. In essence, this provision precludes FDA from ever fully reinstituting its unpopular policy of withholding 510(k) clearance from companies on a "reference list" of firms that had been found in noncompliance during GMP inspections. FDA, as part of its reengineering initiatives, ended its use of the reference list in reviewing 510(k)s for Class I and Class II devices in March 1997, but the policy had continued in effect for reviews of preamendments Class III products.

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