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An MD&DI March 1997 Feature

CLINICAL TRIALS

Sponsors of clinical trials need to become familiar with the new IDE manual to interact better with FDA and to speed product development.

The new guard at FDA's Center for Devices and Radiological Health (CDRH) in Rockville, MD, has brought new life to an old classic: the investigational device exemption (IDE) manual.

Since the manual was last issued, in 1992, the center has undergone a nearly complete change in the personnel responsible for shaping the policies on clinical studies of investigational devices and evaluating IDE applications. This revision of the manual reflects the efforts of the center, under its new leadership, to clarify its expectations of clinical trials sponsors.

According to FDA, the purpose of the IDE regulation is to encourage the discovery and development of medical devices while also protecting the public health. But to many sponsors, the regulation is an obstacle--a governmentally mandated rite of passage that manufacturers of new medical devices must endure to gain regulatory approval.

Despite their different viewpoints, regulators and industry must communicate. Ideally, increased interaction between manufacturers and FDA will shorten the regulatory process and minimize delays in the development of new devices. Understanding the new IDE manual is a good way to start developing better interaction with FDA. The new manual offers a comprehensive explanation of the IDE regulation, and any manufacturer who plans to conduct clinical trials should become thoroughly familiar with it.

The document has four major sections: an overview of the IDE regulation; an outline of how to submit an IDE; a compilation, which accounts for half of the manual, of the guidances and policies relevant to the IDE process; and a description of the bioresearch monitoring program.

OVERVIEW

The overview section of the manual summarizes the IDE regulation, which is given in 21 CFR 812. It repeats some parts of the regulation verbatim, but also often modifies the language or organization of the document to make concepts more accessible. The topics covered by this overview are the abbreviated requirements for a non-significant-risk device study, exempted investigations, contents of an application for an original IDE and for supplemental applications, and an explanation of FDA's decisions on applications, including the grounds FDA uses for approval or withdrawal. The responsibilities of sponsors in organizing and conducting an investigational study, responsibilities of investigators in conducting the study, and reporting and recordkeeping requirements are also outlined.

HOW TO SUBMIT AN IDE APPLICATION

The intent of this section is to communicate specifically the items that CDRH's Office of Device Evaluation (ODE) prefers in an IDE application, both in substance and in form, to ensure that applications will be substantively and administratively complete and review cycles will be minimized.

The section includes a suggested original IDE application checklist, which sponsors can use as a screening tool to determine whether their applications are administratively complete.

Typical problems that ODE has encountered with original IDE applications are listed. These problems range from premature IDE submissions to inadequate reports of prior investigations and inadequate investigational plans. The suggested format for IDE submissions is given in great detail; even the size of the margins and thickness of the binders are recommended. Suggested formats for IDE progress reports and final reports are also supplied.

An underlying theme of this section is that no detail, however trivial, should be omitted if a manufacturer wishes to increase the likelihood of timely FDA approval of an IDE.

NEW AND REVISED GUIDANCES

The heart of the new IDE manual is its compilation of numerous guidance documents and policies that ODE has developed to clarify specific requirements of the IDE regulations, and to assist manufacturers in wading through the IDE process. More than half of the guidances are new to the IDE manual, having been initially issued or updated since the 1992 edition. These new guidances, which are summarized below, provide fresh insight into ODE's current thinking about the design, conduct, and analysis of investigational studies of medical devices.

· "Goals and Initiatives for the IDE Program," July 1995. Perhaps one of the most important recent ODE policy statements concerning the IDE process is found in this memorandum. In fiscal years 1993 and 1994, ODE approved only one out of four original IDE applications in the first 30-day review cycle. Under the direction of Susan Alpert, ODE has since sought to reverse the trend of few approvals in the initial review period and, therefore, in part, to fend off congressionally mandated FDA reform.

This memorandum sets forth the ODE goals of substantially increasing the approval rate in the first 30-day review cycle and decreasing the average number of review cycles. Initiatives that have been implemented to foster an interactive review process, and thereby help ODE meet these goals, are described.

The essence of these initiatives is pre-IDE submissions and pre-IDE meetings, in which sponsors are encouraged to submit preliminary information for ODE review and to meet with ODE staff before making a formal IDE application. Procedures for such communications are described in this memorandum. The current IDE fax policy, which permits FDA to consider additional information faxed by sponsors concerning an IDE application that has already been submitted, is also described.

· "Statistical Guidance for Clinical Trials of Nondiagnostic Medical Devices," January 1996. The Temple Report, released by FDA in March 1993, concluded that there were significant deficiencies in the design and, therefore, the conduct of clinical studies performed by sponsors in support of their device marketing applications.

This report led to CDRH's current preference for randomized, controlled clinical trials to support virtually all original premarket approval (PMA) applications and many hybrid 510(k)s. Issued in the wake of these developments, this guidance, prepared by CDRH's Office of Surveillance and Biometrics, provides a comprehensive treatment of the clinical trial process from a statistical perspective. Running the gamut from clinical trial design to conduct and analysis of the clinical investigation, the document provides an explanation of each trial element, and discusses why it should be incorporated and what problems will arise if it is omitted. A useful appendix on sample size is also included.

· "Biological Evaluation of Medical Devices: The Use of ISO-10933," May 1995. Before a new device is studied in humans under an IDE, FDA requires that it be systematically tested to ensure that any risks from device materials will be well understood. Beginning in 1987, FDA relied on the "Tripartite Biocompatibility Guidance for Medical Devices," 1986, to determine the appropriate tests to evaluate the biocompatibility of investigational devices. The International Organization for Standardization (ISO), in an effort to harmonize biocompatibility testing, subsequently developed a standard for biological evaluation of medical devices (ISO 10993). To harmonize biological response testing with the requirements of other countries, FDA adopted part 1 of the ISO standard in July 1995. The guidance document includes matrices laying out initial and supplementary evaluation tests for consideration by manufacturers and a flowchart for the selection of toxicity tests.

· "Significant and Nonsignificant Risk Medical Device Studies," October 1995. The IDE regulations describe both significant-risk (SR) and non-significant-risk (NSR) studies. Distinguishing between SR and NSR studies is of critical importance to IDE sponsors and investigators, because NSR device studies have fewer regulatory controls than SR studies do and are governed by abbreviated IDE requirements.

This FDA information sheet guides sponsors through the decision between SR and NSR, and lays out the institutional review board (IRB) and sponsor responsibilities following the determination. The guidance replaces a July 1986 blue book memorandum of the same title, but contains updated and expanded examples of SR and NSR devices to help sponsors decide to which category their own devices belong. Because the consequences of an incorrect choice of SR or NSR can have significant consequences, sponsors should carefully review this memorandum before initiating an IDE study.

· "PMA/510(k) Expedited Review Process," May 1994. Sponsors are always eager to advance new devices to the marketplace as rapidly as technological development and the regulatory process will allow. In the interest of public health, FDA has determined that it should review 510(k)s and PMA applications for certain devices in an expedited manner. These include revolutionary or breakthrough devices, devices that treat life-threatening or irreversibly debilitating conditions, or those that provide a demonstrable public health benefit.

This memorandum describes FDA's criteria for determining whether expedited review should be granted, and the procedures that sponsors must follow to seek expedited review. It replaces the 1986 memorandum "510(k) Expedited Review" and the 1989 memorandum "IDE/PMA Expedited Review Process."

· "IDE Refuse to Accept Procedures," May 1994. According to ODE, many IDE applications are incomplete or substantially inadequate, lacking information clearly required by the IDE regulation and all components necessary to permit substantive review. The IDE refuse-to-accept procedures establish guidelines by which an IDE that does not meet a minimum threshold of acceptability will not be accepted by ODE for substantive review and approval.

The most significant part of this memorandum is a lengthy checklist for administrative review of all original IDEs. To ensure that an IDE application is sufficiently complete for FDA review, sponsors should make certain that all listed filing review elements described in this document are contained in their submissions. This IDE refuse-to-accept policy complements ODE's PMA refuse-to-file and 510(k) refuse-to-accept policies.

· "Implementation of FDA/HCFA Interagency Agreement Regarding Reimbursement Categorization of Investigational Devices," September 1995. The Health Care Financing Administration (HCFA; Baltimore) is permitted, under the statute governing Medicare, to reimburse for medical products that are deemed "reasonable and necessary" for diagnosis or treatment. Because of Medicare's historical interpretation of "reasonable and necessary," Medicare coverage was traditionally denied for investigational devices.

In September 1995, however, FDA and HCFA entered into an interagency agreement to expand Medicare coverage to include investigational devices, and this new coverage should facilitate patient enrollment in clinical trials. This memorandum describes the criteria FDA uses for deciding whether investigational devices should or should not receive Medicare coverage. The interagency agreement is also included.

· "FDA Information Sheets for IRBs and Clinical Investigators," reissued October 1995. The FDA Office of Health Affairs, with assistance from ODE, developed a series of information sheets, which were originally issued in 1989, to help IRBs protect human research subjects. Also of considerable interest to sponsors who are preparing for a clinical study of an investigational device, these sheets include information on advertising for study subjects, charging for investigational devices, and paying research subjects. A guide to informed consent documents, which describes the consent process, required elements of an informed consent form, and common problems with the consent document, is an important aid to sponsors preparing informed consent materials.

PREVIOUSLY ISSUED GUIDANCES

In addition to the above guidances and policies issued or updated since the release of the 1992 IDE manual, the new manual includes several previously issued documents.

· "Feasibility Studies," May 1989. Although this memorandum is somewhat outdated, given ODE's recent greater flexibility regarding use of pilot or feasibility device clinical studies, it does provide an essential overview of feasibility studies, including the concept of and the IDE requirements for such studies. Feasibility studies are also discussed in the "Statistical Guidance for Clinical Trials," which was described above.

· "Monitoring of Clinical Investigations," February 1988. No matter how well designed a clinical trial is, the failure to monitor a study can lead to the collection of inadequate or inaccurate data, diminishing or destroying the value of the clinical trial. This guidance provides sponsors with directions on proper selection of a study monitor, written monitoring procedures, and essential elements of monitoring site visits.

· "Sponsor and Investigator Responsibilities for Significant Risk Device Investigations." This document is designed to assist sponsors and investigators to understand and comply with the IDE regulations when conducting clinical investigations of SR devices. The general duties of sponsors are described, as well as the selection of investigators, study monitoring obligations, investigational device promotion, and study recordkeeping and reporting requirements. Specific responsibilities of investigators are also described.

· "Emergency Use of Unapproved Medical Devices," October 1985. FDA recognizes that during the development and testing of an investigational device, emergencies may arise in which an unapproved device offers the only alternative for saving a dying patient, and an IDE has not been approved or the patient's physician is not an investigator in the study. This guidance describes the circumstances that, according to FDA, constitute an emergency and the actions that a physician should take in such an emergency.

· "Notice of Availability of Investigational Medical Devices," April 1986. While IDE regulation prohibits the promotion or test marketing of investigational medical devices, this document lays out certain precautions that a manufacturer should take to make known the availability of an investigational device within the confines of a clinical study.

· "Waiver for Additional Investigational Sites." An excerpt from the IDE form letter to a sponsor, this brief document describes circumstances under which FDA will waive its requirements for submission of supporting information or prior FDA approval for the addition of certain investigational sites.

BIORESEARCH MONITORING

The bioresearch monitoring program at CDRH was expanded in 1992, after then-FDA commissioner David Kessler called for increased scrutiny of clinical trial data, and became the Division of Bioresearch Monitoring within the Office of Compliance in May 1993. The division monitors and inspects sponsors, clinical investigators, IRBs, and nonclinical laboratories involved in the testing of investigational devices. In the current FDA environment, bioresearch monitoring inspections are conducted not only while clinical trials are in progress, but also after almost every original PMA application is filed.

The objectives of FDA's bioresearch monitoring program--to ensure the quality and integrity of data submitted in product applications and the safety of human subjects in clinical trials--as well as the program's related functions and inspections are described in the IDE manual. All IDE sponsors should become familiar with the bioresearch monitoring program functions and inspectional programs to ensure that their clinical trials are conducted in compliance with the IDE regulation and to ensure that adequate and accurate data have been collected to support a PMA or 510(k) application.

CONCLUSION

In the post-Temple Report era of new medical device clinical trials, it is increasingly important for sponsors of investigational studies to be aware of all IDE requirements and ODE guidelines, policies, and preferences concerning IDE studies, and to be willing to engage in an interactive review process with the agency. The updated IDE manual provides a wealth of information in these areas. Thorough review and implementation of the manual by sponsors should enable FDA to accelerate review of an IDE application. Review and use of the manual will also benefit sponsors of clinical trials and the public by shortening the approval process for critical new medical devices.

Gerard J. Prud'homme is a partner with the law firm of Hogan & Hartson (Washington, DC). He concentrates his practice on medical device and drug law.

ILLUSTRATION BY JOHN BERRY.

Copyright © 1997 Medical Device & Diagnostic Industry