5
Monitoring of Postmarket Study Commitments Involving Medical Devices

“We have not done a great job [in following through on post-market studies]…. There is basically very little confidence among our premarket reviewers in saying, ‘We can study this and answer these questions postmarket.’ In many cases, those questions never get answered.”

Daniel Schultz, Director, Center for Devices and Radiological Health (quoted in Dickinson, 2004a, unpaged)

The quote above reveals that the U.S. Food and Drug Administration (FDA) recognizes that it has not done well in monitoring the status and fulfillment of studies that it has required in connection with the premarket approval of medical devices or subsequently. To the extent that significant questions related to device safety have been asked and then neglected by the agency, the result may be avoidable harm to patients and their families and a breach of public trust. As this report was being completed, the agency announced plans to create a monitoring system and shift responsibility for monitoring to the unit within the Center for Devices and Radiological Health (CDRH) that is responsible for postmarket surveillance.

As described in Chapter 3, FDA may require studies of medical devices after they have been approved. Most such studies are ordered as a condition for approving a premarket approval application (PMA) or a Humanitarian Device Exemption (HDE). In addition to these “condition-of-approval” studies, section 522 of the Federal Food, Drug, and Cosmetic Act (P.L. 75–717) allows FDA to direct studies or other information collection for certain high-risk, implanted, or life-sustaining Class II or III devices after their approval or clearance. (At least once, as described later in this chapter, FDA has required both a condition-of-approval study and a 522 study for a Class III device.) Because both condition-of-approval studies and Section 522 Postmarket Surveillance studies are necessarily conducted after mar-



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 183
Safe Medical Devices for Children 5 Monitoring of Postmarket Study Commitments Involving Medical Devices “We have not done a great job [in following through on post-market studies]…. There is basically very little confidence among our premarket reviewers in saying, ‘We can study this and answer these questions postmarket.’ In many cases, those questions never get answered.” Daniel Schultz, Director, Center for Devices and Radiological Health (quoted in Dickinson, 2004a, unpaged) The quote above reveals that the U.S. Food and Drug Administration (FDA) recognizes that it has not done well in monitoring the status and fulfillment of studies that it has required in connection with the premarket approval of medical devices or subsequently. To the extent that significant questions related to device safety have been asked and then neglected by the agency, the result may be avoidable harm to patients and their families and a breach of public trust. As this report was being completed, the agency announced plans to create a monitoring system and shift responsibility for monitoring to the unit within the Center for Devices and Radiological Health (CDRH) that is responsible for postmarket surveillance. As described in Chapter 3, FDA may require studies of medical devices after they have been approved. Most such studies are ordered as a condition for approving a premarket approval application (PMA) or a Humanitarian Device Exemption (HDE). In addition to these “condition-of-approval” studies, section 522 of the Federal Food, Drug, and Cosmetic Act (P.L. 75–717) allows FDA to direct studies or other information collection for certain high-risk, implanted, or life-sustaining Class II or III devices after their approval or clearance. (At least once, as described later in this chapter, FDA has required both a condition-of-approval study and a 522 study for a Class III device.) Because both condition-of-approval studies and Section 522 Postmarket Surveillance studies are necessarily conducted after mar-

OCR for page 183
Safe Medical Devices for Children keting of a device is permitted, this report refers to both types of studies collectively as postmarket study commitments. The statutory provisions for postmarket studies reflect Congressional awareness that the data and assessments associated with the approval or clearance of a complex medical device may leave meaningful unanswered questions about uncommon adverse events, effects in groups not studied (e.g., children), and long-term effects. To the extent that FDA encourages and accepts smaller, faster, and otherwise more limited studies to promote earlier consideration of a device for approval and reduce burdens on sponsors, more questions may remain for the postmarket period. Thus, attention to the specification and monitoring of postmarket study commitments becomes more critical. This chapter examines FDA’s monitoring of the status and fulfillment of commitments for postmarket studies of medical devices. It starts by providing some background on concerns about the monitoring of postmarket studies as they initially arose with pharmaceutical products. It also describes growing interest in public access to information about findings from such studies through some kind of clinical trials registry. The chapter then reviews the FDA’s monitoring of postmarket study commitments for devices. The final section presents the committee’s conclusions and recommendations about monitoring and public information. The discussion of trade secrets and confidentiality in Chapter 3 provides important additional context. This chapter does not report on studies that sponsors initiate voluntarily. Sponsors often undertake such studies to support expansions in the labeling of a device to cover new uses or populations. Voluntary studies may also be negotiated between sponsors and FDA at the time a device is approved, possibly as an alternative to a required study. In addition, sponsors may initiate further studies to provide information sought by Medicare and private health plans to guide coverage decisions. Recent years have seen Medicare and some other health insurers become interested in supporting clinical trials of some innovative products or procedures as a way of obtaining better data for clinical and coverage decision making (see, e.g., IOM, 2000a).1 1   In 2000, the President issued an executive memorandum that, in essence, directed the Medicare program to pay the routine costs of patient care and the costs of treating medical complications associated with participation in clinical trials (CMS, no date). The Centers for Medicare and Medicaid Services (CMS) recently announced related initiatives, including that Medicare would cover positron emission tomography (PET) for some Medicare beneficiaries who are at risk for Alzheimer’s disease and who enroll in a clinical trial approved by Medicare (CMS, 2004).

OCR for page 183
Safe Medical Devices for Children BACKGROUND Although the regulation of devices differs from the regulation of drugs in some respects, the monitoring of study commitments is essentially a generic task. Thus, a brief review of the evolution of FDA monitoring of postmarket study commitments for drugs will provide useful context for the consideration of such monitoring for studies involving medical devices. FDA Shortfalls in Monitoring Postmarket Drug Studies In 1992, new regulations provided FDA with authority to grant accelerated approval for drugs to treat serious or life-threatening conditions based on clinical trial data about certain surrogate endpoints or clinical endpoints other than survival or irreversible morbidity (21 CFR 314.510; FDA, 1992).2 These regulations remain in place. Should uncertainty exist about the relationship of surrogate endpoints to clinical benefits or observed clinical benefits to ultimate outcome, the regulations specify that applicants are to continue research to verify clinical benefit, usually by continuing studies that are already under way.3 In addition, applicants may also commit to conduct postmarket studies after a drug has been approved. If a mandatory postmarket study is not completed or does not confirm the expected benefit, FDA may order the drug withdrawn from the market (21 CFR 314.81(d) and 21 CFR 314.530). In 1996, the Office of Inspector General (OIG) of the U.S. Department of Health and Human Services (DHHS) undertook a study of the effectiveness of FDA monitoring of postmarket studies for prescription drugs (OIG, 1996). It found that the Center for Drug Evaluation and Research (CDER) had established a listing of study commitments associated with original drug applications and a list of drugs for which study commitments had been met (or determined to be infeasible or unnecessary). Key agency staff (e.g., CDER division directors and the reviewers who propose specific condition-of-approval studies) were not, however, aware of the list, and the list was not public. This limited the list’s potential value in identifying study commitments that had not been met. 2   The regulations specified that the surrogate endpoints should be “reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit” (21 CFR 314.510; FDA, 1992, p. 58944). 3   For drugs under review that are subject to requirements for studies in pediatric populations under the Pediatric Research Equity Act of 2003 (P.L. 108–155), FDA allows such studies to be deferred until after a drug is approved for use with adults. Deferred studies are considered postmarket studies and if not completed, FDA may declare the drug to be misbranded. Studies may be waived under certain conditions (e.g., if they cannot be practically or ethically conducted). FDA can also require studies of already marketed drugs that lack adequate pediatric labeling if voluntary efforts to secure the necessary clinical studies have failed.

OCR for page 183
Safe Medical Devices for Children The OIG report concluded that FDA—specifically CDER—lacked effective methods to track study commitments and was too dependent on the memory of individual staff members. Although the report credited the agency with taking steps to improve its procedures and systems, it also found that the agency had no formal standards to establish whether commitments for postmarket studies of prescription drugs were met. The time taken by the agency to review submitted reports for postmarket studies and determine whether they were acceptable varied from a few days to several years. In its report, OIG recommended that FDA should establish accountability for monitoring postmarket study commitments for drugs and develop standards, procedures, or guidelines for doing so. The report recognized that the agency’s limited resources had been subject to further pressure by legislative provisions for accelerated review of premarket applications for drugs. Action to Monitor Postmarket Study Commitments for Drugs In the FDA Modernization Act of 1997 (P.L. 105–115), Congress added new responsibilities for both FDA and companies related to postmarket study commitments for drugs (21 USC 356(b)). It required sponsors who had postmarket study commitments to report annually to FDA on their progress in fulfilling the commitments. In addition, for drugs and biologics, the 1997 legislation required FDA to report annually in the Federal Register on sponsor performance and to submit a report on postmarket studies to Congress in 2001. The legislation provided further that FDA was to treat information related to the studies as public information “to the extent that the information is necessary to identify the sponsor, establish the status of the study, and find the reasons, if any, for failure to complete the study.” Subsequently, in the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (P.L. 107–188), Congress provided that FDA’s website include information about unfulfilled drug study commitments (21 USC 356(b)). The legislation also allowed the agency to require the sponsor responsible for such a study to inform relevant practitioners about unfulfilled commitments and any questions of clinical benefit or safety that continue unanswered as a result. Congress did not otherwise provide for the public availability of information about study findings, and the database created by FDA does not include such information. In March 2002, FDA presented the required report to Congress on studies involving drugs and biologics (FDA, 2002p). It also published the requisite annual reports in the Federal Register in 2003, 2004, and 2005. In the 2005 report, FDA stated that annual status reports were due but not submitted for 16 percent of the open study commitments associated with

OCR for page 183
Safe Medical Devices for Children new drug approvals (FDA, 2005j). Of the studies concluded from October 1, 2003, through September 30, 2004, 27 percent were described as concluded because they were judged to be no longer needed or not feasible. In contrast, the corresponding figure for the previous 12 month period was 6 percent (FDA, 2004x). Of the 1,191 drug studies described as having open commitments, 68 percent were labeled as “pending,” by which the agency means that the study has not been started but is not considered delayed (i.e., behind its original schedule) (FDA, 2005j). This figure has attracted criticism (see, e.g., Nature Publishing Group, 2005). On the agency’s study commitments website, the entries for study commitments (which are organized by sponsor) provide brief details about the purpose of the study. They identify study commitments by status, for example, pending, ongoing, delayed, terminated, submitted, fulfilled, or released (i.e., sponsor released from study commitment). The agency has not, to date, required that sponsors to inform practitioners about unfulfilled study commitments and any related unanswered questions (personal communication, Beth Duvall-Miller, Project Management Officer, Center for Drug Evaluation and Research, October 22, 2004). Information about study status is removed one year after a sponsor fulfills a study commitment or is released from that commitment. Thus, those outside FDA cannot use the database to obtain information about the fate of these past study commitments. Entries in the online database identify whether studies resulted from accelerated approval or requirements of the Pediatric Research Equity Act of 2003 (P.L. 108–155). As of January 31, 2005, 78 drug applications with such pediatric study commitments were listed, including those completed within the preceding year. Of these, 66 were described as pending (i.e., not started). The drug study database does not allow a search for postmarket pediatric studies that were not required under P.L. 108–155. Because no search capacity exists for these study commitments, a study-by-study review of database entries is required to identify them. Also, because information about study findings is not included in the database or made accessible by a link to other information sources, the database does not contribute to the greater availability of public information about the safe and effective use of drugs with children. Proposals for a Registry of Clinical Trials The FDA study commitments database for drugs is not intended to serve as a registry of drug studies for the purposes of making more comprehensive information available about what clinical trials have been initiated and completed and with what aims and results. A number of groups have proposed some form of clinical trials registry in response to concerns about commer-

OCR for page 183
Safe Medical Devices for Children cial, professional, journalistic, and other biases that favor reporting of positive findings and discourage reporting of unfavorable or inconclusive study results. This disparity in reporting deprives clinicians and the public of balanced and potentially critical information (see, e.g., AMA, 2004a,b; DeAngelis et al., 2004; Steinbrook, 2004). A related concern is that when the details of original study designs or protocols are not public, investigators or sponsors may be encouraged to report incidental and misleading positive findings from analyses that were not planned in the study protocol, while ignoring the unfavorable results of analyses of the original study hypotheses. One consequence is that meta-analyses, review articles, editorials and other commentaries, and prescribing information may be inaccurate or misleading because the authors lack adequate information about the original study questions and study design (Steinbrook, 2004; see also Chalmers, 1977; IOM, 2000a, 2003; Dickersin and Rennie, 2003; Couzin, 2004). An additional, ethical argument for greater public access to clinical trials information derives from the obligations to research participants of research sponsors (and those who review and approve research). “If the knowledge gained in a trial is never communicated to others, then their [research participants’] contribution is unrealized and the covenant between researcher and patient [research participant], indeed between ethical review boards and patients, is broken” (Dickerson and Rennie, 2003, p. 517). In 2003, an IOM report on the responsible conduct of clinical research stated that the “creation of a comprehensive clinical trails database that is soundly structured for public use would ensure that information … would be available to contribute to generalizeable knowledge regardless of whether [the] results are viewed as positive or negative by investigators, sponsors, or publishers” (IOM, 2003, p. 204). Proposals for clinical trial registries vary in comprehensiveness, quality, and force, differing, for example, on what types of interventions and study designs would be included and whether registration would be mandatory or entirely voluntary.4 In general, the more comprehensive registry propos- 4   Under provisions of the FDA Modernization Act, FDA worked with the National Institutes of Health (NIH) to create a clinical trials databank for pharmaceutical products only (FDA, 2002h). At the top of the website for database is the phrase “linking patients to medical research,” which captures the primary intent of this databank (http://www.clinicaltrials.gov/). Listings provide information about a trial’s purpose, locations, and eligible participants, and they include phone numbers to call for more details. The 1997 legislation directed FDA to report on the feasibility of including device clinical trials in the database. That report, which was submitted in November 1999, recommended that no action be taken to include devices until experience with registration of pharmaceutical trials was evaluated (FDA, 1999a). The report also recommended that inclusion of device trials be limited to life-threatening or serious conditions for which no alternative therapies exist.

OCR for page 183
Safe Medical Devices for Children als—including those offered by the American Medical Association (AMA) and the International Committee of Medical Journal Editors—would require research sponsors to provide information about the original study protocol (e.g., the original study hypothesis, study populations, and planned analyses as approved by an Institutional Review Board [IRB] or equivalent body). They would also require sponsors to publish or post key findings in some form once a study was completed, although critical questions arise about the listing of information that has not been through some sort of peer review or vetting process. Proposed incentives or sanctions include requiring registration as a condition for Institutional Review Board approval of a research protocol (AMA) or refusal by major medical journals to publish articles based on trials that had not been prospectively registered (journal editors). Action by Congress might be required. Some proposals cover only drugs (e.g., that of the Pharmaceutical Research and Manufacturers Association, see http://www.clinicalstudyresults.org). The journal editors’ proposal would include only prospective clinical trials with intervention and comparison groups. They thus would exclude many single-arm, so-called pivotal clinical studies that are initiated and relied on to support initial FDA approval of high-risk medical devices or additional indications for their use. They likewise would exclude many of the postmarket studies discussed in this chapter. Others have called for more inclusive criteria (see, e.g., Rennie, 2004). Most proposals appear to envision that the registration of a trial would be public from the outset. In commenting on proposals to include device trials in an existing trials databank, the device industry has argued that an early and detailed listing of trial information could reveal trade secrets and other confidential information and thereby damage the competitive advantage associated with being the first company to introduce an approved device in an industry that derives far less protection from patents than the pharmaceutical industry (see FDA, 1999a).5 Respecting sponsors’ concerns about confidentiality, the goal of open information about results of trials covered by FDA regulations might still be served by allowing information about studies to remain confidential for a period of time prior to completion of a study (unless the details are already in the public domain, e.g., through release of information by sponsors). Many important questions remain about how to construct a trials reg- 5   Other industry concerns are that requirements for registering trials and associated responsibilities (e.g., responding to inquiries from people interested in enrolling in trials or simply wanting more information) would impose particular burdens on small companies, especially if requirements extended beyond studies involving serious or life-threatening conditions for which no alternative therapy existed.

OCR for page 183
Safe Medical Devices for Children istry that will serve the public interest. One of the most important involves criteria for registration and publication that will avoid the publicizing of studies that are badly designed, poorly executed, or inappropriately analyzed or that are not intended to build scientific and clinical knowledge. The discussion below returns to this issue as it relates to monitoring and reporting required postmarket device studies. MONITORING OF POSTMARKET STUDY COMMITMENTS FOR MEDICAL DEVICES Congress has not established monitoring requirements for required postmarket device studies that are equivalent to those created for drug studies. Section 104 of the Medical Device User Fee and Modernization Act of 2002 (P.L. 107–250), however, requires a report from the agency by 2007 on the effect of medical device user fees on FDA’s ability to conduct postmarket surveillance, the extent to which device companies comply with postmarket surveillance requirements (including postmarket study commitments), any improvements needed for adequate postmarket surveillance, and the amount of funds needed to do so. The agency is in the early stages of developing this report. The committee’s investigation of the current status of FDA monitoring of postmarket study commitments of devices (also provided for in P.L. 107–250) yielded little information about the objectives for required studies or the extent to which companies have met their commitments. Information available on the website of CDRH, which was helpful in much of the committee’s work, was minimally useful for this task. Currently, no current overall compilation or summary of information on study commitments or their status is available from CDRH. In an effort to learn more about the monitoring of postmarket study commitments, the committee sent a letter to CDRH. The letter included questions about condition-of-approval studies (for devices with a PMA), Section 522 Postmarket Surveillance studies, and any postmarket studies associated with the clearance of a 510(k) device. Studies Required at the Time of Device Approval CDRH, in its letter of response, referred to an internal database that contains information about PMA approvals that included requirements for condition-of-approval studies (Tillman and Gardner, 2004). As described in the letter, the database is not searchable and is limited to information in the approval letter. It thus does not include details about study focus and design that are determined subsequently or nor does it incorporate information about study status or results. It also is not public.

OCR for page 183
Safe Medical Devices for Children The CDRH letter stated that the agency is updating its information technology system and reviewing how it communicates requirements for the studies. It noted that the agency expects to create a searchable database that includes more information about condition-of-approval studies. Separate information from FDA indicated that the great majority of postmarket studies involve clinical investigations, but a few specify additional bench or animal studies (personal communication, Thomas P. Gross, M.D., Director, Division of Postmarket Surveillance, CDRH, November 9, 2004). Although FDA cannot require studies as a condition for clearing a device under 510(k) procedures, it can encourage voluntary studies as part of discussions with sponsors related to clearance decisions. (Subsequent to clearance, the agency can order a Section 522 Postmarket Surveillance study.) Given that no comprehensive information is available on required postmarket studies, it is not surprising that such information is likewise not available on these kinds of voluntary studies. As this study was nearing completion, FDA released an internal two-year-old report on the status of conditions-of-approval study commitments (after the New York Times filed a request for it under the Freedom of Information Act) (Meier, 2005). The report, which was essentially completed in 2003, examined the period from January 1, 1998, through December 31, 2000. It found that 45 (35 percent) of the 127 PMAs approved during the period examined included provisions for a postmarket study (Brown et al., 2005). For 26 of these, the report authors could find no mention of the studies in the manufacturer’s annual reports (which are supposed to include such information). After additional data collection, including a survey of the lead reviewers for the approval applications, the authors found information on 16 of the unmentioned studies but could find nothing for 8. For 11 studies for which results were due (or past due), the agency had not received results for 6. The report provided no details about the topics of the required studies. Subsequently, AdvaMed, a trade association representing device manufacturers, sent a letter to the Director of CDRH that reported the results of a survey of its members about the status of the 45 postmarket study commitments that were mentioned in the CDRH report (Secunda, 2005). The letter stated that 12 of its members were responsible for 22 of those 45 study commitments. These companies reported that 16 of the 22 studies were completed on time (as the time table was understood by the companies), that 2 were completed within a year of the expected date, and that 2 studies were ongoing. One study had been cancelled because the company withdrew the indication for which the study was requested, and the start of another study was being delayed until the product was widely enough distributed to generate a sufficient number of study subjects. The letter did not discuss whether the companies had appropriately reported on the stud-

OCR for page 183
Safe Medical Devices for Children ies in their annual reports. The committee considers the AdvaMed report encouraging for the studies it covered. It does not affect the committee’s judgment that the agency must have an effective system for monitoring and reporting of the status of postmarket device studies. In an effort to learn more about study commitments, committee staff read individual, online approval letters for the period from January 1, 2001, through December 31, 2004. Of the 168 letters read, 74 had some provision for postmarket study or information collection. As discussed in Chapter 6, some provisions involved pediatric use of a device. The committee could not review most approvals of PMA supplements (which may include study provisions or approve study protocols) because few are available online. The committee also identified postmarket study commitments in the online letters of approval for humanitarian device exemptions. Among six such devices explicitly approved for use with children since December 1997, one—for a left ventricular assist device—was subject to requirements for further study (H030003, FDA, 2004a). The committee did not attempt to determine the specific status of the study commitments it identified. (It expects that many, if not most, studies would not yet be completed and that the most recently ordered studies might not have started.) As described in Chapter 3, study protocols and findings are considered confidential unless the findings lead to a public health notification or similar action. Taken together, the information available to the committee paints a disappointing picture of the agency’s performance in monitoring study commitments for medical devices, particularly given the criticism directed at the agency in the 1996 OIG report on the monitoring of postmarket drug studies. Agency staff report that they are working to create a system to track what postmarket study commitments exist and where they stand in terms of progress toward completion (Tillman and Gardner, 2004). Committee recommendations appear at the end of this chapter. In response to the committee’s question about postmarket studies involving devices used with children or devices with possible pediatric as well as adult uses, the agency stated that it had not recorded such information in the past. Because the Medical Device User Fee and Modernization Act of 2002 provided that user fees for PMA applications and 510(k) notifications be waived for devices intended solely for pediatric use, the agency will be able in the future to identify those applications and any studies associated with those devices. Such applications, by definition, do not involve devices with possible pediatric applications that are approved or cleared based on studies with adults. Thus, this mechanism will not help identify studies related to pediatric use of these devices.

OCR for page 183
Safe Medical Devices for Children Studies Required After a Device Is Marketed In response to committee questions about postmarket studies ordered by the agency after market approval or clearance of a medical device, the letter from CDRH stated that the agency had “an Oracle-based document tracking system for these studies that contains information about the [postmarket surveillance] order, the plan submitted by the manufacturer, and all subsequent submissions, including interim and final reports” (Tillman and Gardner, 2004, p. 3). The letter also reported that CDRH has, in recent years, required only two Section 522 Postmarket Surveillance studies.6 The progress of the plans for the two current studies is being monitored by an interdisciplinary review team, and “limited experience” indicates “that manufacturers are honoring these commitments” but “[n]either of the studies has yet reached the expected plan completion date” (Tillman and Gardner, 2004, p. 5). Of the two Section 522 Postmarket Surveillance studies identified by FDA, one involves a device used in fever reduction that was cleared for marketing on August 1, 2003 (K014241, FDA, 2003). In May 2004, FDA required further study of a larger number of patients than were initially studied. The objective was to obtain more information about the mortality of patients treated with the device (in accord with the labeled indications for use) compared to patients receiving standard care. As the committee requested, FDA provided a copy of the letter. The second Section 522 Postmarket Surveillance study involves an endovascular stent that was approved for marketing in 1999 (P990020, FDA, 1999). The original PMA approval letter included a provision for a 5-year study to assess the long-term safety and effectiveness of the device by continued evaluation of the subjects included in the study used to support the request for approval. The approval letter directed the company to analyze existing and newly collected patient data by gender to better identify the experience of women who received the device. Finally, recognizing the “learning curve” associated with a new, complex device, FDA required the company to continue its physician/team training program and evaluate its adequacy. 6   As described in Chapter 3, Congress eliminated mandatory Postmarket Surveillance in 1997. In 1998, FDA issued a guidance document that described which surveillance requirements would continue and which would end (FDA, 1998i). For example, surveillance was to continue for saline breast implants but end for vascular grafts. In response to an inquiry about requirements that were left open in 1998, FDA responded that four studies of coronary stents remained open but should be closed out soon, and three studies of home-use prothrombin time test kits were still active (personal communication, Thomas P. Gross, M.D., Director, Division of Postmarket Surveillance, CDRH, November 16, 2004).

OCR for page 183
Safe Medical Devices for Children Then, in June 2001, FDA required the manufacturer to collect additional information to compare premarket and postmarket patient populations, examine types and rates of adverse events during premarket and postmarket periods, and determine compliance rates for patient follow-up (FDA, 2001m).7 The committee requested and received a copy of the letter directing this study. In December 2003, based on information received after market approval, FDA issued a public health notification for physicians with information about long-term mortality risks with the stent (Feigal, 2003). The data used for the public health notification were also used in a paper authored by FDA staff and an academic physician that was published on the website of the Journal of Vascular Surgery. Subsequently, as recounted in a July 2004 story in the Wall Street Journal, the article was removed from the website after objections and reference to legal action from the manufacturer of the device. The article was later withdrawn completely by FDA on grounds that the conclusions went beyond the public health notification (Mathews and Burton, 2004; see also Cronenwett and Seeger, 2004; Greenfield, 2004). According to the newspaper article and a statement by the surgery journal’s editors (Cronenwett and Seeger, 2004), the company argued that the article relied on data that were confidential and proprietary and could not be used without company permission.8 Like other recent incidents involving physician and public access to information from clinical studies involving antidepressant use with children and other drugs, this incident raises questions about the lack of public information about the results of postmarket commitment studies and the appropriate boundaries 7   Two months earlier, in April 2001, FDA had issued a public health notification discussing problems with this device and one other (Feigal, 2001a). The notification stated that one device had been the subject of a voluntary production suspension and recall after the company revealed that it had failed to report many device malfunctions and adverse events (including severe vessel damage) and that an internal audit revealed problems with complaint handling, manufacturing quality systems, documentation procedures, and staff training. With respect to the other device, FDA described concerns about serious adverse events (e.g., aneurysm rupture, device migration) and reported that it was working with the manufacturer to collect additional data. 8   The editors of the surgery journal expressed extreme disappointment that they were prevented from publishing an article with “data that we believe are important to readers” and that they viewed as “identical to the data in … other public documents” (Cronenwett and Seeger, 2004, p. 210). In a letter to the editors, the lead clinical investigator for the stent trials—who was highly critical of FDA’s 2003 public health notification—called for publication of the article so that clinicians could judge whether it provided support for the agency’s conclusions (Zarins and Bloch, 2004). The committee understands that the sponsor has expressed interest in an independent evaluation of the information it submitted to FDA but that it is still discussing the matter with FDA.

OCR for page 183
Safe Medical Devices for Children of trade secret and confidentiality requirements governing FDA (see, e.g., Ault, 2004; Avorn, 2004; Elliott, 2004; Richwine, 2004). Under federal regulations, failure to comply with any conditions set upon the approval of a device constitutes grounds for withdrawing approval of the device (21 CFR 814.82(c)). As far as the committee is aware, this drastic penalty has never been applied for failure to complete a condition-of-approval study. For Section 522 Postmarket Surveillance studies, regulations provide that failure to conduct a required study would be a prohibited act such that the device would be misbranded under the agency’s statute and that the agency could, among other penalties, impose civil money penalties (21 CFR 822.20). The committee is not aware of any situations when these penalties have been applied. CONCLUSIONS AND RECOMMENDATIONS A Monitoring System Should Be Established Based on the information available to it, the committee must conclude that FDA has lacked effective procedures to monitor the fulfillment of postmarket study commitments as defined at the beginning of this chapter. The agency has lacked a basic, searchable listing of devices for which further studies were specified as a condition of their approval for marketing. Furthermore, it has not maintained any system for systematically monitoring the status of these study commitments based on periodic reports or updates from either its own staff or sponsors. The agency was able to identify the two postmarket surveillance studies (required under 21 CFR 822) that have been ordered in recent years. Overall, CDRH’s arrangements for keeping track of postmarket study commitments for devices have been weaker than those criticized as inadequate in the Inspector General’s 1996 report on monitoring of such commitments for approved drugs. The committee recognizes that some requirements for certain postmarket studies may lack a compelling rationale, but that does not justify a failure to monitor study commitments. Manufacturers have—and should have—opportunities to make the case that a study is not feasible or will not produce useful results. FDA has released drug companies from study requirements in a number of instances, and the committee understands it has also done so for some device study commitments, although the committee has no information to judge the reasonableness of any such actions. Given current deficiencies in monitoring, the committee has been pleased to learn that the agency is in the early stages of creating a system to identify and track postmarket study commitments and their progress toward completion. Responsibility for tracking studies is being reassigned within the CDRH to the unit responsible for postmarket surveillance. No

OCR for page 183
Safe Medical Devices for Children details were available about such matters as the timetable for rectifying current deficiencies or the allocation of adequate resources to track studies without undermining other postmarket surveillance activities. As described earlier, FDA has until 2007 to prepare its required report to Congress on the extent to which companies comply with postmarket study commitments. The report to Congress should not be a one-time undertaking. Rather, it should be part of a continuing program of monitoring and public reporting of study commitments and their status. The structure of the system for tracking and reporting study commitments for drugs and biologics provides a reasonable starting point for a CDRH monitoring program that includes a public information component. Some modifications are, however, desirable, including expanded search capabilities for the public database. Given the dearth of published information about device safety and effectiveness with children, a CDRH database should be searchable for any postmarket study commitments that involve pediatric populations or questions. (As noted above, the CDER public database cannot be automatically searched to identify all studies with pediatric questions but only those required under the Pediatric Research Equity Act of 2003.) If FDA releases a sponsor from a study commitment, the monitoring database should record that with a meaningful explanation. Likewise, if a study is submitted but not accepted by FDA, that should be recorded with any follow-up actions described. Acceptance of a study should reflect the agency’s determination that the study fulfills the commitment by being responsive to the questions originally posed for it. The committee believes that the monitoring system should also cover studies voluntarily agreed to by manufacturers as part of the discussions surrounding the approval or clearance of a device. Such studies may represent a particularly clear instance of FDA and manufacturer agreement on the importance of follow-up investigations. Recommendation 5.1: Congress should require FDA to establish a system for monitoring and publicly reporting the status of postmarket study commitments involving medical devices. The system should also cover voluntary studies negotiated between FDA and manufacturers as part of the device approval or clearance process. The public database should, among other features, allow easy determination of the status of postmarket studies that involve questions about device use with children. This recommendation reflects the committee’s view that commitments for postmarket studies are a safeguard when FDA has important questions that are not answered by premarket studies. This safeguard is weakened when study commitments are not systematically tracked toward fulfillment.

OCR for page 183
Safe Medical Devices for Children The absence of a credible monitoring system also diminishes FDA’s credibility as guardian of public health. Although FDA can act and is acting on its own to establish a monitoring system, Congress should make clear that key information about the status of studies (not merely their existence) should be public. Findings from Postmarket Studies Involving Children Should Be More Accessible The safeguard offered by postmarket studies is further weakened when useful findings generated by completed studies are not available to clinicians and patients or families. One limitation of the drug study monitoring database as a prototype is that it does not provide information on the disposition of study findings, for example, whether they resulted in a change in product labeling. In fact, that database does not provide any information about study findings—positive, negative, or inconclusive. The committee recognizes that Congress did not require that system to provide public access to information resulting from the required studies. A study monitoring database for devices should, at a minimum, include a link to information about device labeling changes, safety alerts, and other decisions or actions that result from study findings. The database also should provide approved summaries of key findings or something equivalent. (Although recommendations about the creation of a clinical trials registry per se are beyond the scope of this committee, the issue of public availability of information about the safety and effectiveness of medical devices used with children is not.) If the results of a postmarket pediatric study do not warrant public availability (e.g., because the study was inadequately implemented), the reasons should be explained. In addition to directing that FDA make public information about the status of study commitments, Congress should provide for the responsible reporting of study findings. As discussed in Chapter 7, the creation of an independent drug safety board and the developing of responsible procedures for making information from postmarket studies publicly available should provide some guidance on procedures for evaluating the soundness of study findings and the appropriateness of making information public. Again, an important objective is to avoid publicizing findings from studies that are badly designed, poorly executed, or inappropriately analyzed. To the extent that the agency successfully works with manufacturers on the design and execution of postmarket studies, that should also provide an important element of quality control. Criteria for public reporting should take into account manufacturer’s legitimate rights involving trade secrets or certain confidential commercial information.

OCR for page 183
Safe Medical Devices for Children Recommendation 5.2: FDA’s system for monitoring and reporting postmarket study commitments should include information about the disposition of study findings, for example, a change in the labeling of a device. It should also provide for the responsible and understandable reporting of the source, methods, and findings of monitored postmarket studies. Beyond study monitoring, another step the agency should consider to increase accountability for postmarket surveillance is to provide its advisory committees with periodic follow-up information on the products they have reviewed. Such information should cover the status, methods, and findings of required postmarket studies and also include adverse event reports, safety alerts, recalls, or other actions associated with previously reviewed products. When a manufacturer is released from responsibility for information collection, the rationale should be described. This information may help advisory committees judge whether their conclusions about approval were prudent and whether their follow-up questions were reasonable. The next chapter discusses what the committee was able to discover—given the absence of a database of study commitments—about postmarket studies relating to children’s growth and development or active lifestyles. The chapter also examines some of the methodological, ethical, and practical challenges in conducting pediatric device studies.