To generate data that are credible in the eyes of regulators and the public, sponsors of medical device clinical research must take a strategic approach to clinical studies compliance so they can meet scientific, regulatory, and business objectives and demonstrate to the public their firm commitment to their product's safety.
The Struggle against Noncompliance Trends
According to the Global GCP Compliance Report 2006 and compliance statistics from CDRH's Division of Bioresearch Monitoring (BIMO), the state of clinical compliance for medical devices was on a downward trend between 2002 and 2004. The number of serious violations doubled during that period.1,2
In addition, BIMO statistics show that the number of warning letters issued to clinical researchers, sponsors, and institutional review boards (IRBs) that involved medical device research increased from an average of 17 per year between FY 1998 and FY 2002 to 44 in FY 2004.2 The good news is that recently released 2005 compliance statistics indicate that industry and agency efforts have resulted in an improvement in compliance rates and a reduction in the number of warning letters.
During FY 2004, CDRH BIMO issued 10 warning letters to medical device clinical research sponsors and 24 to medical device clinical investigators.1 In that same period, the Center for Drug Evaluation and Research (CDER) did not issue any BIMO-related warning letters. The Center for Biologics Evaluation and Research (CBER) issued no warning letters to sponsors, and it issued five warning letters to clinical investigators.3
Figure 1. (Click to Enlarge) Inspection of research sponsors, investigators, and IRBs have generated an increasing rate of OAI reports, doubling from FY 2002 to FY 2004. NAI = no
action indicated; VAI = voluntary action indicated; OAI = official action indicated. Source: CDRH.
CDRH has provided a variety of statistical analyses of recent bioresearch monitoring compliance trends. As Figures 1–3 illustrate, inspections of research sponsors, investigators, and IRBs have generated an increasing rate of Official Action Indicated (OAI) reports, doubling from FY 2002 to FY 2004. It is important to note that during this period, CDRH BIMO staff have conducted approximately twice as many investigations as a result of external complaints than in previous years. These types of investigations yield a much higher rate of noncompliant conditions than the more common routine inspections.
A review of CDRH warning letters issued to clinical research sponsors indicates that monitoring deficiencies—including failure to report adverse device effects, discrepancies between source documentation and data included in the premarket approval (PMA) application, and failure to identify clinical investigator protocol violations—constitute the largest proportion of items included in these letters.1 Other violations cited in these warning letters include failures to obtain prior CDRH or IRB approval of clinical investigations.
The largest category of observations included in BIMO-related warning letters addressed to clinical investigators was “failure to follow the investigational plan.” For example, investigators failed to conduct patient examinations or lab tests required in the study protocol, were unable to account for all of the investigational devices shipped to their site, enrolled patients that did not meet protocol eligibility criteria, or failed to report protocol deviations to the sponsor (see Tables I and II). This analysis also noted a considerable number of informed-consent problems such as failing to obtain consent, obtaining consent after the investigational procedure had been performed, and using consent forms that do not conform with 21 CFR 50.4
Compliance statistics from outside CDRH provide some context for the device data. The CDRH data translate to a long-term OAI rate of 13% for CDRH BIMO, compared with 3.2% for CDER BIMO inspections. CBER compliance data provide another type of comparison. CBER occupies a unique position within FDA due to its oversight of products approved via a biologic license application and via PMA or 510(k) processes.
Key Factors Affecting Compliance
According to Patricia Holobaugh, CBER BIMO branch chief, “[Smaller device companies] haven't come to understand the ‘culture of compliance' that many larger and more experienced firms have adopted to conduct quality studies.”1
Table I. (Click to Enlarge) Common sponsor deficiencies, FY 1998 through FY 2004.
Although culture is a central factor, there are other key factors at work in the medical device industry that are influencing compliance rates.
Fundamental differences exist between the medical device industry and the pharmaceutical and biologics industries.5 Certainly, these differences cannot excuse fundamental noncompliance; however, they may help identify possible root causes behind noncompliance issues. As mentioned earlier, the dramatic difference in product life-cycle time between the device industry and the pharmaceutical and biologics industries greatly influences project timing and resources.
Life-cycle issues are perhaps the strongest driving factors in structuring medical device clinical research programs. Other factors, including resources, clinical trial design, and site management, also have a great effect on compliance.
Resources and Planning: Budgets and Workloads. Medical device companies are typically much smaller than drug or biologics companies. In fact, many device companies are considered start-ups and have little or no internal development experience. They often employ people with a high level of technical expertise, but with less clinical compliance experience than in more-established organizations. Studies conducted by these smaller companies generally involve fewer patients than drug studies; however, overall complexity is often similar because of the tasks that are unique to device studies. This includes more-complicated analytical methodology required to reduce bias and to address issues such as device reliability and the training of device users.
These challenges are compounded by the vastly shorter product life cycle for most medical devices compared with a typical pharmaceutical or biologic. The need to rapidly enroll patients in a device study can, in some cases, cause sponsors to significantly modify their plans. For example, if a device sponsor expects to recruit a specific number of eligible patients per month from each site, but finds that actual recruitment rates are half of that, the sponsor may consider adding additional sites.
Clinical monitoring resources may not always be adjusted consistent with the increased number of sites. This results in overburdened clinical monitors and, consequently, clinical investigators who lack appropriate regulatory and protocol training and supervision. This scenario almost inevitably leads to noncompliances, although it is certainly not a universal occurrence.
Table II. (Click to Enlarge) Investigator deficiencies, FY 1998 through FY 2004.
Clinical Trial Design: Monitoring and Protocol Design. The vast majority of device studies, especially those for implantable devices, cannot be masked. The implanting surgeon is always aware of the type of device used for a particular case. Although masked assessors can reduce this source of bias, it frequently cannot be eliminated, as in drug studies where the use of a placebo control is considered routine. In addition, following the instructions in the protocol for the use of the investigational device is essential.
Administration of the test article in a drug study is usually a trivial task of asking a patient to swallow a tablet or submit to an injection. Devices, especially therapeutic devices, must be used in strict accordance with sponsor instructions. Clinical monitors have the added burden of ensuring that the device has been used in accordance with the protocol and of directing investigators' innovations into constructive channels. There are many competing interests when a protocol is designed. Sponsors should work to include procedures that are easily executed and easily documented.
Research Site: Selection and Training. Inventors of investigational devices are often involved either as clinical investigators or as company officials responsible for investigations. Many successful device development efforts closely involve the device developer in various aspects of the clinical investigation but, in some cases, their intense focus and dedication to the use of the device can lead to a reduced focus on regulatory compliance.
Even though some of the informed-consent citations included in CDRH BIMO warning letters refer to issues such as the complexity of the language in the consent form or the content of the form that should have been identified by IRBs, research sponsors still have a responsibility to review those forms and ensure that they are appropriate.
Some device industry representatives have suggested that clinical investigator inexperience may be a factor that should be considered. Certainly, investigator and study coordinator training during site initiation visits and investigator meetings can help to increase regulatory compliance, reduce administrative challenges, and keep the study on schedule and on budget.
Most clinical investigators participate in several clinical research studies at any given time. In many cases, pharmaceutical studies command more of their attention and resources than device studies. Industry observers suggest that this can be due to many factors, including higher monetary compensation for the investigator and institution, or academic prestige associated with the pharmaceutical studies. When possible, the selection of dedicated and focused investigators can improve compliance and speed patient recruitment.
Fostering Compliance: The Regulators' Approach
Figure 2. (Click to Enlarge) CDRH sponsor compliance rates. NAI = no action indicated; VAI = voluntary action indicated; OAI = official action indicated. Source: CDRH.
FDA has spent a considerable amount of time discussing clinical compliance issues with industry, investigators, and IRBs. Michael Marcarelli, PharmD, director of CDRH BIMO, has stated that additional guidance documents are in preparation, including one for sponsors describing how to monitor device clinical trials. He has also discussed applying the quality system regulation corrective and preventive action (CAPA) system to clinical research. Advantages of this approach include the fact that such systems already exist on the operations side of device companies.
Many of the medical device noncompliances cited in BIMO warning letters can be traced to problems found in routine clinical monitoring reports that are not followed up and rectified. CAPA systems include mechanisms to ensure that follow-up and corrective actions are completed and reviewed to confirm their effectiveness. However, CAPA systems are designed for use inside a company, and some industry sources have expressed concern that using them for clinical research where independent clinical investigators are involved would be counterproductive, eventually leading to poorer communications with research sites. Also, in many segments of the medical device industry, there is competition for alliances with investigators who possess special expertise and can rapidly recruit patients. Rather than devote additional time to CAPA responses, such investigators could choose a sponsor that does not use such a process.
As regulatory guidance evolves, medical device companies should provide input and focus on their own efforts to improve compliance performance.
Steps toward a Successful Compliance Focus
A medical device company can take several approaches to manage compliant trials. Often the highest return on the compliance investment occurs with actions taken early in the process to address key factors that affect compliance. These actions can include careful attention to protocol and case report design, selection of experienced investigators, and use of experienced trial managers.
As the trial moves forward, using experienced clinical research associates and training them and investigator site personnel to properly manage protocol requirements are key elements for success. Systems for capturing data, whether they are paper based or electronic, are also important. Matching resources and the workload so that the sponsor personnel and site personnel can effectively interact is an essential component throughout the course of the trial.
Figure 3. (Click to Enlarge) CDRH investigator compliance rates. NAI = no action indicated; VAI = voluntary action indicated; OAI = official action indicated. Source: CDRH.
Although solutions need to be customized to a particular company's business model, there are essential questions each organization needs to ask to help evaluate critical compliance issues and to begin to adopt a best-practice framework:
• Is there a mechanism in place to ensure that proper clinical monitoring resources are provided throughout the life of a clinical trial?
• Are protocols designed so that they can be easily executed and so key data can be easily documented?
• Is there a robust clinical auditing function within the organization or externally? How are the audit data used?
• Are root causes of noncompliances identified? Are research systems then modified to address those issues?
• Are the organization's clinical research and site personnel properly trained?
• Do existing processes such as investigator meetings and on-site training adequately prepare clinical investigators and staff to conduct studies?
Once a high-level evaluation has been conducted by answering these and other important questions, an organization can determine whether it should designate its own resources or whether it needs to seek outside assistance to help assess, plan, and implement preventive or corrective measures.
Industry, FDA, clinical investigators, and their institutions must all work together to improve compliance rates for medical device clinical research. High-quality data will benefit industry, resulting in faster approval and clearance times. It will also benefit FDA because all stakeholders in the clinical research process, including the general public, will continue to maintain their confidence in the process and in the industry's products.
Business concerns drive the device development process and dictate available time and financial resources. Both the industry and FDA need to identify systems and tools that can help to ensure compliance.
1. Global GCP Compliance Report 2006: US, EU, Japan (Philadelphia: Barnett Educational Services Div., Medical Marketing Services, Parexel Intl., 2006).
2. CDRH BIMO Division [online] (Rockville, MD); available from Internet: www.fda.gov/cdrh/comp/bimo.html.
3. FDA Warning Letter database [online] (Rockville, MD: FDA, 2006 [cited 3 January 2006]); available from Internet: www.accessdata.fda.gov/scripts/wlcfm/searchwl.cfm.
4. Code of Federal Regulations, 21 CFR 50.
5. J Toth-Allen, “Medical Device Aspects of Clinical Research,” SoCRA Source 45 (2005): 32–37.
Barry Sall is a senior regulatory consultant at Parexel International Corp. (Waltham, MA). He can be e-mailed at [email protected].