Clinical Considerations

Medtech manufacturers can smooth products’ paths to market by optimizing their clinical trial strategies.

LaDale K. George

September 1, 2007

12 Min Read
Clinical Considerations


The critical path to market for medical devices and other therapies is paved through clinical trials. In recent years, navigating this pathway has become more challenging and expensive, and less finite and predictable.

Due to a string of high-profile reevaluations and recalls of new medical therapies that have caused serious problems in patients, various government authorities are increasing the level of scrutiny used to evaluate the conduct of and data generated during clinical trials. The government is also demanding that greater numbers of clinical trials be conducted to support the approval of new products. Companies in the medical device industry must therefore upgrade the capability of their clinical trial systems to address these new challenges and ultimately remain successful.

Recent events, including the reevaluation of the Taxus and Cypher coronary drug-eluting stents and the recall of the prescription medication Vioxx, have prompted the call for increased scrutiny of the way in which clinical trials are conducted, as well as for an expansion in the number and duration of clinical trials. These calls have emanated from consumer groups, government agencies—including the U.S. Department of Health and Human Services Office of Inspector General (OIG)—and members of Congress seeking to better ensure the safety and efficacy of medical devices and drugs being used in the United States.

Each group of stakeholders has raised particular concerns regarding the quality and volume of information being made available to FDA by manufacturers of medical devices and drugs. Specifically, they question whether the level of information currently being presented is adequate for the agency to conduct a meaningful deliberation about the safety and efficacy of the medical intervention. In a report issued in June 2006, OIG noted that FDA's approval process is based on data derived from clinical trials conducted on a relatively small number of human subjects, often ranging between 1000 and 5000 people.1 The office indicated that once a product is approved by FDA, its use expands exponentially, often resulting in an increased expression of adverse reactions associated with the product.

In the case of drug-eluting stents, FDA released a statement in January 2007 indicating that new data suggest a small but significant increase in the risk of stent thrombosis (blood clotting) in patients treated with the Taxus and Cypher devices as opposed to bare-metal stents.2 FDA's circulatory system devices advisory panel noted that the size of the premarket clinical studies was insufficient to detect or characterize significant adverse events that occur at low rates. Thus, the panel concluded that larger and longer premarket clinical trials—and longer follow-up periods for postapproval studies—will be needed to better assess the benefit and risk profile of drug-eluting stents.

On the drug side, the case of Vioxx provides an even more dramatic example of concerns associated with the sufficiency of clinical trials. According to FDA reports, the approval decision for Vioxx was based on data derived from premarket clinical trials conducted on 5000 human subjects. When recalled, however, more than 1 million patients were using the drug; more than 100,000 patients suffered serious side effects.

Regulatory Reaction

In response to concerns raised by the drug-eluting stent and Vioxx cases, the Center for Devices and Radiological Health (CDRH) is focusing more attention on the level of monitoring done by clinical trial sponsors and is developing a more systematic process for evaluating postmarket data. In addition, FDA has stepped up its level of scrutiny in overseeing the conduct of clinical trials. As part of FDA's bioresearch monitoring program, in 2006 the agency posted on its Web site 18 warning letters related to the conduct of clinical trials. Issued to both manufacturers and investigators, these letters identify significant deficiencies in compliance with applicable federal regulations associated with the way the clinical trials in question are being conducted.3 Such questions of conduct raise further concerns related to the quality of data being collected and presented to the agency, as well as the level of protection from unnecessary risks being afforded to human subjects. Such concerns exist for both premarket clinical trials and postmarket clinical studies.

In addition to calling for increased scrutiny of clinical trial performance, FDA has indicated that effective safety analysis must involve an expansion of the number and duration of clinical trials, particularly in the area of postmarket clinical studies. In 2005, CDRH issued a report that examined the agency's processes for continued evaluation of medical devices that were approved for marketing on the condition that the manufacturer provide ongoing systematic collection and evaluation of data.4 The report findings were grim. The report states that CDRH imposed conditions for approval on 45 of 127 approved medical devices from 1998 to 2000. At the time of the report, the agency was unable to locate the sponsors' required annual reporting information for 26, or 58%, of the devices that received conditional approval.

Recently, FDA announced actions to strengthen its postmarket program for medical devices. In a statement issued in November 2006, the agency announced a series of steps that it will undertake to improve the way it monitors the safety of medical devices after they reach the marketplace.5 According to CDRH director Daniel Schultz, MD, the agency intends to enhance the postmarket problem assessment process, which will involve increased use and reliance on data generated from postmarket clinical studies.

As a result of actions in the marketplace and concerns raised by various stakeholders, sponsors and investigators who are conducting or planning to conduct a controlled clinical study—premarket or postmarket—will be operating under the more-watchful eye of FDA. Meanwhile, stakeholders continue to call on FDA to increase the required number and duration of clinical trials in order to develop more-comprehensive and evolving data on the safety and efficacy of medical devices. In response to these developments, it will be useful for sponsors and investigators to be mindful of the old adage dictating that the best defense is a good offense.

Thoughtful planning is the key to navigating the complexity of the current clinical trials landscape. Immediately following the successful completion of preclinical testing, sponsors should develop and implement a critical path strategy for their clinical trial phases. Such a strategy should include the key components discussed in the following sections.

Engagement with FDA and CMS

FDA provides an opportunity for early and regular engagement with sponsors prior to the submission of an investigational device exemption (IDE) application. The FDA Modernization Act of 1997 authorizes the agency to engage in two early collaboration meetings with sponsors. Such meetings are intended to encourage dialogue between FDA and sponsors prior to the submission of an IDE in order to establish clear direction for testing and development of devices. During the meetings, FDA will provide sponsors with information regarding the type of scientific evidence that will be necessary to demonstrate the safe and effective performance of their devices. In addition, these meetings provide a forum for FDA and sponsors to collaborate in determining the least-burdensome way to evaluate devices that have a reasonable likelihood of success.6

In addition to FDA, sponsors should also plan to engage the Centers for Medicare and Medicaid Services (CMS) on issues related to reimbursement of their new technologies. With more than 40% of the healthcare reimbursement dollars in the United States being administered by CMS, it is critical for sponsors to evaluate the likelihood that the product will qualify for reimbursement by CMS both during and following the trial. Ideally, such evaluation should be undertaken well in advance of a product's debut on the market.

Pursuant to the Social Security Act, CMS is required to make reimbursement coverage decisions based on whether a device or other medical intervention is reasonable and necessary. CMS bases this determination on medical devices' demonstrated performance as being both safe and effective—the same criteria that FDA uses to evaluate market approval. In addition, CMS will consider the safety and effectiveness of a new medical device in comparison with the performance of existing approved medical interventions that are covered for reimbursement.

Sponsors should consider meeting with CMS to seek advice on standards of safety and efficacy. Having such information up front will enable sponsors to more accurately develop the design of their clinical trial protocols and identify target endpoints that will support future reimbursement determinations.

Development of the Study Design and Protocol

The success or failure of a clinical trial begins with the study design and protocol. In order to meet FDA and CMS standards, clinical trials should be designed to demonstrate the safety and efficacy of the medical device, as well as to distinguish the performance of the medical device from other products already on the market.

Unfortunately, some clinical trials are designed in a manner that does not reflect all of the information learned in preclinical testing. They may also target endpoints that would be lucrative if proven, but are beyond the capability of the device. Furthermore, clinical trial sponsors often do not distinguish their medical devices from existing products when designing their studies.

Before advancing a medical device to a clinical trial, sponsors should work closely with key opinion leaders in the design of the study and the protocol. Having outside experts weigh in on the process can help ensure that there is strong science supporting the advance of the product to clinical evaluation, the existence of therapeutically relevant and predictably achievable endpoints, and the presence of signature characteristics of the medical device.

Selection of Support Services

Since few medical device companies or pharmaceutical manufacturers have the internal capacity to execute a large, multicenter clinical trial, clinical research organizations (CROs) have emerged to provide support in the areas of site selection and contracting, operational management and orchestration, data collection and analysis, and compliance monitoring. Not all CROs are created equal. Not all are well versed or equipped to handle clinical trials in every therapeutic area or to work with sponsors of varying size and complexity. Sponsors need to be mindful in selecting a CRO that is right for the sponsor, the therapeutic area, and the geographic span of the study sites.

In addition to CROs, the execution of a multicenter clinical trial can benefit from the selection of a central institutional review board (IRB). The ability to consolidate the approval of protocols, amendments, and informed consent forms, as well as the credentialing of principal investigators and the recording and evaluation of serious adverse-event reports, can greatly enhance the likelihood of a successful and efficient clinical trial. Few issues will grind a clinical trial to a halt like the delays caused by the sometimes-idiosyncratic activities of local IRBs.

Additionally, one of the most beneficial support services available for a clinical trial is a central laboratory. Significant attention should be given to finding ways to limit variations in laboratory techniques, standards, and performance. Variations in these areas could alter the accuracy and consistency of clinical tests, leading to variation in data and safety and efficacy analysis. The use of a central laboratory can reduce the likelihood of aberrant variations and safeguard the quality of the data, as well as reduce the amount of time necessary to implement laboratory protocol changes and reduce the training and communications costs associated with implementing such changes.

Selection of Research Sites and Investigators

Research sites and principal investigators control the flow of clinical trials. Such control begins with feasibility assessments, continues through budgeting, contracting, subject recruitment and retention, and clinical performance, and ends with data documentation and study closeout. As a result, the selection of sites and principal investigators is one of the most important decisions a sponsor will make.

Frequently, sponsors are initially attracted to prominent academic medical centers as research sites. Such locations often boast a strong pool of key opinion leaders who may serve as principal investigators. Unfortunately, many such academic medical centers have not proven to be optimal clinical trial sites due to slow administrative turnaround time, cumbersome committee and department structures, high overhead costs, and smaller volumes of eligible patients.

Recent trends suggest that sponsors are finding large integrated health systems and large medical groups to be more fruitful grounds for their clinical trials. These institutions and practices are typically more streamlined in both administration and clinical operations, and they see larger volumes of patients who are less sick. As a result, administrative tasks, like budgeting and contracting, are completed in a shorter amount of time, the administrative and operational overhead is usually significantly less, and subject recruitment and retention occurs at higher levels.

Sponsors should weigh the benefits and burdens associated with each research site and principal investigator. A balance in the selection of prominent academic medical centers and large integrated community providers will enable more-successful clinical trial execution.

Management of Communications

Sponsors entering a medical device into clinical trials will be inundated with questions from both internal and external sources about the company and its product. For companies that are attempting to secure financing to support the execution of the clinical trial or general investment in the company, failure to effectively communicate could jeopardize funding sources. A misstatement—whether an inaccurate claim about the medical device or a promise based on an unachievable timeline—can be disastrous.

Sponsors may want to consider the value of engaging external support to assist their internal public relations and investor relations teams in defining their various audiences, developing the correct messages, and ensuring that the right messages are targeted to the right audiences. Even though the news is not always good, effective communications management always produces a more positive outcome.


1. Code of Federal Regulations, 21 CFR 312.21.

2. “Update to FDA Statement on Coronary Drug-Eluting Stents,” (Rockville, MD: FDA, 2007); available from Internet:

3. “FDA's Electronic Freedom of Information Reading Room,” (Rockville, MD: FDA, 2006); available from Internet:

4. Condition of Approval Studies as a Postmarket Tool for PMA Approved Cohort 1998–2000 (Rockville, MD: Center for Devices and Radiological Health, FDA, 2005); available from Internet: epi_rep.pdf.

5. “Medical Device Postmarket Transformation Initiative,” (Rockville, MD: Center for Devices and Radiological Health, FDA, 2006); available from Internet:

6. Early Collaboration Meetings under the FDA Modernization Act (FDAMA); Final Guidance for Industry and for CDRH Staff (Rockville, MD: Center for Devices and Radiological Health, FDA, 2001); available from Internet:

LaDale K. George is a partner in the healthcare industry team of Foley & Lardner LLP (Chicago).

Copyright ©2007 MX

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