Clinical Trials: A Pathway Under Scrutiny and Expansion

10 April 2007 Publication

The Pulse

The critical path to market is paved through clinical trials. Navigating this pathway is becoming 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 from, clinical trials. The government also is demanding 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 in order to adjust to and take advantage of these new challenges and ultimately remain successful.

Recent events, including the reevaluation of the TAXUS® and CYPHER® coronary drug-eluting stents (DES) and the recall of the prescription medication VIOXX®, have promoted the call for increased scrutiny of the way clinical trials are conducted and for an expansion in the number and duration of clinical trials. These calls have emanated from consumer groups, government agencies, including the United States Department of Health & Human Services, Office of the Inspector General (OIG), and members of Congress seeking to better ensure the safety and efficacy of drugs and medical devices being used in the United States.

Each of these voices has raised particular concerns with the quality and volume of information being made available to the U.S. Food and Drug Administration (FDA) by the manufacturer of the medical device or drug (sponsor). These groups question whether the information presented is inadequate for the agency to conduct a meaningful deliberation about the safety and efficacy of the medical intervention. In a report issued in June 2006, the OIG noted that the FDA’s approval process is based on data derived from clinical trials conducted on a relatively small number of human subjects, often ranging between 1,000 to 5,000 people. The OIG indicated that once a product is approved by the FDA the use of this product expands exponentially, which often results in an increase expression of adverse reactions associated with the product.

In the case of the DES, the FDA released a statement on January 4, 2007 indicating that new data suggest a small but significant increase in the risk of stent thrombosis (blood clotting) in patients who have been treated with the TAXUS® and CYPHER® devices. The FDA Circulatory System Device Advisory Panel noted that the limited size of the pre-market clinical studies were insufficient to detect or characterize significant adverse events that occur at low rates. According to, the DES market is a $6.6 billion per year industry, and estimates that nearly four million American patients have been treated with a DES. The FDA panel recommended that larger and longer pre-market clinical trials and longer follow-up for post-approval studies will be needed to better assess the benefit and risk profile of DES.

This occurrence was never more evident than in the case of VIOXX® where, according to FDA reports, the approval decision for VIOXX® was based on data derived from pre-market clinical trials conducted on 5,000 human subjects. However, when recalled, over one million patients were using the drug; and over one hundred thousand patients had suffered serious side effects.

In response to these concerns, the Center for Devices and Radiological Health (CDRH) has focused its attention on examining the level of effective monitoring by the sponsor of the conduct of the clinical trials and on developing a more systemic process to evaluate post-market data. The FDA has stepped up the level of scrutiny in overseeing the conduct of clinical trials. As part of the FDA’s Bioresearch Monitoring Program (BIMO), the agency has issued over 18 warning letters related to the conduct of clinical trials. These letters identify significant deficiencies from compliance with applicable federal regulations associated with the way the clinical trial is being conducted, which raise concerns with the quality of data being collected and presented to the agency and/or the level of protection from unnecessary risks being afforded to the human subjects. This concern of effective monitor exists for both pre-market clinical trials and post-market clinical studies.

In addition to increased scrutiny of clinical trial performance, the FDA has indicated that effective safety analysis must involve an expansion of the number and duration of clinical trials, in particular in the area of post-market clinical studies. In 2005, CDRH issued a report entitled “Condition of Approved Studies as a Postmarket Tool for PMA Approved Cohort 1998-2000.” In this report CDRH examined the agency’s processes for continued evaluation for medical devices that were approved for marketing subject to the requirement for ongoing systematic collection and evaluation of data pursuant to Federal Regulation, Title 21, Part 814.82. 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, and at the time of the report the agency was unable to locate the sponsors’ required annual reporting information from 26 (58 percent) of these devices.

Recently the FDA announced actions to strengthen its post-market program for medical devices. In a statement issued on November 9, 2006, the FDA announced a series of steps the agency will undertake to improve the way it monitors the safety of medical devices after they reach the marketplace. According to Dr. Daniel Schultz, Director of CDRH, the agency intends to enhance the post-market problem assessment process, which will involve the increase use and reliance on data generated from post-market clinical studies.

As a result of actions in the marketplace and concerns raised by various stakeholders, those sponsors and investigators who are conducting or planning to conduct a controlled clinical trial, pre-market, or post-market will be operating under a more watchful eye of the FDA. However, the FDA’s increased vigilance in the area of compliance will be coupled with calls to the FDA for an increase in the number and duration of clinical trials in order to develop more comprehensive and evolving data on the safety and efficacy of medical devices. In light of these two seemingly contradictory messages, sponsors and investigators should be mindful of the adage, “the best defense is a good offense.”

Thoughtful planning is the key. Immediately following the successful completion of pre-clinical testing, a sponsor should be engaged in developing and implementing a critical path strategy for the clinical trial phase, which addresses:

  • Engagement with the FDA and the Centers for Medicare and Medicaid Services
  • Development of the study design and protocol, focusing on the target endpoints
  • Selection of support services, including contract research organization (CRO), central institutional review board (IRB), and central lab
  • Selection of research sites and investigators
  • Management of communications, including investor communications

A well-designed, tightly contracted, and soundly implemented clinical trials critical path will generate quality data and protect the rights of human subjects in a manner that ensures both efficiency of operations and compliance with federal regulations.

This article is a part of the April 2007 edition of The Pulse, a newsletter for leaders in the Medical Device Industry.