FDA to Strengthen Clinical Trials Oversight

FDA’s Woodcock: Modernizing clinical trials

At the end of June, FDA announced a series of new policy and regulatory developments intended to strengthen the agency’s oversight and protection of patients in clinical trials and the integrity of resulting data. Experts in the field agree that the agency’s initiative will have a significant impact on the ways that medical device manufacturers conduct clinical trials—but the full implications of the initiative are far from clear.

Launched as part of FDA’s Critical Path Initiative, the Human Subject Protection and Bioresearch Monitoring (HSP/BIMO) Initiative is expected to help the agency modernize its approach to bioresearch monitoring. The HSP/BIMO steering committee will be chaired by FDA deputy commissioner for operations Janet Woodcock, MD, and will include representatives from FDA’s Center for Biologics Evaluation and Research; Center for Drug Evaluation and Research; Center for Food, Safety, and Nutrition; Center for Veterinary Medicine; Office of Regulatory Affairs; and the Office of the Commissioner.

“As clinical trials continue to evolve, in particular becoming increasingly large, decentralized, and global, FDA’s approach to bioresearch monitoring and human subject protection must also evolve and modernize,” Woodcock told attendees at the annual meeting of the Drug Information Association, in Philadelphia.

Woodcock said that the new initiative would enable FDA to make the most of its resources to ensure the safe conduct of clinical trials, “including taking appropriate opportunities to leverage existing oversight done by private entities to accomplish the agency’s risk minimization goals.”

But precisely how the agency intends to change its monitoring of medical device trials is unclear—especially in light of the makeup of the HSP/BIMO committee. “The most striking thing about this is that nobody on the steering committee represents the Center for Devices and Radiological Health,” says Helen Colquhoun, MD, president and CEO of Pleiad Inc. (Cambridge, MA), a clinical research organization (CRO) specializing in medical devices.

“The most important aspect of the initiative—which has yet to be enunciated in a specific guidance document—is the general move toward increased oversight of medical device clinical trials,” says Colquhoun. “There are going to be more inspections of trial sites, sponsor offices, and clinical research organizations. This should be of particular concern to medical device manufacturing executives because many companies still do not fully comply with the investigational device exemption regulations that govern clinical trials.”

Global Trial Strategies

Stark: Seeking confirmation.

The increasingly global scope of medical device trials presents significant challenges for both regulatory agencies and trial sponsors. “It is much, much easier to get a study started in Europe—especially in Germany—than in the United States;” says Nancy J. Stark, president of Clinical Device Group Inc. (Chicago). “ I see many companies doing their first in-human studies in Europe. Then, when they come to the United States, they want to use the foreign data and, if necessary, do a ‘confirmatory study’ of 30 to 40 people in the United States.

“But there are no regulatory or statistical definitions for a confirmatory study,” says Stark. “Everybody talks about them, but no one knows what they are.”

“The agency’s recognition of the situation is late but on target,” says Linda Alexander, founder and CEO of Alquest Inc. (Minneapolis), a full-service CRO specializing in medical devices, in vitro diagnostics, and biologics. “Global trial conduct has become a necessity due to the difficulty of starting trials in the United States and the even greater difficulty of recruiting patients to participate.”

Alexander: Overcoming difficulties.

In order to minimize the costs and time delays involved in collecting clinical data, companies will be wise to gather data outside the United States, says Alexander. “FDA’s biggest struggle is with public perception—not with the science or the risk of device trials,” she says. “Companies that minimize FDA’s exposure by approaching the agency with ‘no-risk’ trials—because the company has already gotten substantial evidence elsewhere—will have a much easier time.

“Countries such as India—which have little device regulation but practice Western-style medicine, have highly experienced investigators, and can enroll many patients rapidly—are particularly attractive,” she adds.

Colquhoun isn’t so certain that medical device manufacturers are committed to conducting their clinical trials on a global basis. “I’m not sure that medical device trials are really becoming ‘global’ in the same sense that pharmaceutical trials are,” she says. “It is relatively common for companies to conduct trials in the United States and EU, but much less common for them to involve other countries.

“Some of the large stent trials are conducted elsewhere—in Australia, South America, or South Africa,” she says. “But in general, medical device manufacturers conduct trials in the major markets in which they will sell, because part of the added value of conducting a trial is preparing the market.”

But Stark notes that she has been invited to talk about FDA regulations for device trials in South America, India, and Indonesia. “If these countries are interested in U.S. device regulations, then you know that companies are doing studies there and importing the data,” she says.

In the near future, says Stark, international competition over the clinical trials business for medical devices could become intense, and FDA’s new initiative “could potentially have a huge effect.”

“If adopted, changes that have been proposed for the clinical investigation standard compiled by the International Organization for Standardization— Clinical Investigation of Medical Devices for Human Subjects (ISO 14155)—would equalize U.S. regulations, European regulations, and the International Conference on Harmonization’s good clinical practices,” says Stark. ^1–3 “But European organizations are very much opposed to changes in the ISO 14155 standard, because strengthening the standard means they would lose their competitive advantage in the clinical trials industry.”

“If everyone is playing on a level regulatory field, clinical trials will be done where it is cheapest,” says Stark. “If it is just as hard to start a study in Germany as it is in the United States, why would a U.S. manufacturer go to Germany to conduct its clinical trials?”

By bringing about greater regulatory harmonization, FDA’s latest initiative could mean that Europe will lose its competitive advantage. In that case, says Stark, “more studies will go to China and India.”

More Complexity

“Medical device trials are certainly becoming larger and more complex, as devices become more sophisticated, hybrid therapeutic devices become more common, and the marketplace more crowded,” says Colquhoun.

In its press release announcing the HSP/BIMO initiative, FDA observed that today’s clinical trials are very different from those conducted when the agency first began inspecting them in 1977.

“In an effort to protect the rights and welfare of human subjects and to verify the quality and integrity of data submitted for review, FDA established over time a bioresearch monitoring program that included the development and implementation of compliance programs to provide guidance for inspections of investigators, sponsors, contract research organizations, institutional review boards, and bioequivalence facilities,” said the agency’s release.

“With the expansion of clinical trial studies and sites, electronic record-keeping in the studies, and greater participation by vulnerable subjects in clinical trials, the role of FDA’s bioresearch monitoring compliance programs must expand and evolve as well.”

Colquhoun: An end to sloppy trials.

Colquhoun says that the agency’s efforts will force medical device manufacturers to conduct better clinical trials. “My view is that there will no longer be an opportunity to get away with a sloppy trial,” she says. “In my experience, both large and small companies, new and well established, do not always comply with the regulations. This often occurs either because senior management has the attitude that it does not really matter (only the results matter, not the way the data were collected), or because the funds to do things properly are not made available, so corners are cut.”

Stark agrees that current trials practices leave a lot to be desired. “Right now, the mistakes are hidden because recordkeeping isn’t adequate,” she says. “But under the agency’s new initiative, this will change. Monitoring, recordkeeping, generating meta-data, being able to reconstruct every step of a clinical study from original records—these are the things that FDA will care about.

“If a company carries out these activities correctly, any mistakes that it makes—like not giving a subject a treatment, for instance—will show up immediately,” Stark adds.

“Companies should monitor FDA’s reports of inspectional activity, its receptiveness to foreign data, and the percent of data the agency still expects to come from U.S. trials,” says Alexander. “T o ensure FDA acceptance, design and control of trials outside the United States will need to focus on data integrity.

“Device trials inside the United States will be best conducted at highly focused research centers where data quality can be controlled,” she adds. “Executives should ensure they have the right people focused on conducting each part of the study process, including collecting data, data documentation, data management and analysis, and constructive monitoring and auditing.”

For more expert advice on getting the most from clinical trials, see the article by Helen Colquhoun, “Capitalizing on Clinical Research,” which appears in the September/October issue of MX: Business Strategies for Medical Technology Executives. The article is also accessible online by visiting the MX Web site at www.devicelink.com/mx.

References

1. Clinical Investigation of Medical Devices for Human Subjects, Part 1: General Requirements, ISO 14155-1: 2003 (Geneva: International Organization for Standardization, 2003).

2. Clinical Investigation of Medical Devices for Human Subjects, Part 2: Clinical Investigation Plans, ISO 14155-2: 2003 (Geneva: International Organization for Standardization, 2003).

3. ICH Harmonized Tripartite Guideline for Good Clinical Practice, guideline E6 (R1), (Geneva: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996 [cited 18 August 2006]); available from Internet: www.ich.org/cache/compo/276-254-1.html.

© 2006 Canon Communications LLC

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