Medical Device Link.

Clinical Trials: What Executives Need to Know

Is the money spent on clinical trials being used wisely? Executives of device companies need a grasp of the pitfalls of clinical research.

Jeffrey N. Gibbs

Innovation is the lifeblood of the medical device industry. Medical device manufacturers must constantly develop new products and upgrade existing ones. However, while other industries can develop new products—such as computers and software—that can swiftly enter the marketplace unimpeded, new medical devices must pass through a narrow gate presided over by FDA. Getting by that gatekeeper often requires conducting clinical trials.

Not all new device marketing applications need to be supported by clinical data. Although many premarket notifications (510(k)s) do contain such data—particularly for newer types of products—most are not supported by human testing. Similarly, supplements to many premarket approval (PMA) applications do not require clinical data.

Nevertheless, most novel medical devices will need clinical data to qualify for market approval. In fiscal 1999, FDA received 175 investigational device exemption (IDE) applications, and roughly the same number again in 2000. IDEs are necessary for significant-risk devices. Since many clinical studies involve devices that do not pose significant risk to study patients and are therefore conducted without IDEs, the IDE count substantially understates the volume of clinical research with devices.

Of course, it is not enough simply to conduct a clinical study. The study also must be done properly. Failure to correctly carry out a clinical trial so as to yield an FDA approval can prove a costly waste of time and money. Even worse, a poorly conducted study can result in regulatory sanctions by FDA against the manufacturer.

There are many ways in which clinical studies can go awry. Essentially, though, problems fall into the categories of study design and study execution.

For the past decade, FDA has been placing great emphasis on the design of studies for medical devices. The agency has required companies to meet tight standards and use rigorous criteria. For example, FDA has regularly required companies to develop clinically defined study end points, to use control groups if feasible, and to establish predetermined statistical criteria for efficacy and safety. A study that is improperly designed in the agency's eyes will not result in approval, no matter how well implemented.

Recently, however, FDA has been giving much more attention to the execution of clinical trials. It has significantly stepped up its monitoring of clinical studies, looking for cases where device companies and investigators fail to comply with FDA regulations. The agency's increased efforts have been spurred in part by widespread reports of shortcomings in clinical research.

Medical technology executives should be aware of FDA's heightened scrutiny of clinical trials and proceed with studies with full knowledge of what the agency expects. This article summarizes the necessary factors involved in properly executing a clinical study to support an FDA application.

Selecting Investigators

A prerequisite to successfully completing a clinical study is to choose the right investigators. The single most important criterion to keep in mind in making this decision is that the physicians selected must have the qualities required to be good investigators.

A pervasive fallacy is that well known or highly skilled physicians will be good investigators. Neither professional renown nor outstanding medical competence automatically means a physician will be a suitable investigator. Fame and medical expertise are pluses, but investigators need to know how to conduct a clinical trial.

Performing clinical trials requires a different set of skills from those needed to be a good clinician. For instance, successful clinical research hinges on meticulous attention to recordkeeping. Being a good investigator involves maintaining proper, timely documentation. The failure of clinicians to maintain adequate records is, in fact, one of the shortcomings most frequently cited by FDA in its inspections of clinical investigators. Moreover, a good investigator is one who strictly follows the protocol. The creativity that serves a physician well in treating a patient may, in a clinical study, result in deviations from protocol and, thus, unusable data.

A prudent clinical trial sponsor will make sure that its investigators have training in clinical studies. Although FDA regulations require that investigators be "qualified by training," it is not clear whether the training requirement relates to clinical training, training as an investigator, or both. The phrase has generally been regarded as applying to medical training, but it could be interpreted as mandating training in clinical studies. Even if the regulation is ambiguous, the research community is now explicitly requiring training. The National Institutes of Health recently began to require that grant applications contain certification that investigators and their staffs have been trained in good clinical practices. Many institutional review boards (IRBs), the bodies that oversee studies of medical devices, are also starting to mandate that investigators and their staffs be trained.

In evaluating potential investigators, sponsors need to look beyond the physician and assess the staff as well. While investigators receive the most attention, the study staff typically does the bulk of the work. A study site with an incompetent clinical research coordinator is almost doomed to fail, no matter how skilled the investigator.

Another important consideration is whether the investigator can enroll enough evaluatable subjects in the study. Having a large patient population in the general medical discipline is helpful but not sufficient. Enrolled patients must fit the needs of the specific protocol; for example, they must meet the inclusion and exclusion criteria. If a clinical study calls for pediatric orthopedic patients, for instance, the sponsor should make certain that the patient population treated by the orthopedist includes an ample number of pediatric patients. Moreover, the investigator must be able to follow the patients for the period specified in the protocol.

FDA regulations require that each investigator enter into an agreement with the sponsor. The regulation itemizes the elements the agreement should contain at a minimum, such as ensuring that informed consent is obtained from participants and arranging for supervision of all testing. Responsible executives of the sponsoring manufacturer should look beyond the minimum elements of the regulation (see sidebar, page 95) to create a document that will more effectively protect the interests of the sponsor.

Auditing the Study

FDA regulations direct the sponsor to audit the study. Even if this were not required, it would make good business sense as a way for the sponsor to protect its investment.

Typically, audits are performed at three different points. First, a prestudy audit is done to qualify the investigator and the site. One or more audits are carried out during the clinical trial itself to ascertain if the study is being conducted properly. Finally, a closeout audit is performed in order to determine that the documentation is in good order, resolve data discrepancies, confirm that all investigational devices are accounted for, and verify compliance with the protocol and FDA regulations.

Not all studies follow this pattern. For example, if the investigator has been used by the sponsor in the recent past, a qualifying audit may be unnecessary. A short-term study may not require interim audits. An in vitro diagnostic study with banked specimens needs only limited auditing, if any. A study assessing an acute-use product and a long-term cardiac study are monitored very differently. The important point is that auditing practices should be sufficient to detect problems promptly, before they become costly or irreversible.

Of course, detecting a site's shortcomings is not enough. Once problems are spotted, corrective measures must be implemented immediately. Possible solutions include additional training, clearer directives or procedures, resolution of discrepancies in paperwork, frequent telephone calls to the site, and more monitoring visits. If the problems are serious and deep-rooted, the sponsor may have to discontinue use of the site. This is particularly likely if the deviations from acceptable conduct relate to subject safety, such as failure to file adverse event reports; to subject welfare, such as repeated failure to obtain informed consent; or to the integrity of the data, which is crucial to the success of a premarket approval application.

It is very important that effective corrective measures be implemented as soon as problems are found. Sponsors often identify the same deficiencies in repeated sequential audits of a site. It is not uncommon for a monitor to find problems at a site, report those problems to the sponsor, and find them again during the next visit. One recent FDA warning letter cited the manufacturer thus: "There is no documentation that action was taken to correct deviations from protocol by investigators or that investigators were warned that they would be discontinued from the study if they did not comply with the protocol." Company executives must not lose sight of the importance of responding to the audits. If serious problems with a clinical study are allowed to fester, the sponsor runs the risk of accruing tainted data and exposing itself to regulatory sanctions.

Complying with the Requirements

Clinical trials must comply with a variety of fundamental requirements that fall generally into two major categories. Some of these requirements relate to ensuring the accuracy of investigational data, and others to protecting the welfare of study subjects.

To begin with the second category, FDA regulations mandate that all participants in clinical trials provide informed consent. This requires, in virtually all situations, the subject's signing a written consent form before he or she enters the study. This seemingly simple requirement becomes complex when minors, patients with cognitive defects, emergency-care cases, or non-English-speaking subjects are involved. A hospital in Los Angeles, New York City, or other multicultural region may need to prepare consent forms in multiple languages. No excuses are permitted: failure to secure valid written consent from study subjects violates FDA regulations and may result in legal exposure under state law.

Another key element of subject protection is review by the IRB. A clinical study cannot begin at a site until the investigator's review board gives its authorization. An investigator must not start prematurely. The IRB also must periodically review and approve the clinical study. In addition, non-significant-risk (NSR) clinical studies may be undertaken without IDE oversight only if the IRB concurs that the study is, in fact, NSR. The IRB approval letter should specifically state both that the study has been approved and that the IRB found the study to be NSR.

The IDE regulations also impose a variety of reporting requirements upon the sponsor, which company executives must observe. Unanticipated adverse device events must be reported by the sponsor to FDA and the IRB within 10 days of occurrence. Also, if a subject is enrolled without giving informed consent, both FDA and the IRB must be notified within 5 days. And a report updating FDA on the status of the clinical trial must be submitted each year.

FDA's IDE rules prescribe other elements of study conduct as well. The study must be conducted in accordance with its protocol. Study records must be maintained for a specified period. Investigational devices must be properly labeled, and each device used must be clearly accounted for.

Complying with all these regulatory requirements is no simple task, but it is an obligation that clinical research managers must accomplish. FDA regularly audits device clinical trials for adherence to its regulations. Most audits are routine; the agency will usually audit some sites that generated the data to support a PMA. "For cause" audits are responsive to some suspected problem, perhaps to reports by a whistle-blower or to the use of investigators who have previously had problems. Recent FDA inspections have turned up a wide range of violations by sponsors (see sidebar, page 96).

Consequences of Noncompliance

Perfection is a condition not easily attainable. Perfect compliance by sponsor and investigators with all regulatory requirements of a clinical study throughout a trial of even modest duration is highly improbable. Minor problems are to be expected and should not create problems. Significant noncompliance, however, can have serious ramifications.

If FDA identifies noncompliance by the sponsor, it can invoke a range of sanctions, which include FDA-483 notices of observations, warning letters, and civil penalties. In extreme cases, particularly where fraud is suspected, the agency can seek to prosecute the sponsor or place the company on its Application Integrity Policy list. This penalty precludes approval of additional products until the company proves to FDA that future applications are untainted.

FDA can also reject the study data. If the agency finds that patients have been enrolled who do not meet inclusion and exclusion criteria, or that the case report forms were incorrectly completed, or that patients were not examined at the time specified in the protocol, or that patients are lost to follow-up so that their outcome is not known, reviewers may raise a series of questions, delaying approval. If the problems are too profound, or the data submitted are perceived to be unreliable, the data may be summarily rejected.

A failure to comply with FDA regulations can also result in civil liability. Historically, few lawsuits involving subjects allegedly injured in clinical studies have arisen. Given the recent rash of negative publicity pertaining to clinical trials, however, the risks of litigation may grow as patients become less tolerant of mistakes made in the course of clinical research. The likelihood of success of any suit that is brought is greater if the plaintiff can show that the trial violated FDA regulations.

Conclusion

Clinical studies play a critical role in determining which device manufacturers succeed and which fail. Developing a breakthrough product targeted at a huge patient population will mean little if the company does not generate clinical data that meet FDA's standards. While it is necessary to design the study properly, a good design is not in itself sufficient. The well-designed study needs to be complemented by sound execution. Device companies that conduct clinical studies to support FDA approval have to create the infrastructure, allocate the resources, establish the procedures, and train the personnel essential to the successful completion of investigational studies.

Jeffrey N. Gibbs is a partner in the law firm of Hyman, Phelps & McNamara (Washington, DC).

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