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Beware pitfalls when conducting U.S. research in foreign countries

Clinical Trials Compliance Discontinued, February 4, 2004

Beware pitfalls when conducting U.S. research in foreign countries

In recent years, more and more clinical trials have been moving overseas. A recent study by researchers at Tufts University in Medford, MA, found that U.S. drug companies are increasingly looking to recruit subjects in Eastern Europe, Latin America, and other nations because it's often easier to find people in those places who are willing to enroll in trials.

Although recruitment may come easier, compliance and ethics issues can increase when trials move overseas. "Distance makes it harder to kick the tires," says attorney Robert Nicholas, a partner in McDermott Will and Emery's Washington, DC, office.

Studies conducted overseas may be subject to U.S. standards, according to Nicholas. These include studies

 that are paid for by the U.S. government
 in which data will be submitted to the FDA

If you are not going to use the data in the United States and the trial takes place outside the American border, FDA does not have jurisdiction over the clinical trial, says Nicholas.

Number of trials increasing
In recent years the FDA has received more data for regulatory approvals from outside the United States, says Nicholas. The ultimate sanction for the FDA is its ability to reject trial data. So the principal investigator and institutions need to ensure that data are acceptable to the FDA.

Investigators who submit fraudulent data to the FDA are also subject to disqualification, possible criminal prosecution, and other penalties.

The number of FDA inspections of clinical studies, including those conducted abroad, has actually dropped in the past two years, says Nicholas. However, these statistics should not be viewed as a reduction of FDA concern about clinical studies. Rather, they more likely reflect that FDA has received fewer regulatory submissions for new drugs in the same period. The percentage of inspections may have fallen, but the number has actually risen over the years, says Nicholas.

In 2002 there were 487 clinical study-related inspections of drugs conducted by the Centers for Drug Evaluation and Research, according to Nicholas. Of these

287 involved U.S. clinical investigators
30 involved foreign clinical investigations
166 were reviews of IRBs
15 investigations were related to sponsors,
monitors, or contract research organizations

There were 490 inspections of clinical research in 51 countries outside the United States between 1980 and 2002, Nicholas said.

In 2002, the top five problem areas for clinical investigator inspections abroad included the following:

Failure to follow protocol
Failure to keep adequate and accurate records
Problems with informed consent
Failure to report adverse events
Failure to account for the disposition of study

Complying with the FDA
When the FDA looks at trials abroad, it is focused on the following key issues:

 Subject safety
 Integrity and compliance

The following are two ways in which the FDA controls clinical studies conducted abroad, says Nicholas.

1. The sponsor of the study, whether an individual investigator or a company, applies for an investigational new drug (IND) application or an investigational device exemption (IDE). If the study is conducted under either an IND or IDE, the trial must meet FDA's IND or IDE requirements in order for the FDA to consider the data.

2. When no IDE or IND is filed with the FDA, studies must meet the standards of the country in which they are conducted or conform with the ethical principals outlined in the Declaration of Helsinki, whichever is stricter. The Declaration of Helsinki is an international agreement regarding ethical and other principles for the conduct of clinical research involving humans that includes provisions on informed consent and oversight of the research.

International efforts to harmonize clinical research requirements in the United States, Europe, Japan, and other countries have led to the adoption of a generally recognized set of standards for design, conduct, and data requirements for clinical research involving human subjects. Adherence to the International Conference on Harmonisation's Good Clinical Practice: Consolidated Guidance, will help ensure that data generated will be acceptable to regulatory authorities in several countries, Nicholas says. Following the above requirements for your clinical investigation conducted abroad will help ensure that FDA will not automatically reject study data. However, if the conditions of use of the drug or device studied differ substantially from those expected in the United States, or if the population studied is significantly different than the U.S. population expected to be treated with the study product, FDA may require product approval to bridge studies or additional clinical data to establish the relevance of the study to the FDA label.

In addition to these standards, international trials conducted in Europe will have to follow a new directive beginning May 1. Approved in 2001, member states in the European Union (EU) are required to have implemented legislation effective by May of this year. The research directive is intended to facilitate clinical research in the EU. In many ways the directive is similar to FDA's IND requirements, but there are significant differences, including a centralized database requirement. The directive will place additional requirements on investigations conducted in European states, according to Nicholas.

Potential trouble spots
The difficulty of meeting FDA standards for research conducted abroad likely will vary depending on where the trial is conducted, says Nicholas. For example, a trial conducted in the United Kingdom, which has an established, long-term regulatory regime and experienced investigators, will likely be less complex than trials conducted in developing countries that do not have a vast history when it comes to research.

It is therefore more important to take special care when working in developing nations. "It's important to know that the parties you are working with are knowledgeable about the regulatory requirements, have the infrastructure in place to conduct the study," and regularly monitor the trials, says Nicholas.

Potential trouble spots
One of the problems researchers may encounter when conducting clinical trials in developing countries is ensuring compliance with protocol, particularly with drug regime and with recordkeeping requirements.

In nations where there is no well-defined health care infrastructure and concepts of recordkeeping are not very rigorous, more care will be needed to meet the standards required by the FDA, says Nicholas. It is key, therefore, to ensure that you are working with people who are well trained and understand the regulations, says Nicholas.

It is also critical to understand cultural differences that can affect a trial. For example, it might be culturally inappropriate for a male physician to interview a female subject. "It's important to know the landscape where you are working," Nicholas says.

This is particularly critical during the informed consent process. The National Bioethics Advisory Commission in 2001 released a set of guidelines for investigators conducting trials overseas in developing nations (see related story below). These guidelines are a good starting point for investigators looking to ensure that the highest standards are met.

Tips for preventing problems with overseas trials

In 2001, the National Bioethics Advisory Committee (NBAC) released a report outlining recommendations for clinical trials conducted in developing countries.

These recommendations seek to prevent more "prosperous countries" from "exploit[ing] participants from developing countries heavily burdened by disease," the report states.

"Though no simple answers emerge, we have identified principles that ought to govern such research," Harold Shapiro, NBAC chair and president of Princeton University in New Jersey, said in a written release. "While we cannot remove all of the risks from research at home or abroad, we can reduce the risk of exploiting vulnerable populations." Samplings of NBAC's recommendations include the following:

 Substantive ethical requirements
U.S. researchers and sponsors should comply with high ethical standards for conducting human subjects research. Trials should undergo prior review by ethics review committees; have a reasonable risk-benefit ratio; ensure voluntary informed consent by subjects; and provide an "equitable distribution of the burdens and benefits of research."

 Responsiveness to health needs
The NBAC wrote, "No population, especially a vulnerable one, should be the focus of research unless some of the potential benefits of the research will accrue to that group after the trial."

 Research design
Clinical trials should provide members of any control group with an established, effective treatment, regardless of whether the treatment is available in the subject's home country. Studies that do not meet this standard should justify any "alternative design" to ethics review committees.

 Community involvement
Researchers and sponsors should involve community research representatives in the design and implementation of the trial.
 Voluntary informed consent from participants
"Researchers should not propose, sponsors should not support, and ethics review committees should not approve research" that does not include voluntary informed consent from the subjects in clinical trials, according to Shapiro. "Informed consent should be an ongoing process throughout the research and not merely an initial documentation of willingness to participate in the research," he added. "In addition, U.S. regulations focus primarily on the informed consent document and require written consent. This is impossible for illiterate individuals, and such documents may be viewed as dangerous to sign in countries with oppressive regimes," he says. "Ethics review committees should be allowed to waive the requirement for written consent when alternative means are available to ensure participants' comprehension and voluntary participation."

 Making consent culturally appropriate
Remember to make the informed consent process sensitive to the culture of the subject population. It's important to involve community representatives in developing an informed consent process to ensure that subjects will understand the intent of the clinical trial.

"Researchers should develop culturally appropriate ways to disclose this information," Shapiro said. In some cases, researchers may need to get permission from community leaders in addition to subject participants and involve family members in the informed consent.

However, remember that in order for a subject to participate in a trial you must have the individual's consent in addition to any other consents obtained.

 Post-trial benefits
When a trial ends, an ethical dilemma often remains: What care should be provided to subjects after the trial ends? NBAC recommends before the trial begins that researchers and sponsors ensure that participants will have continued access to all experimental interventions "that [have] proven effective for the participants."

 Ethics review
According to NBAC, all protocols "must be reviewed and approved by a U.S. Institutional Review Board and by an ethics review committee in the host country, unless the host country or host country institution has in place a system of equivalent substantive ethical protections."