Global Trials Draw Regulatory Scrutiny

The global expansion of pharmaceutical production and clinical research has put pressure on the FDA to step up its oversight of foreign drug development and production. The scandal over contaminated heparin imports has spurred Congressional investigations and proposals for legislative reform. And with thousands of clinical trials taking place all over the world, policy makers want to know how well FDA and sponsors can ensure the validity of foreign data and of investigator compliance with good clinical practices (GCPs).

Biopharmaceutical companies are eager to launch studies in these regions to gain access to larger numbers of patients with untreated conditions. Local clinical trials also can facilitate entry into fast growing Asian markets for medical products. But the rapid expansion of research in China, India, and other newly industrialized nations—and variations in national legal requirements related to informed consent and ethics board oversight—create challenges for ensuring appropriate protection of patients.

Jill Wechsler

Clearer rules

One FDA response is to clarify its requirements for conducting foreign clinical studies intended to support a market application in the United States. FDA will accept data from overseas trials not conducted under an IND (investigational new drug application); the agency even has approved a few drugs solely on foreign studies. About half of all trials submitted to support pivotal studies include at least some foreign data, pointed out FDA Senior Advisor for Clinical Science David Lepay at DIA's annual meeting in June. And reliance on non-U.S. data is likely to rise along with growth in overseas trials.

To ensure that foreign data will be accepted by the agency, FDA published a final rule in April, which goes into effect in October, clarifying that studies must follow GCPs, including approval by an independent ethics committee or institutional review board (IRB). This policy replaces an earlier requirement that clinical trials must follow the ethical principles described in the 1989 version of the Declaration of Helsinki—a controversial change that has raised questions about U.S. support for international ethical guidelines.

The rule describes what information sponsors should provide about investigators, research operations, protocol design, and trial oversight to demonstrate adherence to GCPs and an ability to ensure data quality. FDA emphasizes that sponsors cannot just certify compliance with GCPs but have to document how they meet requirements. FDA seeks to be flexible, to minimize duplicative information requests, and to accommodate multinational studies with sites in and outside the United States.

Transforming Clinical Trials

Separately, FDA is supporting efforts to harmonize procedures and policies for conducting international clinical trials for medical devices. The Global Harmonization Task Force (GHTF) for developing and updating medical device regulatory requirements has issued a proposed document outlining general principles of clinical investigations for medical devices. FDA published a notice in July seeking comments on the GHTF approach and how it differs from U.S. policy.

More inspections

Under its final rule on foreign clinical studies, FDA notes that it retains the right to validate clinical research data in the United States and abroad through on-site inspections. FDA normally audits several pivotal study sites listed in an application, but the growth in overseas trials makes it difficult for the agency to keep up the pace. FDA has doubled the number of international GCP inspections for drugs from less than 50 in 2000 to more than 100 last year. These foreign inspections account for about 10% of FDA's 1024 bioresearch monitoring (BIMO) inspections in 2007. That's still a paltry number, and it includes very few site visits in Asia despite a surge in research activity in India and China. The number of overseas GCP inspections is expected to grow in 2009 due to rising political pressure plus increased resources to support FDA oversight of food and drug imports.

FDA's familiarity with political and scientific issues affecting foreign drug development is slated to gain from on-the-ground regulatory offices in critical parts of the world being established under commissioner Andrew von Eschenbach's "Beyond our Borders Initiative." The first in-country operation will be in China, followed by similar offices in India, Europe, Latin America, and the Middle East.

FDA hopes to open offices in Beijing, Shanghai, and Guangzhou by year end with a relatively small staff of 13. They will conduct some site inspections, but primarily will work with local regulatory authorities to better track enforcement activities, to become more informed of legal and political issues affecting drug regulation, and to further acquaint Chinese regulators and manufacturers with U.S. quality standards and enforcement policies.

India is next in line, and FDA is negotiating to establish offices in New Delhi and Mumbai to oversee the vast volume of drugs and active pharmaceutical ingredients (API) exports and to better monitor burgeoning research activity. More than 500 registered trials are being conducted in India, up from about 50 five years ago. Major research centers in India have established IRBs and emphasize compliance with GCPs as well as policies set by the U.S. Office for Human Research Protections (OHRP).

More cooperation

Despite additional funding to support more foreign inspections and overseas operations, there is broad agreement that FDA will never have enough resources to catch everything. This reality is building support in the United States and abroad for collaborations among regulatory authorities to leverage resources and reduce redundant oversight activities.

FDA has more than 70 cooperative arrangements with foreign counterparts that facilitate information sharing on inspections and safety. Some 30 confidentiality agreements permit disclosure of more detailed reports and data. Such information can help regulators learn more about foreign facilities and research activities in making decisions about where to target foreign inspections.

Another collaboration will test the benefits of better coordinated foreign drug manufacturer inspections. FDA is teaming up with the European Medicines Agency (EMEA) and Australia's Therapeutic Goods Administration to consult on inspection schedules and reports, initially for active ingredients manufactured in China and India. If successful, the program could expand from APIs to drug products and other activities.

Third-party certification provides a further approach for more efficient use of regulatory resources. FDA seeks to accredit government and independent entities capable of verifying that certain operations or products comply with U.S. standards. Similarly, accreditation of clinical investigators, research sites, and ethics committees in the United States and abroad has been discussed by OHRP, FDA, and research organizations as a way to streamline oversight while ensuring compliance with research standards.

FDA also is expanding support for regulatory "capacity building," particularly to broaden understanding of ethical standards involved in clinical research and the importance of local ethics boards in protecting the rights of human research participants. More capable regulatory authorities in other regions can further bolster FDA efforts to ensure compliance with GCPs.

Although information sharing and joint inspection activities can make the foreign inspection process more efficient and productive, neither FDA, EMEA nor other regulatory authorities are ceding their right to make independent enforcement decisions regarding any research site or facility. The hope is, though, that joint oversight will breed confidence in the approaches and decisions of colleagues, explained EMEA Head of Inspections Emer Cooke at the DIA annual meeting. These collaborative activities eventually could lead to increased reliance on each other's inspections, Cooke suggested, adding that "cooperation, not competition" is the key.

Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com