Recent policy changes emphasize the need for sponsoring organizations to be even more vigilant in establishing, updating and monitoring their systems for compliance with clinical research requirements,
whether conducted domestically or in a foreign locale.

Both the European Medicines Agency (EMEA) and the U.S. Food and Drug Administration (FDA) have taken recent actions, jointly and independently, that demonstrate an increasing focus on safety and enforcement issues with clinical research. The recent changes announced by the FDA and EMEA demonstrate a renewed concern and greater emphasis on regulatory controls and procedures, particularly with regard to adherence to Good Clinical Practice (GCP) requirements for clinical trials conducted outside of the European Union and United States. Nevertheless, both agencies are attempting to accomplish these changes with maximum cooperation and minimum disruption to industry.

Discussion

FDA Reforms

In May 2009, Deborah Autor, director of the FDA’s Center for Drug Evaluation and Research (CDER) Compliance Office, was quoted as saying, “In today's rapidly changing environment, complacency is not an option . . . I do predict more action. Tell your clients and companies to get going.” Recent actions by FDA have supported this prediction and could be interpreted as evidence of a new FDA policy focusing on increased safety and enforcement in clinical research.

On August 10, 2009, the FDA announced that it would make changes to the manner in which the FDA disciplines medical researchers who violate federal regulatory requirements, announcing that it would modify procedures to permit the agency to process such actions faster. The FDA has designated an administrative law judge to serve as presiding officer for administrative hearings of researcher misconduct, assigned the Good Clinical Practice Program office to oversee disqualification proceedings and assigned dedicated staff to debarment proceedings. Several members of the U.S. House of Representatives Committee on Energy and Commerce, the committee with principal FDA oversight, have also requested that the U.S. Government Accountability Office (GAO) examine FDA’s debarment and disqualification procedures, although GAO has yet to release this report.

At a presentation to the Food and Drug Law Institute in Washington, D.C., on August 6, 2009, FDA Commissioner Margaret Hamburg cited enforcement of the law as “critical to the agency’s public health mission,” and announced six “initial steps to strengthen enforcement at the FDA.” Each of these steps is directed at improving the ability to more effectively and quickly address potential violations of FDA laws and regulations. Specifically, Commissioner Hamburg announced the following steps:

  • FDA will set post-inspection deadlines, providing generally no more than 15 working days after the issuance of an FDA Form 483 (Notice of Inspectional Observations) at the inspection exit interview to respond before FDA proceeds with a warning letter or enforcement action. These changes will be announced in the August 10, 2009, Federal Register and will be effective for Form 483 reports issued on or after September 15, 2009.
  • FDA will speed up the issuance of warning letters, one of the agency’s principal enforcement tools, by limiting review of warning letters by the FDA’s chief counsel to only “significant legal issues.” This change eliminates a policy established in 2003 requiring review of all warning letters by the office chief counsel prior to issuance.
  • FDA will work more closely with regulatory partners at the local, state and international level to develop effective risk control and enforcement strategies.
  • FDA will prioritize enforcement follow-up, making it a priority to follow up with appropriate action, such as inspection or investigation, once a warning letter is issued or a major product recall occurs.
  • FDA will no longer issue multiple warning letters before taking enforcement action, and will now consider immediate action prior to issuance of a warning letter in cases that raise significant health concerns or egregious violations.
  • As a carrot to encourage quicker remedial action by recipients of warning letters, FDA will establish a “close-out” process, whereby an organization that has received a warning letter that has been determined by FDA to have corrected the violations, usually through re-inspection, may be issued a “close-out” letter indicating that the issues in the warning letter have been successfully addressed.

EMEA Reforms

The EMEA has indicated within recent publications that it also intends to pay increased attention to enforcement issues relating to researcher misconduct, specifically relating to GCP compliance, in the coming years. EMEA has expressed a specific intent to target GCP compliance issues with regard to clinical trials conducted in non-EU countries where the data is used to support applications for marketing authorization in the European Union. Moreover, the EMEA has stated within its Work Plans that it intends to continue to focus on enforcement activities related to GCP compliance.

The EMEA Strategy Paper titled “Acceptance of Clinical Trials Conducted in Third Countries, for Evaluation in Marketing Authorisation Applications,” issued on December 5, 2008, announced the intention of the EMEA to address a “growing concern . . . about how well these [clinical] trials are conducted from an ethical and scientific/organizational standpoint (including GCP compliance) and about the available framework for the supervision of these trials.” Within the Strategy Paper, it states that the “EMEA Work Programmes for 2008 and 2009 set out a number of actions relating to clinical trials conducted in third countries,” including verification of GCP and ethical compliance at the time of evaluation of the data, greater transparency of the evaluation process and increased GCP inspection for clinical trials performed outside the European Union. The Strategy Paper sets forth a three-year plan of activities for December 2008 to December 2010 to address pre-authorization, concurrent review during application and post-authorization monitoring of compliance with clinical development processes.

Moreover, the EMEA Work Plan for GCP Inspectors Working Group for 2009, issued January 2009, states that one of its three priorities is to “[d]evelop processes and capacity building in relation to GCP and inspections of clinical trials conducted in third countries.” This provides further support for the EMEA’s increased attention to GCP and other research noncompliance issues, particularly with regard to clinical trials data gathered in non-EU countries.

EMEA-FDA GCP Initiative

In addition to other activities the FDA and EMEA have undertaken independently to address research misconduct and GCP compliance, both agencies have recently undertaken a new cooperation initiative to conduct joint inspections and share information about clinical research data. On July 31, 2009, the EMEA and the FDA announced that they have jointly agreed to launch the EMEA-FDA GCP Initiative. The Initiative is a joint effort between the CDER and the EMEA to “ensure that clinical trials submitted in drug marketing applications in the United States and Europe are conducted uniformly, appropriately, and ethically.”

The Initiative will be governed by the confidentiality agreement between the EMEA and the FDA announced on September 12, 2003, which permits sharing of pre- and post-approval regulatory information about medicinal products subject to evaluation or authorized under the centralized procedure, including regulatory issues, scientific advise, orphan drug designation, inspection report, marketing approvals and post-authorization surveillance information. SeePublic Statement, “EU-FDA Bilateral Meeting.”

The Initiative will have three key objectives:

  • Conducting information exchanges between the United States and the European Union on GCP information
  • Conducting collaborative GCP inspections
  • Sharing information in interpretation of GCP

The Initiative is planned to begin with an 18-month pilot phase, beginning on September 1, 2009, that is limited in scope to consideration of those products regulated by CDER (over-the-counter and prescription drugs, including biological therapeutics and generic drugs) and/or the EMEA under EU centralized procedures (human medicines derived from biotechnology processes, such as genetic engineering; advanced-therapy medicines, such as gene-therapy, somatic cell-therapy or tissue-engineered medicines; medicines intended for the treatment of HIV/AIDS, cancer, diabetes, neurodegenerative disorders, autoimmune diseases and other immune dysfunctions, or viral diseases; and officially designated “orphan medicines,” or medicines used for rare diseases). Once the pilot phase is completed, the EMEA and FDA will jointly assess the results of the pilot and develop an amended process and scope for the fully implemented Initiative.

The Initiative marks a significant step towards the continuing globalization of regulation of human medicines and the adoption of GCP as an international standard for conducting clinical trials. For example, on April 28, 2008, the FDA announced revised guidance on the standards under which the agency will accept data from foreign clinical trials in support of domestic applications and submissions. 73 Fed. Reg. 22800, 22812 (Apr. 28, 2008). The FDA’s revised regulations now require foreign clinical trials used as support for an investigational new drug, a new drug approval or an abbreviated new drug approval application be conducted in compliance with GCP regulations.

Conclusion

The recent actions of the FDA and the EMEA with regard to increased attention to clinical research misconduct and compliance with GCP demonstrate an increased focus on enforcement activities relating to safety issues in clinical research. Both the FDA and EMEA have shown through recent policy changes and announcements that they both intend to pay closer attention to whether clinical research is being conducted in an ethical manner and in compliance with regulatory requirements and GCP principles. Nevertheless, both agencies have made it clear that they intend to accomplish their goals while attempting to cooperate with industry needs for prompt action and resolution of issues.

These policy changes emphasize the need for sponsoring organizations to be even more vigilant in establishing, updating and monitoring their systems for compliance with clinical research requirements, whether conducted domestically or in a foreign locale. Sponsoring organizations must ensure, and be in a position to demonstrate, compliance with international standards of practice such as GCP, as well as compliance with additional requirements that relate to the location (e.g., the United States or the European Union) of the submission for marketing approval.