FDA Voices
Good Clinical Practices Are Not Optional: The FDA’s Commitment to Human Subject Protections and Gold Standard Science in an Era of Global Clinical Research
By: Michael Davis, M.D., Ph.D., Acting Director, Center for Drug Evaluation and Research; Karim Mikhail, B.Pharm, MSc, Acting Director, Center for Biologics Evaluation and Research; Michelle Tarver, M.D., Ph.D., Director, Center for Devices and Radiological Health, R. Angelo de Claro, M. D., Director, Oncology Center of Excellence
For decades, Good Clinical Practice (GCP) has provided the ethical and scientific foundation for clinical investigations submitted to the U.S. Food and Drug Administration. Its purpose is straightforward: establishing a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that helps ensure that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected. All clinical trials of investigational products submitted to the FDA must comply with GCP.
Today, this foundation is being tested by the scale and globalization of modern clinical research. While there are various benefits to this global expansion, it is also introducing new risks to oversight, transparency, and data integrity. Multi-regional trials without an American patient at all or with only a small percentage of patients in the United States present a variety of concerns for American patients, for the FDA, and, increasingly, for policymakers in Congress. Trials that fail to enroll American patients can be less easily generalized to the population the products are intended to treat. It also means Americans are losing out on the opportunity to participate in trials of innovative or breakthrough medical products.
The third concern with predominantly foreign clinical trials is the focus of this blog: it is more challenging and costly for the FDA to inspect foreign study sites in the same manner as it inspects domestic sites, including the use of unannounced inspections. In addition, the host country may not have the regulatory capacity or authority to provide oversight of clinical trials commensurate with the FDA’s expectations.
The FDA’s position is clear: GCP is not a bureaucratic formality. It is the scientific and ethical foundation on which our regulatory decisions rest.
The Evidentiary Foundation of Regulatory Decision-Making
Every FDA decision to approve a drug, biologic, or medical device depends on the reliability of the data submitted by the sponsor. The legal requirements for the FDA accepting data for regulatory decisions includes protection of human subjects, independent ethical review, informed consent, and the ability of the FDA to inspect trial sites and audit records.
The FDA must be able to validate clinical data in order for it to be used in support of regulatory decision-making. This standard does not depend on geography. It holds whether a trial was conducted in Boston or Beijing, in a well-resourced academic medical center, a community clinic, or a clinical research unit managed by a contract research organization.
The consequences follow directly. If the FDA is unable to validate that data submitted was collected in accordance with GCP, including in sites where the FDA’s ability to perform in-person inspections is constrained or denied, FDA regulations allow the agency to refuse to accept such evidence in support of a marketing application. For medical devices, the same principles apply: all evidence provided in a device submission must be credible, including clinical evidence, and the FDA relies upon only valid scientific evidence to determine whether there is reasonable assurance that a device is safe and effective. For all medical products, if falsified or otherwise invalid data, including duplicated data, are identified during FDA review, or once on the U.S. market, the FDA has the authority to eliminate that data from consideration, and if the remaining evidence cannot sustain the marketing authorization, deny, withhold, or rescind such authorization.
This is not a new policy. It is the logical application of existing law to a rapidly evolving reality.
A Changing Landscape: The Rise of Foreign Clinical Data and Its Challenges
The FDA monitors all aspects of the conduct and reporting of FDA-regulated research through its Bioresearch Monitoring program, a comprehensive program of on-site inspections, data audits, and remote regulatory assessments.
When clinical data, particularly as part of phase 1, investigator-initiated trials, or first-in-human clinical trials, are generated outside the United States, the FDA’s ability to review trial protocols or exercise oversight of the trial sites is limited. Companies should not assume that there is a lower probability of FDA inspection by conducting studies abroad. The FDA is committed to assuring an even playing field for all sites the agency has jurisdiction over. Further, for some foreign inspections of clinical trial sites, the FDA has been denied access or has been told that inspection would require the agency to sign agreements that restrict the scope or conduct of the inspection or attest to geopolitical principles unrelated to the inspection.
Before the FDA opens the door to let a product reach the American market, sponsors and clinical investigators must open their doors to the FDA. That means access to sites and records, including source data, and consent documentation.
The FDA is committed to greater transparency in this area and is actively exploring mechanisms to inform sponsors and the public when inspection access has been denied or conditioned. Sponsors should treat the inability to inspect or access all relevant data as a material factor in their regulatory strategy, not an administrative footnote.
To directly address these challenges — including those specific to oversight of trials conducted outside the United States — the FDA is taking several concrete actions:
Expanding inspection coverage: The FDA is adding resources for foreign Bioresearch Monitoring (BIMO) inspections to expand oversight at foreign clinical trial sites, including through inspecting more phase 1 and early-stage trials, and by expanding the scope of some inspection assignments to include more trials occurring at the facility. The FDA is also planning updates to the risk-based criteria it uses to help identify sites for inspection to better reflect compliance risks for trials conducted in specific countries or regions.
Improving communication with sponsors: The FDA is being more systematic about communicating to sponsors and the public when trial sites and relevant personnel and documents have not been available for inspection, or where inspections were conditioned on agreements the FDA cannot execute. Sponsors who are considering relying on data from those sites should factor this information into their regulatory strategy from the outset.
Strengthening internal reviewer training: The FDA is providing additional training for medical product reviewers to help them identify clinical trial sites where there may be concerns about whether studies have been conducted in accordance with GCPs where required — including, critically, that informed consent was obtained, freely given, and documented as required. Reviewers will be equipped to identify and escalate data integrity concerns. The rights, safety, and well-being of clinical study participants must be protected.
Foreign Data Not Collected Under an IND or IDE: A Priority Area
The FDA recognizes that multinational studies may include domestic sites conducted under an Investigational New Drug (IND) or Investigational Device Exemption (IDE) application, foreign sites conducted under an IND or IDE, and/or foreign sites not conducted under an IND or IDE. Foreign clinical studies not conducted under an IND or IDE may be accepted in support of a U.S. marketing application if the studies were conducted in accordance with GCP, including review and approval by an independent ethics committee and informed consent obtained from all subjects (21 CFR 312.120). As more applications rely on studies conducted outside the United States, the FDA is placing greater scrutiny on whether those data are reliable, inspectable, and ethically derived.
The FDA is prioritizing a more rigorous and systematic review of foreign studies (and sites) not conducted under an IND or IDE and submitted as support for an IND or IDE marketing application. The FDA is particularly concerned about Early Feasibility Studies and Phase 1 studies and sites in countries or regions where geopolitical conditions make informed consent difficult to ensure, or where documented human rights concerns create a heightened risk that consent was not freely and voluntarily given. Audits of clinical trial conduct (across trial phases) have revealed instances of fabricated participants, falsified health conditions, falsified laboratory results, and concealed adverse events.
Commitment to Oversight and Transparency
The FDA also intends to have a renewed commitment to oversight and transparency. This includes:
Increased transparency of inspection findings. When the FDA identifies concerns related to human subject protection or data integrity in sites outside the United States, the FDA will make more information from inspections publicly available, as appropriate, so that sponsors, patients, and the public can understand where deficiencies have been identified and take that into account in development plans. Some of this information is already available and routinely updated on the FDA’s website.
Heightened scrutiny of foreign data generated outside of an IND/IDE non-IND studies and sites. The FDA will be increasing its attention to clinical studies (and sites) not conducted under IND or IDE, and specifically in jurisdictions where conditions raise concerns about data integrity or genuine informed consent. The agency will use all available tools — including requests for additional information, reanalysis, and inspection — to satisfy itself that GCP was met before such data can be accepted in support of a regulatory decision.
Active engagement at the pre-submission stage. The FDA will discuss the provenance and IND or IDE status of foreign clinical data with sponsors early in development. Early discussions, including through pre-IND meetings, Type B meetings, and Q-submissions for devices, will better position both parties to identify and address data integrity, human subject protection, and related issues prior to application review.
Unreliable or Unethical Data is not Evidence – it's Risk
The United States has long been the preeminent center of clinical research precisely because the regulatory system here provides a credible assurance that approvals mean something. Patients, physicians, and payers make decisions based on the FDA’s determinations. Those determinations are only as good as the evidence underlying them. The FDA does not allow its approval authority to serve as the terminal validation of evidence that was never truly trustworthy or unethically derived.
This is not protectionism, and it is not a geopolitical statement about any particular country’s scientific capacity. Many foreign research institutions produce clinical data of the highest quality, and the FDA actively welcomes and relies on such data. What the FDA is saying, plainly and with full intent to act on it, is that the standard is the standard. Geography does not change the evidentiary requirements. And it is incumbent on those sponsors coming to the FDA to meet these requirements.
For innovation to reach patients, those patients must be willing to participate in clinical research. That willingness is built on trust. Trust that researchers are acting in their interests. Trust that the regulator reviewing the data can distinguish reliable evidence from unreliable evidence. The FDA is worthy of that trust, and it expects the clinical research enterprise — in the United States and globally — to share that obligation.
The message to sponsors is straightforward: plan your development programs to comply with all GCPs and proper human subject protection, in trial settings where FDA access will not be impeded from day one and data integrity and informed consent are prioritized. If you are building a regulatory strategy around clinical data from sites where the FDA has been unable to inspect, or from circumstances where the conditions for ethical research are in serious question, think again.