When FDA Accepts Data From a Trial Run Abroad

Answer first: two conditions, and one of them is about verifiability

The rule is 21 CFR 312.120, headed "Foreign clinical studies not conducted under an IND." It says FDA will accept, as support for an investigational application or an application for marketing approval, a well-designed and well-conducted foreign clinical study not conducted under a US investigational application, if two conditions are met.

The first is that the study was conducted in accordance with good clinical practice. The second is short and consequential: FDA is able to validate the data from the study through an onsite inspection if the agency deems it necessary.

That second condition is not about the science. It is about whether the agency can go and look. A study whose records could not be inspected does not meet the rule regardless of how well it was run.

The regulation then adds a sentence that prevents a misreading. Although FDA will not accept as support a study that does not meet those conditions, it says, FDA will examine data from such a study. Examining and accepting as support are different acts, and the rule keeps them apart.

Context for why this rule exists at all: under 21 CFR 312.20 a sponsor may not begin a covered clinical investigation until a US investigational application is in effect. Section 312.120 is the route for studies that were never under one.

The regulation defines good clinical practice in its own text

This is unusual and useful, because the phrase is otherwise used loosely. For the purposes of this section, the regulation says, good clinical practice is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected.

Two objectives, stated together: credible and accurate data, and protected subjects. The definition treats them as one standard rather than as competing goals.

It then names what the standard specifically includes. Review and approval — or provision of a favorable opinion — by an independent ethics committee before initiating a study. Continuing review of an ongoing study by that committee. And obtaining and documenting the freely given informed consent of the subject, or of a subject's legally authorized representative if the subject is unable to provide it, before initiating a study.

There is a narrow carve-out for emergencies. Good clinical practice does not require informed consent in life-threatening situations when the ethics committee reviewing the study finds, before initiation, that informed consent is not feasible and either that the conditions present are consistent with those described in the US regulations governing exceptions from consent, or that the measures described in the protocol or elsewhere will protect the rights, safety and well-being of subjects.

The eleven things a sponsor has to describe

Paragraph (b) requires a sponsor or applicant submitting foreign data to describe the actions it took to ensure the research conformed to good clinical practice, either directly or by cross-reference to another part of the submission. The list is specific enough to be worth reading in full.

The investigator's qualifications. A description of the research facilities. A detailed summary of the protocol and results of the study — and, should FDA request, case records maintained by the investigator or additional background data such as hospital or other institutional records. A description of the drug substance and drug product used in the study, including components, formulation, specifications and, if available, bioavailability of the specific product used.

If the study is intended to support effectiveness, information showing that the study is adequate and well controlled under 21 CFR 314.126 — the same standard applied to domestic evidence, with its stated purpose of distinguishing a drug's effect from spontaneous change in the disease, placebo effect and biased observation.

The name and address of the ethics committee that reviewed the study, and a statement that it meets the regulatory definition — with the sponsor required to maintain supporting records including the names and qualifications of committee members and to make them available on request. A summary of the committee's decision to approve or modify and approve the study, or to provide a favorable opinion. A description of how informed consent was obtained.

A description of what incentives, if any, were provided to subjects to participate. A description of how the sponsor monitored the study and ensured it was carried out consistently with the protocol. And a description of how investigators were trained to comply with good clinical practice and the protocol, plus a statement on whether written commitments by investigators to comply were obtained — with any signed commitments to be maintained and made available for agency review.

The incentives item is the one most likely to be overlooked and the most revealing. What subjects were offered is part of the record the agency expects to see.

Waivers, records, and one boundary the section does not cross

The regulation includes a waiver route at paragraph (c). A sponsor or applicant may ask FDA to waive any applicable requirement of the acceptance conditions or the supporting-information list, in an investigational application or amendment, or in a marketing application, amendment or supplement.

A waiver request must contain at least one of three things: an explanation why compliance is unnecessary or cannot be achieved; a description of an alternative submission or course of action that satisfies the purpose of the requirement; or other information justifying a waiver. FDA may grant a waiver if it finds that doing so would be in the interest of the public health.

Records have a defined life. If the study is submitted in support of a marketing application, the sponsor or applicant must retain the required records for two years after an agency decision on that application. If it is submitted in support of an investigational application but not a marketing application, for two years after the submission of that investigational application.

And there is a boundary the section marks explicitly rather than leaving to inference. Marketing approval of a new drug based solely on foreign clinical data, it says, is governed by a different regulation. So 312.120 answers whether foreign data may be used as support. It does not by itself answer whether an approval may rest on foreign data alone.

What this changes when you read a claim about a study

The practical value of knowing this rule is that it converts a vague suspicion into a specific set of questions with documented answers.

A trial conducted abroad is not, for that reason, weaker evidence. The regulation applies the same effectiveness standard — 21 CFR 314.126 — to a foreign study intended to support effectiveness as to a domestic one. What differs is the paperwork proving the conditions were met, and the requirement that the agency be able to inspect if it decides to.

It is also worth being precise about what a clinical investigation is in this context. The definition at 21 CFR 56.102(c) covers any experiment involving a test article and one or more human subjects that either must be submitted to FDA in advance, or need not be but whose results are intended to be later submitted to, or held for inspection by, FDA as part of an application for a research or marketing permit. Intent to submit is part of the definition.

So when a company says a product was studied overseas, the answerable questions are: was the study intended to support a US application; was an independent ethics committee involved before it started and during it; how was consent obtained and documented; what incentives were offered; and, if effectiveness is being claimed, does the study meet the adequate and well-controlled standard. Each of those is something the regulation requires to exist in writing.