ICH Guidelines Clarification

Question 1:

My question is regarding the ICH guidelines regarding document retention (4.9.5). We are an SMO representing investigators and have retained numerous trial-related documents for trials that have been closed for 2 or more years. Many of these INDs/compounds are FDA approved for the marketing application for the indication being investigated. There is no language in our original contracts regarding file retention/destruction. When we wrote to the sponsor to find out what to do with the documents (destroy, return, retain, etc) the sponsor respond with the following language:

As per ICH/GCP guidelines, Section 4.9.5, it is the responsibility of the investigator to retain trial-related documents until at least two years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least two years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period, however, if required by applicable regulatory requirements or by an agreement with the sponsor. Please note that the study completion date does not impact the retention time period of records. It is determined by the ICH/GCP guideline which dictates that status of the compound in relation to clinical development of the investigational product (i.e. if studies continue to be conducted against a compound, even if it has received FDA approval, the Investigational New Drug (IND) is active with the FDA; and therefore continued retention of trial-related records is required by the investigator).

We interpret the same guideline to mean that after 2 years after the drug is approved for the indication for which it is being investigated we do not need to retain the trial-related documents. The sponsor is telling us we must retain the documents until all INDs for the compound are closed, which could be years.

Is this just one sponsor's interpretation or is this the guideline -- that as investigators we are responsible for keeping the documents of a trial until all INDs for a compound are closed, regardless of whether or not the new INDs are related to the protocol and study we conducted.

Also, under FDA guidelines 312.62(c) is more specific in that it states 2 years post-approval for the indication being investigated.

Any clarification would be much appreciated. Please do not hesitate to contact us with any questions.

Answer 1:

I think the answer depends on where the studies took place, and whether they were conducted under a US IND.

Sponsors, monitors, clinical investigators, and contract research organizations that conduct or assist in the conduct of clinical studies for drugs, biologics, and medical devices in the United States must comply with the Food and Drug Administration's (FDA's) regulations for the conduct of such studies. Regulations are enforceable under the Federal Food, Drug and Cosmetic Act. As part of FDA's bioresearch monitoring program, FDA sends its own field investigators out to inspect sponsors, monitors, clinical investigators, and IRBs to ensure that these establishments have followed FDA's regulations during the conduct of the studies. Should FDA's field investigators uncover any deviations from the regulations, then FDA can take enforcement action, such as sending a regulatory letter to the firm, or applying administrative sanctions (e.g., disqualification of a clinical investigator; requiring an IRB to withhold approval of new studies or directing that no new subjects be added to ongoing studies). FDA may also refer cases for criminal prosecution.

If a non-US study is conducted under an IND, then FDA would expect the study to comply with FDA's regulations.

The ICH E-6, Good Clinical Practice: Consolidated Guidance, by contrast has been adopted as official guidance for studies conducted in the US. Guidance differs from regulations, in that guidance represents FDA's current thinking on a topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach can be used if the approach satisfies the requirements of the applicable statutes and regulations. Anyone who wishes to discuss an alternative approach may contact the FDA staff responsible for implementing the guidance. In contrast to regulations, guidance is not enforceable.

When the E6 (GCP Consolidated Guideline) was developed, it was understood that there might be differences in some national GCP requirements between the U.S., the European Union, and Japan, but the purpose of developing ICH E6 was to ensure that studies conducted abroad would meet a standard that would allow for the results to be mutually acceptable to all of the parties involved in developing this standard. Although ICH E6 closely tracks FDA's regulations, there are some instances in which FDA's regulatory requirements are more detailed than those contained in ICH E6; in other cases, the ICH E6 is more detailed than FDA's regulations.

So, which one do you follow? The bottom line is that U.S. regulatory requirements (i.e., FDA regulations) must be met for studies conducted in the United States and for non-US studies conducted under IND. That is, you would need to follow the requirements in 312.62(c).

If a non-US study is not conducted under IND, then following ICH E6 would help to ensure that the study results would be acceptable in the US (if they're submitted in support of a marketing application here).

A site might be required to follow ICH E6, by the regulatory authorities in a non-US country where the research took place, if ICH E6 was officially adopted as regulations by that country. In that case, the essential documents might need to be kept longer than two years, if required by the country's regulations, or at the request of the sponsor.

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