Post updated 28 January 2011: Just what is a trial master file or TMF? What are “Essential Documents?” How does FDA expect to see researchers document a clinical trial? Are there differences between FDA and EMA, the European Medicines Agency in TMF requirements? UPDATE: Read the Final version of the “EMA Reflections” Document on EDC, released after this post was originally published.
It is interesting to note that although “TMF” is a standard industry term in the United States and is used by regulators around the world, the FDA doesn’t actually have a TMF inspection and rarely uses the term. FDA regulations are vague about the exact documents required for a clinical trial. In a response to an inquiry about documents answered by “GCP Questions,” a program within the Office of the Commissioner, FDA stated on 02 November 07:
“FDA’s regulations are intentionally pretty general, the reason for this is that the agency believes that sites and sponsors should have the necessary flexibility to adopt procedures that will comply with the regulatory requirements, and make sense (given the complexity of the study and available staff), without being unnecesarily burdensome.”
While this may be a commendable intent, it isn’t particularly helpful. I understand that regulations and guidance documents can’t be overly specific, but vague guidance on regulatory compliance leads to what I call, “regulation by rumor.” People will use an anecdote they have heard about what they think an FDA investigator wants in order to determine what documents FDA considers essential to a clinical trial. This can cause real problems between a clinical site and a monitor or auditor. There are genuine differences on how to document protocol deviations and other issues.
The term “trial master file” comes from the ICH E6 Guidance Document on Good Clinical Practice (E6). (Links to E6 and other documents related to this post are listed at the conclusion of the post.) Section 8 of E6 is called, “Essential Documents for the Conduct of a Clinical Trial.” In the introduction to Section 8 the Trial Master File is discussed. I consider E6 to be the authoritative document on the subject. Section 8 has a comprehensive list of Essential Documents, their location and what is necessary before, during, and after a clinical trial. When I define “TMF” I use the documents listed in Section 8 as my primary guidance. The only significant addition to this list (that I am aware of) is the FDA requirement for a Final Report, from the investigator to the sponsor. (I have an article on Final Reports at the conclusion of this post.)However, some regulatory authorities don’t seem to be emphasizing E6 as much as they may have in the past. It has been suggested that there might be additional “Essential Documents” although no regulatory agency that I know of has published a comprehensive list that could complement E6. Also, it has been suggested that there may be a “Good Clinical Practice” standard other than E6. FDA stated this when they rewrote the requirements for Foreign Clinical Studies Not Conducted Under an IND (21 CFR 312.120). Where you can find an alternative GCP isn’t discussed.
I think that E6 gives sound recommendations for GCP compliance. We should be using it more, not less. It has been published in the Federal Register as official FDA Guidance. It is the only guidance that FDA has on the TMF.
When discussing the TMF one of the trickiest issues involves electronic records, including electronic medical records (EMRs) at a hospital or medical center. There is a lot of grey area as far as protecting privacy, access to EMRs, and the validation of an institution’s EMR system. Unfortunately there isn’t a definitive guidance document on the topic of EMRs. FDA does have a guidance document on “Computerized Systems Used in Clinical Investigations.” It is found in the Important References section on your right, along with E6. Another resource that I recently became familiar with is a document from EMEA with the clever name of “Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials.” I’ve attached a PDF copy for your viewing pleasure at the bottom of the post. It contains some excellent recommendations. (Also attached is the final document released after this post was originally written. It is very similar: See “EMA Reflections”)
The “Reflections” document discusses Assigning Responsibility for maintaining clinical trial records. FDA regulations assign responsibility to either the sponsor or the clinical investigator. The “Reflections” document notes that the clinical site needs to maintain control over source documents and not hand over the responsibility to a sponsor. Source documents are the responsibility of the clinical investigator. This includes worksheets or standardized forms that a sponsor might prepare for a site in order to conduct the study according to the protocol. Even though the worksheets are written by the sponsor, they become the Responsibility of the Investigator. Lately FDA has taken to making this point on Warning Letters. Here’s an example from a recent FDA Warning Letter to a clinical investigator on the subject of “adequate and accurate subject case histories.”
“Your site chose to use the sponsor’s standardized forms as source documents to record and document information related to the subjects’ study visits. Per the standardized form, your site was to “Complete the Inclusion/Exclusion Criteria Worksheet to evaluate for study eligibility.” In the FDA investigator’s review of 16 of 65 subject records at your site, there was no Inclusion/Exclusion Criteria Worksheet found for any of these subjects.”Notice that FDA considers that the site “chose” to use the sponsor’s forms. These records are the responsibility of the clinical investigator. As such, if there is a problem with them during an FDA inspection, then the problem belongs to the clinical site. In this case, the problem was significant enough to result in a Warning Letter. Having solid documentation of a clinical baseline, including recording the Inclusion/Exclusion Criteria are Very Essential Documents. It should be noted that this clinical investigator had a lot of additional problems, not just the sponsor’s standardized forms, or worksheets.
The EMA “Reflections” document gives some good advice for clinical trial recordkeeping. They use the old FDA guidance ALCOA- Attributable, Legible, Contemporaneous, Original, and Accurate and add four additional elements. They are Complete, Consistent, Enduring, and Available When Needed. The last point is particularly important. If you can’t show the document to a regulatory inspector, then for the purposes of the inspection, it doesn’t exist. I would add one additional element; QUALITY. People sometimes place importance on fax coversheets, which are not Essential Documents, instead of the quality of the source documents that document a clinical baseline and protocol-required activities.The quality of the documents used to support an application for a new drug or medical device is sometimes overlooked, to the detriment of Good Clinical Practice. These are the documents used to protect human subjects in research and ensure data integrity. Their quality should allow them to “stand alone.”
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Updates posted 28 JAN 2011- Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma
UPDATE 28 JAN 2011: There is a very interesting Important Notice to IRBs that is on the FDA website. Sort of a Coast IRB redux.
UPDATE 6 January 2011: Two Important New GCP Documents:
There is a Draft Guidance on Electronic Source Documentation in Clinical Investigations. The comment period is for 90 day (April 4, 2011 ?)
There is a new Final Rule on required elements of Informed Consent. You can read the Federal Register Announcement here that includes FDA comments in the preamble. The exact change in 21 CFR Part 50 is:
“Sec. 50.25 Elements of informed consent.
* * * * *
(c) When seeking informed consent for applicable clinical trials,
as defined in 42 U.S.C. 282(j)(1)(A), the following statement shall be
provided to each clinical trial subject in informed consent documents
and processes. This will notify the clinical trial subject that
clinical trial information has been or will be submitted for inclusion
in the clinical trial registry databank under paragraph (j) of section
402 of the Public Health Service Act. The statement is: “A description
of this clinical trial will be available on
http:[sol][sol]www.ClinicalTrials.gov, as required by U.S. Law. This
Web site will not include information that can identify you. At most,
the Web site will include a summary of the results. You can search this
Web site at any time.”
Update: Read the Final Reflections Paper from the European Medicines Agency on Electronic Data Capture:
Also: There are a couple of very good comments to this post by experienced professionals. They are well worth reading.
Here is the E6 document:
Here is the FDA guidance document on “Computerized Systems Used in Clinical Investigations.“
Here are some links that will be of use in researching original data and certified copies:
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