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.
Documentation Requirements for Clinical Trials
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.)
ICH E6 Sets the Standard for Essential Documents
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”)
Electronic Medical Records
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 FDA's Wording in Warning Letters
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.”
References:
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:
E6_ICH_GCP
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:
Compliance Policy Guide 130.400 (equivalent to 7150.13)
Applied Clinical Trials: CDISC Clinical Research Glossary
And finally on Notes to File:
http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article/articleDetail.jsp?id=500437
Please remember, your comments, questions, complaints, and advice are always welcome !!!
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2012 CAPAs in the GCP Environment
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GxP Perspectives 
Hello Carl, thank you for an interesting presentation regarding Trial Master Files. I have a question regarding access to electronic medical records. For patient privacy, it seems that hospitals often deny the sponsor to have direct access to electronic patient medical records. As a result, research staff tend to place copies of the pertinent study information (i.e. source documents that correspond to CRF data) in a ‘shadow chart.’ I am not questioning attribution here, but rather 1) would you happen to know – doesn’t a sponsor’s monitors have the right to obtain direct access as indicated in the informed consent, and 2) does it suffice to place only study pertinent information in a shadow chart? In my opinion, a monitor should be able to evaluate the patient’s overall clinical picture to ensure protocol compliance, and not be limited to documents supplied by the site coordinator. Yet, I am hearing from various sites that they use shadow charts for many studies.
Hi DS:
These are great questions. Thanks for a great topic for my next post!! Briefly, your answer is yes, the ICH E6 definitions section defines “Direct Access” as this:
“1.21 Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor’s monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects’ identities and sponsor’s proprietary information.”
This means that the sponsor should secure, “direct access.” A “shadow chart” does not meet FDA recommendations for ALCOA: Attributable, Legible, Contemporaneous, Original, and Accurate. A “shadow” is not Original. That doesn’t mean that there are not some important uses for a shadow chart, it just means that you need something more.
In addition, a sponsor should have some mechanism for ensuring that the copies of electronic medical records placed in a subject’s charts are complete and accurate. That means having access to the original medical record, which brings us back to “direct access.”
I will have more to say about this important recordkeeping issue in the near future.
Carl
Lots of evidence of GCP (good communication and pragmatism) on your blog plus links to useful locations for further reading.
I am a particular fan of your article on notes to file which I would like to see as recommended reading in induction programmes for anyone involved in clinical research. All too often excessive energy is dissipated on documenting what has happened rather than being channelled more constructively to the corrective action(s) taken to prevent further lapses. The other major snag with so-called notes to file is the recipient is a written document rather than individual who could be directed to take action. Imagine explaining to a child what you do at work when you find something has gone wrong — “oh, I wrote a note to the file”……….. the question is likely to follow is WHY? Indeed, encouraging all those involved in clinical research to stop and ask themselves a few open questions before proceeding to action could yield meaningful outcomes and valuable learning experiences.
It is also interesting how many terms exist in clinical research that are not always matched consistently by what is written in the regulations — you give the example of the Trial Master File. Another interesting example is how often the word TRAINING is used yet, going back to ICH GCP, the only mention of training investigators is in exceptional circumstances (5.18.3) as a measure to asssure appropriate trial conduct where on-site monitoring is not possible. Of course, sponsors should provide investigators with sufficient information to conduct a protocol/trial properly but is this what is intended by the term TRAINING? It seems quite a leap telling an investigator that you’re going to TRAIN them when what you really going to do is provide them with a protocol and details of the test article followed by a discussion of their contents and GCP requirements — I suspect the use of the term training in this context is a source of much misunderstanding.
Perhaps this is semantics? Then again, when I last bought a new car I don’t recall considering myself TRAINED when the salesman gave me the manual together with an overview of the dashboard controls…..fellow motorists I passed soon after leaving the showroom would probably agree!
David
Hi David,
Thanks for your comments. Did you know that training violations are among the hardest to prove for an FDA investigator? The reason is that the requirements are so vague. You have to tie it to a violation unless the protocol requires the training to take place.
There is a recent Warning Letter to a clinical investigator issued by the Center for Drugs that I feel is a training issue- as well as a serious informed consent violation. I will be writing about it over the weekend. I also like your comments on Notes to File. That is a great analogy with the child receiving a note to file when a mistake has occurred. I appreciate your insights. Some excellent comments on training.
Hi Carl,
I have read the post on GCP site training and your thoughtful reply. As you know, with the additional scrutiny being placed on whether a Sponsor is providing appropriate oversight over a CRO once a TORO has been finaled and signed, I anticipate that FDA will be further examining the effectiveness of training at the Investigator’s Meeting and during the site initiation process. What has been your recent experience and do you have an opinion regarding the extent of protocol and GCP training that should be conducted at an Investigator’s meeting?
For those who don’t know Michael he is a longtime consultant in the world of CROs. The TORO is the transfer of obligations between a sponsor and CRO. I have seen some that have been very poorly written. They should “stand alone” and be acceptable to give to FDA during an inspection. To answer Michael’s question, I am always never invited to Investigator Meetings. However, that is the place for substantive investigator input and training – a two way conversation – about the protocol.
I might add that David is a resident of the United Kingdom and a Manager of Clinical Research Training at ACRP, the Association of Clinical Research Professionals. Very useful insight.
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Hi. Where may i find info on the regulations re: the need for wet ink signatures for eTMF documents? In my company’s eTMF system there are about 15 items that I am responsible for. The question I received was this: There are a few deliverables listed that require a wet ink copy to be made available (upon request). Some items require we keep a wet ink signature, some don’t. For those items that do require it, the question is WHY is it required? Is it because of regulatory, legal or procedural reasons? I have no idea how to answer this.
How do I find out WHY a wet ink signature is required for certain elements of the eTMF? Again, my responsibility is DRUG SUPPLIES.
There is no requirement for an ink signature on an electronic record. The best regulatory reference for electronic records, electronic signatures is the FDA Guidance for Industry: Part 11 Scope and Application
Might you be able to expand on this topic? If, for instance, a paper document with wet ink signature is scanned for electronic submission into an eTMF, is there a need to keep the original wet ink signature? Is there a comprehensive list of what items really should have a wet ink archived when using an eTMF system?
Many thanks!
Jess, I will let the TMF gurus know about your question. I would recommend asking on the GxP Perspectives Linkedin Group . Carl-
Hi Carl,
I have a question more so than a comment. I want to know “Are Follow-up monitoring visit letters required? I have noticed a current trend where sponsors/CROs are no longer completing Follow-up letters or requiring one be written and submitted to the PI. When I looked at ICH E6, it states “Relevant communications other than site visits”…. What does that mean? Dear Doctor letters only? It has always been industry standard to write one to ensure the site is aware of observations and corrections needed but I see this changing.
Monitoring Follow-up letters are a lot like an Auditor’s report which have always been confidential. Why would Follow-up Monitoring Visit Letters be any different?
Is it a requirement to include the statistical analysis plan as part of the TMF?
Recommended, not required. ICH E3 outlines the structure and content of clinical study reports. Section 9.7.1 describes statistical and analytical plans. Section 8 of E6 outlines the contents of the TMF. Section 8.4.8 is the clinical study report. In the United States ICH guidance documents are recommendations, not regulatory requirements.
“In the United States ICH guidance documents are recommendations, not regulatory requirements.”
True but let’s put this in context:
(1) Who were the three original sponsors of the ICH process as these were the entities that comprise the ICH Steering Committee so decide which topics would benefit from being harmonised?
(2) How far has each of these co-sponsors gone in terms of codifying guidelines into law or is it more a case of guidelines supporting laws?
(3) What is envisaged by these co-sponsors of ICH as Step 5, implementation in relation to harmonised guidelines
(3) What is meant by guidance or guidelines – should they be ignored as they are not the law?
I think NOT – but let’s here it straight from the horse’s mouth or rather website and then you decide:
[a].http://www.fda.gov/RegulatoryInformation/Guidances/ucm122046.htm
[b]. “Guidance documents accessible from this page represent the Agency’s current thinking on good clinical practice (GCP) and the conduct of clinical trials……..An alternative approach may be used if such approach satisfies the requirements of the applicable statute and regulations.”
[c] “Guidance documents included under the umbrella title of FDA Information Sheets represent the agency’s CURRENT THINKING ON PROTECTION OF HUMAN SUBJECTS IN RESEARCH” (I added the capitals)
Their current thinking……we always want to know what they are thinking so a good starting point is reading ICH E6 which has been with us for more than a decade.
And how many countries have bought into the ICH process? It’s increasingly a case of who hasn’t thanks to activities of ICH’s Global Cooperation Group.
My post relates to the status of guidance documents rather than the inclusion of the Statistical Analysis Plan, in the TMF. The latter is a tad ambiguous but the reference to ICH E3 is helpful. Guidelines, especially E6, should not be viewed in isolation.
The efficacy guidelines, of which E6 is but one, overlap with one another……..all provide valuable reading for clinical research professionals.
ICH provides a common framework for clinical research irrespective of where we are in the world but has always acknowledged the importance of “applicable regulatory requirements” ……………..BUT when we are applying said regulations do we remember ICH or is it a case of Act local think local rather than Act local think global?