TMF Reference Model Update

March 18, 2012

TMF RM

The Trial Master File (TMF)

The recommended and required contents of the TMF, the trial master file, continue to be a concern for clinical trial professionals. This blog continues to support the efforts of the DIA working group for the TMF Reference Model, originally issued in 2010. The most recent updates to the TMF RM within Version 1.2, which was released in December 2011, featuring TMF components at the clinical sites along with those kept by the sponsor. The next version of the TMF RM is planned for release in June 2012. There is expected to be some updated content as a result of feedback received from broad industry use of the model, in addition to extension arms of the model for device and investigator-initiated trials. In this Guest Commentary, Lisa Mulcahy, co-chair for the TMF RM working group, explains the basics of the TMF RM.

The Trial Master File Reference Model

The Trial Master File (TMF) Reference Model (RM) is a supported initiative through the Document and Records Management SIAC of the Drug Information Association (DIA), a recognized and highly respected professional association. Creation of the TMF Reference Model has involved more than 230 representatives, all DIA members, from more than 150 bio-pharmaceutical companies, contract research organizations (CROs), consultancies, technical vendors, industry groups, healthcare, academia, non-for-profit / NGO and regulatory agencies. The attention of participants is drawn to the non-commercial nature of this forum. Although it is acknowledged that the resulting reference model ultimately needs to integrate with commercially available products, this was by no means a forum for promotion of products and companies.

The TMF RM was first released in June of 2010 and is a reference for the biopharmaceutical research industry. The model clearly outlines the content and organization of TMF content, at both Sponsor and Investigator site. TMF RM is a reference for the industry and should not be considered mandatory, but rather as an opportunity for standardization across the industry. The TMF RM can be adapted to an electronic or a paper TMF and does not endorse, nor by design, require, any specific technology for application.

The goal of the TMF RM is to provide a single, unified interpretation of the regulations via document listing which would be accepted across the industry. It does not provide guidance in the process by which the document is the output.

Use of the model

The uptake of the TMF RM is broad and it is at a minimum being used as a tool to compare against sponsor already-defined TMF content. It is most often though being adapted or adopted by companies as it provides a comprehensive listing of content created in support of a clinical trial.

Rationale for the creation of a model

The TMF contains those essential documents that individually and collectively permit the evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements (ICH Guideline for Good Clinical Practice, E6, Section 8).

TMF Reference Model

ICH E6

Regulatory guidance, such as ICH E6 section 8, addresses only a sub-set of TMF documents. Documentation requirements for the set-up and maintenance of quality systems, electronic systems, safety monitoring, and proof of an adequate and well-controlled trial, to name a few, exist in various regulations across many countries or regions, but not in ICH E6.

The following are additional reasons for creation of the TMF RM

• All companies and investigators conducting clinical trials in the pharmaceutical/biotech industry maintain documentation for each clinical trial. Each company has their own unique TMF structure as defined by their SOPs. No comprehensive common model exists for managing TMF documents. Over the conduct of a trial many functions contribute to the TMF, although oversight of the content is usually not one function’s responsibility – resulting in a highly inefficient work processes including but not limited to:

• All drug development companies and CROs expend considerable resources defining the content of the trial master file for each clinical trial. Consequently, Investigators have the challenge of adapting to different formats and TMF content organization with each clinical trial.

• The burden is very high on smaller companies that usually have limited document management expertise and limited financial resources.

• Records and information exchange between collaborating companies is extremely cumbersome, potentially preventing the joint venture or transfer of an investigational product.

• Regulators are challenged with varying terminology and file structures, creating inefficiency and variability during audits
Organization of the model

TMF

TMF Artifacts

Defined in the model are document types, called artifacts, which one would expect to find in a TMF, at both Sponsor and Investigator site. The artifacts are labeled either core, meaning it must be in the TMF as dictated by either the ICH Guidelines, regulations, or the TMF RM group (if applicable for the trial), or recommended meaning the artifact does not have to be produced but if it is created or collected, it is recommended to be in the TMF. Since the industry often uses unique names, alternate names (as relevant) and descriptions are supplied for each artifact. If the artifact is referenced in the ICH Guidelines, this information is captured.

The artifacts have been organized by Zone – where like artifacts are grouped together:

• Zone 1 Trial Management
• Zone 2 Central Trial Documents
• Zone 3 Regulatory
• Zone 4 IRB/IEC and Other Approvals
• Zone 5 Site Management
• Zone 6 Investigational Product (IP) and Trial Supplies
• Zone 7 Safety Reporting
• Zone 8 Centralized Testing
• Zone 9 Third Parties
• Zone 10 Data Management
• Zone 11 Statistics

Artifacts are created and can exist at multiple levels such as trial, country, and site. An artifact, such as “Safety Management Plan” exists at only 1 of the levels, the trial level. In contrast, the artifact “Informed Consent” can exist at all three levels. These levels can be used to define the paper format TMF.
The TMF RM can be found, free to the public using the following link (cut and paste into web browser address bar:

Metadata

The TMF reference model also details basic metadata which can be used as a starting point for building TMF electronic content management processes. This metadata model can be applicable in all electronic settings, from the straightforward file share to the complex enterprise system.

TMF Reference Model

"This model is designed to capture the unique set of documents"

The trial number is captured on each of the artifacts in the TMF RM. Since this model is designed to capture the unique set of documents associated with a single trial, the trial number is attached to each artifact. Inherited metadata such as Product/Compound, Indication, Trial Phase, and Route is also attached to each artifact and would be required to be entered only once, dependent upon system design.

Date format and convention for which date is captured on an artifact present on every artifact and has been left to those interpreting the reference model within already defined processes. Artifacts would have country metadata associated with them if they were to be created for a specific country and a site number/ID if created at the site level.

Lisa Mulcahy

The TMF RM Online

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Please join your industry colleagues in completing the 2012 TMF Reference Model Survey, and use results to inform your TMF best practices.

https://www.surveymonkey.com/s/FPP8DCF

This fifteen minute survey is designed by members of the TMF Reference Model team to provide valuable insight into Trial Master File practices, both paper and electronic, to identify common problem areas, assess changes in practice and reveal opportunities for improvement. All respondents who complete the survey and provide contact information will be provided with the survey results.

Data collection closes June 1st; please join us today.

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======== A GxP Perspectives Editorial ========

It came as a surprise that Wikipedia, under Electronic trial master file, has a subjective entry regarding the TMF RM. Regarding the TMF RM it states: “it fails to specify any electronic format for consistent document and record exchange.” It then goes on to suggest another group is doing a better job: “In an effort to resolve the obstacles around the electronic exchange, sharing and interoperability of electronic trial master files, http://www.etmf.org eTMF.Org was formed in 2011 to develop a standard for the secure exchange and sharing of eTMF archives…” This is an organization that lists four experts on its website. This is in contrast to over one hundred industry professionals, including myself, who have worked over the past few years on the TMF RM.

Wikipedia can be a useful research tool when the articles are objective and well researched. This article is currently rated 3.6 of a possible 5.0 for objectivity. You can read it for yourself, and rate it accordingly at the following link.

Wikipedia eTMF Article

GxP Perspectives welcomes all comments on the TMF and the efforts by the TMF RM working group and others on the best way to advance a coherent, usable TMF guidance.

Carl Anderson, GxP Perspectives

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FDA has issued the final guidance, “IRB Continuing Review after Clinical Investigation Approval.” GCP Guidance Documents may be found here: FDA GCP Website. The new guidance is on the right in the section “In The News.”


India: Quality for Clinical Trials

March 1, 2012

India clinical trials quality assurance

Quality Systems in India

Are Quality Systems in place in India, where the clinical trials industry is exploding?Do clinical trials professionals have the knowledge, skills and experience to run clinical trials where the rights, safety, & welfare of human subjects is protected and where data are reliable for submission to FDA and EMA> In this Guest Commentary QA professional Anusha Reddy demystifies the GCP process in India outlining her approach to quality in clinical trials.

This marks the first edition of GxP Perspectives as a monthly blog. It has been too much work for one person to keep up with a weekly schedule. I will be using the GxP Perspectives Linkedin Group to keep on top of current developments with FDA, as well as discussions by group members. Also, youcan subscribe to the blog on the button to your right on the sidebar.

Join the GxP Perspectives Linkedin Group Here

Improvising Quality in Clinical Trials

By Anusha Reddy

Over the last decade Clinical Trials in India have increased very rapidly in number. India has made a name for itself in the international pharmaceutical field as an ideal destination for worldwide companies to conduct clinical trials which is a test for both the government and the private sector to create a balance between ethics and trade The rise in the business brought sharp focus on the need to manage quality while conducting clinical trials.A need was, however, felt to develop our own Indian Guidelines to ensure uniform quality of clinical research throughout the country and to generate data for registration for new drugs before use in the Indian population. An Expert Committee set up by Central Drugs Standard Control Organisation (CDSCO) in consultation with clinical expert has formulated GCP guideline for generation of clinical data on drugs.

The Drug Controller General of India (DCGI) has introduced several guidelines and regulations, in an effort to maintain and ensure credibility, integrity, safety, well being and quality of clinical trials, some which includes guidelines on approval of clinical trials, CTD, Clinical trial Inspection, registration of clinical trials, CROs, and Ethics Committee’s. It constituted NDAC to review applications of new drugs and clinical trials, introduced prescreening of applications in order to expedite and streamline the process of application by ensuring completeness and has recently made compensation mandatory for injury or deaths during trials and which would increase the number of volunteers and patients going for a trial in India, according to experts.
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quality clinical trials in India

"Each Stage of Data Handling"

Quality in clinical trials should be applied to “each stage of data handling” to ensure that all data are reliable and have been processed correctly. Clinical trials are carried out to allow safety and efficacy data to be collected to provide information for industry and regulators to make decisions about the safety and efficacy of the interventions. Activities like monitoring and auditing are performed in order to ensure that the quality exists and the study is conducted in accordance with the SOPs, Protocol, GCP and applicable regulatory requirements. Pharma and Biotech firms are looking for several different strategies in clinical trials to ensure the highest quality of data. This article tries to discuss on describing and executing the quality in clinical trials.

A good quality clinical trial should, address an important question, have the potential to make an actual difference to patients, use the finest available research techniques, generate significant data, be scientifically and ethically sound. Recognition of GCP at the sponsor, CRO and the investigator site will improve the quality of clinical trials and finally leads to the acceptance of clinical trials.

clinical trials quality India

"Ability to Satisfy Stated or Implied Needs."

As per ISO (International Organization for Standardization) quality is defined as the features and characteristics of a product or service that bear on its ability to satisfy stated or implied needs. In clinical trials, poor quality has much more serious outcomes than discontented customers. Failure to ensure quality in clinical trials can result in undue harm to research participants, invalid data, and consequently, wrong conclusions about the safety and efficacy of the drug being tested. Additionally poor quality is a call for a regulatory inspection.

Determined efforts to improve quality in clinical trials have increased noticeably over the past decade. Recently the Department of Medical Education has imposed a temporary ban on clinical drug trials and research projects in all government and private medical colleges and hospitals in the Karnataka State, India; however, later it was assured that no such measures are being undertaken. The reason behind such decision was especially lack of guidelines to regulate drug trials. An expert committee was set up to study and frame guidelines to regulate and re-organise clinical drug trials, which is a step towards a quality clinical trials.

quality India clinical trials

The Consequences of Poor Quality

There are several reasons for poor quality in clinical trials and preventing them all is not an easy task. The objective should be to limit their number and their effect on the trial outcomes. This can be achieved by taking steps at the initial stage in protocol development and at the trial set up phase to obtain a high quality data in clinical trials; however, this alone does not result in high quality. Furthermore, planning should be accompanied by adequate oversight through proper routine monitoring and auditing of the trials with necessary corrective and preventive actions (CAPA) in place.

Measures should be taken to promote quality improvement in clinical trials by following standard operating procedures and implementing good documentation practices while performing study activities like drug accountability, Informed consent process, Safety reports, protocol deviations/violations and other protocol related activities which will provide reliable results and error free data when submitted to regulatory agencies for approvals.

A quality system proposition to good clinical practice conformance will establish quality in clinical trials by identification and setup of standards, applying them by those involved in the conduct of clinical trial, tracking the areas that are non-complaint with the standard procedures or applicable regulatory requirements, take actions to prevent the recurrence in future in the identified areas.

quality in India

Developing Metrics

Developing and using metrics that are meaningful within an organization facilitate in measuring the quality in clinical trials. For example, preparing a protocol from the stage of drafting to finalizing, here with increase in amendments the time increases and quality is reduced (but number of amendments is often not the reflection of protocol quality). Other example for measuring the quality includes the number of data clarifications forms (DCFs) raised per case report form (CRF); increase in the number of data queries indicates the poor data quality. Based on these metrics one can measure the quality and can improve those areas.

In Conclusion, systems with procedures or measures that assure the quality of every aspect of the clinical trial should be implemented. Quality should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. This extent of transparency and accountability of clinical trial processes ensures ongoing quality control and quality assurance, but in addition, makes it easy to assertively address inquiries from regulatory agencies.

Useful Links:

Indian GCP

Clinical Trial Registration

Prescreening Checklist

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Training Opportunity:

The 3rd Proactive GCP Compliance Conference taking place April 2-4 in Arlington, VA – GCP Conference Website. Leading GCP experts from Lilly, Pfizer, J&J, Novartis, Shire and many more address risk-based approaches to clinical quality that meet requirements and ensure patient safety. Special 15% discount off of the standard registration rate for GxP Perspectives readers. Register online at: GCP Conference and use discount code: P439GXP

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DIA Regulatory Conference this April in India

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In News From FDA:

FDA has issued the final guidance, “IRB Continuing Review after Clinical Investigation Approval.” GCP Guidance Documents may be found here: FDA GCP Website. The new guidance is on the right in the section “In The News.”

From: A Message from the Commissioner
Sent: Wednesday, February 29, 2012 04:14 PM
To: FDA-Wide
Subject: Announcement re Chief Counsel

Dear Colleagues,

I am thrilled to announce the permanent appointment of Elizabeth Dickinson as the Chief Counsel of the Food and Drug Administration, effective Monday, March 12, 2012.

As many of you know, Liz has had a long and distinguished history at the Agency; she joined the Office of the Chief Counsel in 1994. Over the years, Liz has served as legal counsel to the Center for Drug Evaluation and Research and the Office of the Commissioner on innovator and generic drug review issues, orphan drug development, and biosimilars; has implemented pediatric exclusivity and pediatric drug development programs; has worked closely with the Department of Justice on dozens of cases addressing Waxman-Hatch issues and preemption; and has coordinated the development of the Office of the Chief Counsel’s flexible workplace program.

A graduate of the University of Massachusetts and Northeastern University School of Law, Liz is highly regarded by both her internal colleagues and those across the food and drug bar. Over the years, Liz has received numerous awards for distinguished service, leadership and her outstanding legal skills.

Liz has been serving as Acting Chief Counsel since August 2011, and we have been grateful for her hard work and dedication each day that she has been on the job. It is terrific to know that she will be serving the Agency in this role permanently as we move forward. Please join me in congratulating Liz.

Sincerely,
Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs

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