TMF Reference Model Update

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).

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 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.

"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

====

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.

=====

======== 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

====

Join the GxP Perspectives Linkedin Group Here

====

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

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.
.

"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.

"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.

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.

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

====

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

====

DIA Regulatory Conference this April in India

====
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

We have some excellent comments on this post. Please join the discussion and add your own thoughts

Clinical Labs & GCP

GCP for Clinical Laboratories

How to assess clinical laboratories for GCP compliance is one of the more difficult issues facing GxP professionals. Is CLIA the gold standard? How do the good laboratory practice (GLP) regulations impact clinical labs? Isn’t there a handy checklist out there somewhere? What do people mean by “GCLP?” I have been dealing with this issue a lot of late and people are really all over the map. Here are some of the approaches I take, along with a handy-dandy reference list at the bottom of the post.

First, let’s look at the easy part. The primary regulation dealing with clinical laboratories is the Clinical Laboratory Improvement Amendments (CLIA). Wow, that’s simple. However, CLIA specifically states that it does not have jurisdiction over research. CLIA covers the day-to-day laboratory tests that your doctor orders to check up on your cholesterol or hematocrit. For these routine tests, FDA recognizes CLIA certification as an acceptable standard. FDA also recognizes other certifications such as from the College of American Pathologists (CAP). However, FDA does not have its own laboratory program. No, the GLP regulations (Part 58) just don’t apply here. My advice is to keep them on the shelf.

Research Continues into New Laboratory Methods

However, things can get more complex. Not all laboratory tests are CLIA certified, there is a whole lot of research going on out there. Research methods are being developed every day. To make matters worse, just because a lab is CLIA or CAP certified, it does not mean that they have clinical trial experience and knowledge of kit building or blinding procedures. You need to go to their laboratory and see if they are equipped to perform the tasks in your statement of work. You need to perform a chain-of-custody tour to determine that your samples will be handled and analyzed in an appropriate manner, if there is “quality control at each stage of data handling” (ICH E6 Section 5.1.3).

One document that will come in handy is the FDA Guidance for Industry: Bioanalytical Method Validation. If you have a new laboratory method, it should be validated. What about an audit plan? I use the European Medicines Agency (EMA) GCP Inspection Guidance on Clinical Laboratories (Annex II). Links to both of these documents are listed below. The important thing to remember is that you have critical safety and efficacy endpoints being evaluated by the lab and they are highly importance to your study. Give the laboratory the attention it deserves.

Tour the Laboratory

Chronological order is a useful tool in assessing a laboratory. Follow the route of the samples starting with kit building, shipment to the sites, receipt from the sites and how they make it through the laboratory. Remember, the majority of laboratory errors take place Before sample analysis, in the pre-examination phase (source: CDC). In addition, there are more errors reported in the post-examination phase than the examination phase itself. Reporting is of critical importance. Your NDA or PMA might depend on the accuracy of those reports.

I have seen many checklists for conducting clinical laboratory audits. Most of them have issues that can impact their effectiveness. Your audit should be protocol-specific. The lab needs to be able to conduct the analyses required by the protocol. That’s why I use the EMA GCP Inspection Guidance for Clinical Laboratories as a basic audit plan. EMA has a GCP inspection program for clinical labs. Another important point is that not only do you need to pre-qualify a lab, you need to go back during the trial and audit live data. This is true for any critical vendor.

There are a number of resource documents available

Many organizations are working on the clinical laboratory dilemma. You will hear the term “GCLP” quite a bit (for good clinical laboratory practice). It is important to remember that there is not one consistent standard on what GCLP is. Wouldn’t it be nice if we did have a consistent GCLP standard recognized by the world’s regulatory authorities? Here are some important references for clinical labs and GCP. Feel free to make additions to this list in the Comments section below.

EMA GCP Inspection Guidance for Clinical Laboratories

FDA Guidance for Industry: Bioanalytical Method Validation

College of American Pathologists Website

Clinical Laboratory Improvement Amendments (CDC)
(This site has links for genetic testing and Waived Testing)

GCLP – UNICEF, UNDP, World Bank, & WHO

MHRA: Good Clinical Practice for Clinical Laboratories – (Please see the comments/discussion on this.)

On The Blogroll: Dark Daily: News for Clinical Laboratories & Pathology Groups

====

You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).

====

Draft Guidance: Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology. This guidance is open for public comment for 60 days (approximately August 7).
====
FDA has announced a new draft guidance document. Public comment is due by 25 July 2011:

Guidance for Clinical Investigators, Industry, and FDA Staff: Financial Disclosure by Clinical Investigators

===

On LinkedIn

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

====
Please Leave Your Comments & Expertise on GCPs & Clinical Laboratories
====

FDA & OHRP Hold Regulatory Forum at ACRP Meeting in Seattle

Jerry Menikoff of OHRP & Jean Toth-Allen of FDA

FDA and OHRP both presented at a Regulatory Affairs Public Forum at the ACRP Global Conference on Sunday, May 1st.Speaking for FDA were Leslie Ball, MD, Director of the Division of Scientific Investigations (DSI) which initiates the majority of Bioresearch Monitoring inspections at FDA. Also from FDA was Jean Toth-Allen, PhD, Biophysicist, Office of Special Medical Programs. Jerry Menikoff, MD, JD, spoke on the panel as the Director of the US Office for Human Research Protection. The Association of Clinical Research Professionals hosted the forum in a setting more reminiscent of a TV game show than a professional panel that was complete with theme music and multi-colored columns highlighting the stage. However the questions posed were the ones on everyone’s minds and the speakers gave some good answers.

Please note that the Plenary Session on the Regulatory Affairs Public Forum was recorded and is available on the ACRP website for free.

One question brought up the issue of sponsor oversight of outsourced clinical trial responsibilities. Toth-Allen said that the sponsor is ultimately responsible for all of the clinical trial responsibilities and only CROs are specifically mentioned in the regulations. She emphasized the need to have SOPs in place covering how they are going to oversee contracts of vendors and what the contracts should cover. Leslie Ball said that DSI had an increased focus on sponsor and CRO inspections.

Dr. Ball said that she thinks sponsors should look at three qualities when selecting vendors:

1. The overall capability of the organization and staff.

2. That contracts clearly point out who is responsible for specific responsibilities.

3. That the sponsor oversees the vendor’s activities while the trial is ongoing.

When Does FDA Inspect?

Another area of interest was when and where FDA would inspect. Both Leslie Ball and Jean Toth-Allen said that FDA was focusing more on inspections during the actual conduct of the study and not just when a sponsor makes an application to the agency.

Dr. Ball said that with the shift to more sponsor/CRO inspections that FDA inspections were looking at sponsor oversight of ongoing trials. She also said that DSI was developing a risk-based site selection tool that looked at three different levels. First, at the application level, did the application pose certain risks that FDA needed to consider. Then at the trial level, tending to focus on pivotal trials. Then at the site level, were there complaints or a history of non-compliance. She also said that they were looking at data from the application such as the rate of subjects dropping out or very high or very low rates of adverse events.

Dr. Leslie Ball, FDA

Dr. Ball also emphasized that FDA looked at what they considered important, specifically data integrity for primary efficacy endpoints or key safety indicators, and oversight by the sponsor. She noted that many things that are routinely listed on a Form FDA 483, Inspectional Observations, such as study drug accountability sometimes didn’t find their way to a Warning Letter that focused on items of significance to the approval of the application.

Another interesting discussion was on the topic of online informed consent forms, which are beginning to appear. Jerry Menikoff said it depended on the nature of the study when an online consent might be appropriate. Jean Toth-Allen spoke of the need for a verification process, that the online consent was given by a real person.

Discussion on Electronic Medical Records in
Clinical Trials

Finally the panel discussed electronic medical records (EMRs). All three panelists supported the use of EMRs. Toth-Allen said that if an EMR is used in a clinical trial then the institution needs to provide access to verify the record, that it was not acceptable to for monitors to be told that you can’t see it, which elicited a hearty round of applause from the many monitors in attendance. Dr. Ball noted that there were a lot of advantages to EMRS. “You can actually read them,” she said. She also emphasized that EMRs should have the same criteria for clinical trials, that they should be ALCOA– Attributable, Legible, Contemporaneous, Original and Accurate. She also said that although they may not need to be Part 11 compliant, they did need to have an audit trail so that all changes to the record could be traced.

To view the Regulatory Forum visit the
ACRP Website on the Plenary Sessions

=====

On the Blogroll: RegBlog on all things regulatory from the University of Pennsylvania Law School. Covers much more than FDA

=====

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

On The Blogroll: Applied Clinical Trials Blog discusses,
“It Takes a Village: Recruiting Latino and Hispanic Patients.”

ACRP Meets in Seattle for 2011 Global Conference

ACRP Meets in Seattle for 2011 Global Conference

Seattle, WA plays host to the Association of Clinical Research Professionals’ (ACRP) annual Global Conference. ACRP is one of the larger professional organizations focusing on clinical trials and expects 2,000 participants. It will be the first time I have attended their Global Conference and I am looking forward to it. There will be sessions on “Introduction to Imaging in Clinical Trials” and on “Distance-Based Learning for Foreign Study Coordinators.” GxP Perspectives will be there for the entire conference (the pre-conference workshops have already begun) and among the sessions I look forward to is “Comparative Effectiveness Trials.” I am going to try to blog at least twice during the conference on issues I think are of concern to GxP Perspectives readers. If I am super industrious maybe I will blog from the ACRP Global Conference every day.

Here is a new feature that ACRP is offering: “ACRP is pleased to announce that for the first time ever, two live-feed Plenary Sessions from the ACRP Global Conference & Exhibition will be broadcast FREE of charge. Join us May 1 for the Regulatory Affairs Public Forum featuring representatives from global regulatory agencies addressing issues facing clinical trials. Join us May 2 for Innovation & Global Health, a discussion by Tachi Yamada, MD, President, Global Health Program, Bill and Melinda Gates Foundation.”

For more information visit the ACRP Website on the Plenary Sessions

Do You Have a Guest Commentary for
GxP Perspectives?

Another highlight will be the May 1st session on “Your Site Doesn’t Need 60 SOPs, But How Many Does It Need?” The speakers are Christine Pierre, RN and Steven Steinbreuck, MPH and the author of a Guest Commentary on GxP Perspectives on Informed Consent Requirements. Remember, I am always looking for a good Guest Commentary. Send me a note and ask me how-

Leave a Comment to Submit a Guest Commentary!

=====
On the Blogroll: Top 40 Websites (and Tweeters) on the FDA, by FDAZilla (Yes, we made the list.)

Moriah Consultant’s Blog – Commentary by Michael Hamrell, one of the conference speakers
=====

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

=====
Conferences: Pharma/Bio Boot Camp on the eTMF on 20-21 May 2011 in Philadelphia

GCP Protocol Deviations & Violations: Determining the Root Cause

GCP Protocol Violations: Determing the Root Cause

The top violation cited during FDA inspections of clinical sites has consistently been the failure to follow the investigational plan- Protocol Deviations & Violations. Coupled with recordkeeping violations the failure to follow the protocol has been the mainstay of the Form FDA 483, Inspectional Observations, issued by FDA field investigators to clinical sites for decades. However, FDA has recently been pointing out that the root cause can just as easily be poorly designed protocols as noncompliance by a clinical investigator. In the previous post on GCP CAPA plans I note that at least two root causes that should always be investigated. This is particularly true when you find systematic protocol violations. Two areas that should always be reviewed are:

Protocol Design: Frequently you will find a Note to File in a clinical site’s regulatory binder saying that the study coordinator had been “retrained” in the importance of subject compliance. However, if subjects are routinely missing visits or protocol-required procedures you need to take a look at how well designed the protocol is. Were clinical sites consulted when the protocol was written? Is the visit schedule practical? Are the tests easily performed or do they require special efforts by research staff at a busy medical practice? And just how many protocol amendments do you have anyway? It is the clinical site that will receive an FDA 483 but the root cause very well might be found at the sponsor.

Protocol Violations are the Top GCP Violation at Clinical Sites

Protocol Adherence: Sometimes the clinical site is the cause of the deviation. There is a significant difference between the practice of medicine and the conduct of a clinical trial. I can’t count the times that I have been told, condescendingly, that “We’ve been doing this type of medical procedure for quite some time.” That’s all well and good but have you been reading the protocol for quite some time? A clinical trial is an experiment, and frequently requires activities that are not the usual practice of medicine. You may need to order a second blood test, or change the dose of the investigational product.

In cases like this a follow-up letter from the monitor to the clinical site might not be enough. If the root cause is the failure to understand the responsibilities of a clinical investigator then the issue may need to be escalated to someone with the letters “MD” after their name. Sometimes you need a physician to explain the protocol to another physician. Seldom does the “re-education” of support staff work as an effective corrective action.

Determining the root cause of systemic protocol deviations and violations isn’t always easy. However, if you don’t follow the investigational plan you can jeopardize your application. And remember, always investigate at least two possible causes of protocol violations.

==============

In a recent FDA Warning Letter protocol violations are discussed at length.
====

You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).
This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)

====
On the Blogroll: Cancer Sucks

Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.
======
Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

#######

SPECIAL UPDATE: 18MAR2011: FDA has released an updated version of the Compliance Program Guidance Manual 7348.810, Sponsors/Contract Research Organizations/Monitors. There are new sections on registration of clinical trials on ClinicalTrials.gov, Financial Disclosure, the Part 11 Scope & Application Guidance Document, and other issues. If you work for a sponsor, a CRO, or are a contract CRA you MUST read this document. Review Section III, Inspectional.

I am in the process of writing an analysis of this updated compliance program. Please let me know if you have questions or suggestions for points to consider. Thanks!

##########

FDA Clarifies Adverse Event Reports for Clinical Trials

FDA Final Rule Clarifies
AE Reporting for
Clinical Trials

On 28 September 2010 FDA announced that it was issuing a final rule that clarifies safety reporting for adverse events during clinical trials. The final rule impacts drug and biologic regulations for clinical trials conducted under an investigational new drug (IND) application (21 CFR 312) and bioequivalence studies (21 CFR 320). The draft rule was published in 2003 and received numerous comments. These comments, combined with increased concern over drug safety, led to significant changes by FDA. The new rule defines the separation of clinical trial safety adverse event reports and post-market safety reporting. The agency is working on new regulations for post-market safety reports. FDA stated that the separation was necessary to improve the quality of safety reporting, monitor the safety of drugs and biologics, and harmonize adverse event reports internationally. There are some significant differences between the draft rule of 2003 and the final rule published on 28 September 2010 including:

• Replace the defined phrase ‘‘associated with the use of the drug’’with the term ‘‘suspected adverse drug reaction (SADR),’’
• Require submission of expedited reports of ‘‘information sufficient to consider product administration
changes,’’
• Make it clear that safety reports of overall findings or data in the aggregate must be submitted in a narrative format,
• Permit the determination that an SADR is life-threatening to be based on the opinion of either the investigator orsponsor (as opposed to only the investigator),
• Require that the sponsor notify FDA and all participating investigators of each SADR that is both serious and unexpected, based on the opinion ofeither the investigator or sponsor (asopposed to only the sponsor),
• Require a ‘‘minimum data set’’ for each report of an SADR submitted toFDA, and
• Clarify the sources of information that sponsors must review for safety surveillance and reporting purposes.

FDA Adopts ICH E2A Definitions

Perhaps the most significant change in the final rule is that FDA is adopting the terms and definitions in the ICH guidance document E2A that are used throughout the world. Prior to issuing the final rule FDA regulations did not specifically define the term “adverse event” although the term was referred to repeatedly in the regulations and there was a definition for “serious adverse event.” Using the ICH definitions will make it easier for clinical trial professionals to “speak the same language” when conducting research. As FDA clarifies definitions, communications between sponsors and investigators should become easier. Hopefully, researchers will now understand that it isn’t necessary to “report all SAEs immediately.” FDA is stating clearly that:

“… the revisions to the IND safetyreporting requirements will improve theoverall quality of safety reporting andthe agency’s ability to review critical safety information by ensuring that theinformation that FDA receives in an INDsafety report is relevant and useful.

Under former regulations, there may have been over-reporting of serious adverse events for which there was little reason to believe that the drug had caused the event, complicating or delaying FDA’s ability to detect a safety signal.

In this final rule, FDA clarifies definitions, provides examples of the types of evidence that suggest a causal relationship for purposes of reporting asuspected adverse reaction to the IND and participating investigators, and revises the requirements for expedited reporting of serious and unexpected suspected adverse reactions to the IND.”

The ambiguity over reporting adverse events has caused friction between many study coordinators and CRAs. Hopefully, FDA clarifying AE reporting will help researchers focus on issues of significance.

FDA Announcement of Final Rule

At the same time FDA issued a draft guidance on Safety Reporting Requirements which will be the topic of a future post. The comment period is OPEN!

Safety Reporting Requirements for INDs and BA/BE Studies

++++In news from GxP Perspectives++++

TMF Webinar on Thursday, 14 October 2010

Special Announcement: TMF Webinar 14 October

Read the updated article on the Form FDA 1572 in:

Applied Clinical Trials “Closing Thought” on FDA 1572

ALSO: Please join me on LinkedIn at:

GxP Perspectives LinkedIn Group

TMF Update: FDA References on Certified Copies and Original Data

FDA References for Original Data & Certified Copies in Clinical Trials

As clinical trial professionals try to comply with FDA requirements on electronic records there are a number of documents that are referred to that are hard to find. One is the Compliance Policy Guide # 7150.13 referred to in the definitions section of FDA Guidance Document: Computerized Systems Used in Clinical Investigations (May 2007). It is referenced in the description of “Original Data.” FDA states: “FDA is allowing original documents and the original data recorded on those documents to be replaced by copies provided the copies are identical and have been verified as such.” FDA also has a definition of “Certified Copies” in the same guidance document.

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)

Betterchem Link on Compliance Policy Guide

Applied Clinical Trials: CDISC Clinical Research Glossary

Read the Final Guidance from the European Medicines Agency on Electronic Data Capture:

EMA Reflections

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.”

In news from GxP Perspectives read the updated article on the Form FDA 1572 in:

Applied Clinical Trials “Closing Thought” on FDA 1572

Announcement: TMF Webinar 14 October

ALSO: Please join me on LinkedIn at:

GxP Perspectives LinkedIn Group

TMF Reference Model Presented to DIA

TMF Reference Model Announced

The Trial Master File (TMF) Reference Model was presented to the annual meeting of the Drug Information Association (DIA) in Washington, DC in June. There has been a lot of confusion lately as different regulatory agencies have enforced clinical trial TMF requirements in different ways. The TMF Reference Model was developed by the DIA Document and Records Management TMF Reference Model Working Group and at least one major regulatory agency is taking a close look. The Reference Model utilizes Section 8 of the ICH GCP Guideline (E6) Essential Documents as the core “artifacts” for the TMF. They also have recommended artifacts. As sponsors move from paper to electronic and as TMFs become more complex, it is hoped that the reference model can help determine what documents are necessary to satisfy regulatory requirements for clinical trial documentation.

At the Avandia Advisory Committee meeting FDA discussed the TMF publicly for the first time that I am aware of with regards to a sponsor inspection. Anecdotally I know that FDA field investigators are now auditing the TMF. Sponsors and CROs need to review their TMF procedures and document control if they expect FDA to feel that data integrity is a component of their application. Hopefully, the Reference Model developed by DIA will help.

There is a LInkedIn group that discusses the reference model that can be found at:

TMF Reference Model LinkedIn Group

GxP Perspective Post on Reference Document

UPDATE 30 April 2012:

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.

=====

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.”

Read the Final Guidance from the European Medicines Agency on Electronic Data Capture:

EMA Reflections

Update: Read the blogster in Applied Clinical Trials

ALSO: Please join me at:

GxP Perspectives LinkedIn Group

Reflecting on the Trial Master File, the TMF

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

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”)

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

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.”

====

You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).

—-
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:

EMA Reflections

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 !!!

++++In news from GxP Perspectives++++

Announcement: The 18th and 19th of January 2011 I will be at the conference for Developing CAPAs in the GCP Environment, Arlington, VA. And Again in 2012!

2012 CAPAs in the GCP Environment

Read the updated article on the Form FDA 1572 in:

Applied Clinical Trials “Closing Thought” on FDA 1572

ALSO: Please join me on LinkedIn at:

GxP Perspectives LinkedIn Group

Read additional posts on Good Clinical Practice- GCP:

https://carl1anderson.wordpress.com/category/gcp/