TMF Update: FDA References on Certified Copies and Original Data

August 25, 2010

FDA reference original data and certified copy

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There is a Draft Guidance on Electronic Source Documentation in Clinical Investigations.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

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Part 11: How Will FDA Enforce?

July 25, 2010

Part 11 FDA enforce

How Will FDA
Enforce Part 11?

FDA’s announcement that it would begin inspections to enforce 21 CFR Part 11 has set of speculation on how FDA will enforce Part 11 and what they will be looking for. I’ve asked two experts, Len Grunbaum and Emma Barsky for their thoughts. They have written a Guest Commentary for the blog, one I am sure will be used as a resource by many of you concerned with Part 11 compliance. I first met Len at the last FDA training course I took, Advanced GLPs, where he was an instructor on validation. I learned a lot from him and think that he and Emma have a lot to share. Of course I welcome your comments and certainly would want to have additional Guest Commentaries on the subject.

Guest Commentary-

The FDA announced on July 8, 2010 that it will be “… conducting a series of inspections in an effort to evaluate industry’s compliance and understanding of Part 11 in light of the enforcement discretion described in the August 2003 ‘Part 11, Electronic Records; Electronic Signatures — Scope and Application’ guidance….”

So … 13 years after promulgating the regulation and seven years after moderating their enforcement model – by exercising enforcement discretion regarding selected aspects of the regulation – the agency is still not comfortable about something. What can it be? While we cannot speak on the agency’s behalf, the words “in light of the enforcement discretion” imply to us that the agency is looking to 1) understand the disparate risk-based approaches taken by companies with respect to validation, audit trails, legacy systems, copies of records and record retention, and 2) determine how effective these approaches have been in establishing and maintaining data integrity (i.e., data completeness, accuracy and validity). Perhaps FDA will revise the regulation and/or issue new guidance that will reflect its ideas of what it perceives as the “best of breed” in terms of activities that most effectively and efficiently result in compliance with 21 CFR part 11. Who knows?

part 11 enforce FDA

FDA Concern Regarding Data Integrity

We choose to focus our thoughts regarding this FDA’s initiative on data integrity because it is one of the main points that the FDA focuses on during its inspections. And it is because anything that calls data integrity into question will result in regulatory observations which, to date, have mainly been based on the predicate regulations that were put in place to promote data integrity. Therefore, enforcement discretion notwithstanding, we feel that companies will have to demonstrate the following basic quality measures to the agency:

1) All computerized systems that support regulated activities can be relied upon to operate as intended and identify all instances of incomplete, inaccurate and/or invalid data;

2) All regulated activities (e.g., changes to clinical data) can be reconstructed; and, 3) all regulated records (e.g., study data, manufacturing data) are available from the start of the respective process to the date of inspection and can be retrieved in a timely fashion. The way to do it would be to have complete, easy to follow and easy to explain documentation in support of the above-listed items; anything less may give the agency the perception that data integrity issues exist even if such may not be the case.

Listed below are some, but certainly not all, documentation pitfalls to avoid in this context:

Lack of validation documentation that focuses on systems risks (e.g., nature and complexity of interfaces, number of bug fixes) in establishing the testing strategy (e.g., nature and scope of regression testing)

• Lack of challenges to the computerized system in the area of identifying incomplete, inaccurate and/or invalid data

• In a complex database system, lack of details regarding what tables, records, etc., constitute the audit trail

• Lack of policies, and/or documented confirmation of compliance to processes regarding ensuring the retention, continued availability and easy retrieval of regulated records/data

• Lack of a complete and/or accurate record of what changes were implemented to computerized systems that support regulated activities and how they were tested and documented

• Lack of documentation regarding training of personnel who were involved with system development, validation, deployment and maintenance

• Lack of documentation regarding how compliance to 21 CFR part 11 is actually achieved (e.g., confirming required functionality through testing, confirming compliance to procedures, such as logical security, backup and recovery, through the internal audit program).

The bottom line is that documentation must stand on its own. Given that FDA may look at processes and records from several years ago and that staff who implemented computerized applications may no longer be around, it becomes imperative that you do what you must to ensure that all of your documentation for computerized applications is such that it does not raise data integrity-related questions that cannot be addressed in a timely fashion.

Emma Barsky
Len Grunbaum
Partners
The Practical Solutions Group, LLC
Practical Solutions Website

How FDA will enforce Part 11 will unfold over the next year or two. How regulated industry should prepare for upcoming inspections, according to Len & Emma, is to document your validation efforts. I think it is good advice.

Here is the original FDA announcement stating it would enforce Part 11: FDA Part 11 Announcement

Save The Date: On 4-5 November 2010 the Pacific Regional Chapter of the Society for Quality Assurance (PRCSQA) and the Organization of Regulatory and Clinical Associates (ORCA), a Pacific Northwest based organization, will co-sponsor a Fall Training on regulatory compliance topics in Seattle, WA.

The PRCSQA LinkedIn Group will update the agenda for the training. PRCSQA Fall Training workshops have traditionally been “at cost” and are an affordable training opportunity. The sessions will cover both GCPs and GLPs with speakers lined up on vendor management, quality systems, and GLP updates.

/////
UPDATE: My favorite industry magazine, Applied Clinical Trials, now has a LinkedIn Group:
Applied Clinical Trials LinkedIn
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New on the Blogroll: I’m not the only GxP type with a blog. Here is a well-written blog by Jackie Mardell-
Two Decades and Counting

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A new service: Please check out the Services page at the top of the Blog to learn more about GxP Services.
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Part 11: It’s Back

July 14, 2010

Part 11 FDA

FDA To Resume Enforcement of Part 11

FDA has announced that “The Agency (FDA) will be conducting a series of inspections in an effort to evaluate industry’s compliance and understanding of Part 11 in light of the enforcement discretion described in the August 2003 ‘Part 11, Electronic Records; Electronic Signatures — Scope and Application’ guidance (Guidance).” This is a big deal. It has been seven years that FDA has debated Part 11 and began using “Enforcement Discretion.” The Agency announced that: “The Agency expects to begin conducting the Part 11 focused inspections soon.” Part 11, Electronic Records; Electronic Signatures has been one of the most confusing and controversial regulations FDA has ever written. I am now trying to find a Part 11 specialist to let us know the meaning of it all. Read what FDA has to say:

FDA Part 11 Announcement

UPDATE: Read the 25 July Guest Commentary on Part 11 by Len Grunbaum & Emma Barsky

The early report: The best report so far: Angie Drakulich goes into further detail on the changes including an interview with FDA in her report in the blog, PharmTech Talk

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The Blog has just been put on the expanded Top 50 Health Blogs list, which I truly appreciate. However, they constantly change their links to keep it current. Currently I am not there although there are other interesting posts. I now have two “Top Fift” links on the Blogroll.

50 Top Health Blogs


FDA Guidance- Converting Paper Files to Electronic

April 17, 2010

converting paper to electronic FDA guidance

Need to Convert Paper Files?

Converting paper files to electronic records is a practice allowed by FDA and other regulatory agencies. This question is frequently asked by those responsible for maintaining records and the Trial Master File (TMF). Workers who are trying to cut down on the massive amount of storage space needed to comply with FDA record retention policies, an important issue for GCP compliance. However, not only is it allowable, FDA actually tells you how to do it in relatively understandable English. The key guidance document you will need as a reference is:

Guidance for Industry: Part 11; Electronic Records; Electronic Signatures- Scope and Application (August 2003).”

Here is what the agency has to say:

4. Copies of Records

The Agency intends to exercise enforcement discretion with regard to specific part 11 requirements for generating copies of records (§ 11.10 (b) and any corresponding requirement in §11.30). You should provide an investigator with reasonable and useful access to records during an inspection. All records held by you are subject to inspection in accordance with predicate rules (e.g., §§ 211.180(c), (d), and 108.35(c)(3)(ii)). We recommend that you supply copies of electronic records by:

• Producing copies of records held in common portable formats when records are maintained in these formats

• Using established automated conversion or export methods, where available, to make copies in a more common format (examples of such formats include, but are not limited to, PDF, XML, or SGML)

In each case, we recommend that the copying process used produces copies that preserve the content and meaning of the record. If you have the ability to search, sort, or trend part 11 records, copies given to the Agency should provide the same capability if it is reasonable and technically feasible. You should allow inspection, review, and copying of records in a human readable form at your site using your hardware and following your established procedures and techniques for accessing records.”

I was able to get this information from FDA’s excellent resource, “GCP Questions.” There is a link under FDA Stuff, scroll down beneath the Blogroll on the right, as: FDA Answers to GCP Inquiries. That’s also where you will find the Scope and Application for Part 11 link to the FDA Guidance Document.

I would make a very strong recommendation that before you start converting paper files to electronic ones that you develop a standard operating procedure (SOP) for how you are going to do it. Your files are your story of how a clinical trial was conducted. You want to convert files the right way each and every time.

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.”

FDA Guidance on converting paper files to electronic

Do You Have a Topic for the Blog?


I was asked this question by one of the fine people who has become a Fan of the Blog. You can do so as well. Now Facebook gives you the option to “LIKE” the Blog instead of becoming a “Fan.” I think it makes sense. Anyway, visit the site on Facebook, it is a great way to ask a question or keep up with my experiences with volcanoes. By the way, I just had a trip to Europe cancelled because of some volcano. Oh well.

So I welcome your comments and suggestions. In fact, you don’t have to be a Fan to comment. You can do it by clicking on “Leave a Comment” just below!

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Economists, Technology, & Clinical Trials

February 1, 2010

God bless Joseph Stigltz. There is a brief interview with him in the Sunday NY Times Magazine by Deborah Solomon, “Questions for Joseph Stiglitz.” There is a link at the bottom of this post. I have only started paying close attention to what economists have to say in the past few years. This certainly intensified when all hell broke loose in the fall of 2008. Joseph Stiglitz, a professor at Columbia, is a Nobel prize laureate and a very smart man. He also has a dry wit that I find quite funny (some people have doubts about my sense of humor) and I have just ordered his new book, “Freefall: America, Freemarkets, and the Sinking of the World Economy.” I definitely want to know what he has to say about it all.

FDA

Prioritize ???

However, what really caught my attention and led me to write this post is one of the last questions Solomon had for Stiglitz when she asked, “By the way, when I tried you on your cell phone, a voice said, ‘This is the number for Joseph Stiglitz, but he doesn’t check his messages.'” His response? “I just never figured out that part of the cellphone.”

This blog isn’t about economists, its about the regulation of health products by FDA in general and about clinical trials in particular. Clinical trials are very expensive to conduct. In addition, the massive amounts of recordkeeping involved leads to routine mistakes and the destruction of a great many trees. There has been a big push towards electronic medical and regulatory records, electronic case report forms and technology in general. This has generated discussion and debate about how these records should be regulated and whatsteps we need to take. FDA’s initial effort to regulate computerized systems, Part 11; Electronic Records, Electronic Signatures, was met with sharp resistance from industry and enforcement has been scaled back considerably as FDA utilizes “enforcement discretion.” However, most of us understand that these systems need to be dependable and that means, in some way, shape, or form, that they be “validated.”

Unfortunately what I see a lot is that the quality of the system used to maintain records is considered more important than the quality of the actual records that contain the data used to approve new drugs and clinical trials FDAmedical devices. Some folks seem to forget that technology is a means to an end (full disclosure: I am not very tech savvy). As a result, we have seen an increase in the number of FDA enforcement actions. FDA Warning Letters to clinical sites have skyrocketed in the past few years. And in my viewpoint one of the major reasons is the poor quality of clinical trial protocols and recordkeeping. Sometimes you need to take a look at the basics of what you are doing.

Which brings me back to Joseph Stiglitz. Here is a very smart man who is engaged with problem solving. Very Big Problems that impact us all. Yet he doesn’t know how to check his voice mail. As far as I’m concerned, its a question of knowing priorities. Just stop and think about which is a more important activity; understanding the complex economic issues that caused the Wall Street meltdown, or playing with your Blackberry? I appreciate the Stiglitz approach.

Here is a link to the Stiglitz interview by Deborah Solomon:

http://www.nytimes.com/2010/01/31/magazine/31fob-q4-t.html?ref=todayspaper

REMEMBER, YOUR COMMENTS ARE ALWAYS WELCOME !!!

Blogroll Pick: Paul Krugman’s Blog. I’m continuing to list a site on the Blogroll (to your right) each time I publish a post. As long as we are on the topic of economics why don’t we take a look at what another Nobel laureate has to say? Find it on the Blogroll along with a number of other interesting places to visit. Have fun.

http://krugman.blogs.nytimes.com/

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