Reflecting on the Trial Master File, the TMF

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 EMEA, the European Medicines Agency in TMF requirements?

I have been discussing this a lot lately and just gave an audio conference for Thompson Interactive on what is required at a clinical research site during FDA inspections. 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.

The term “trial master file” comes from the ICH E6 Guidance Document on Good Clinical Practice (E6). (Links to E6 and other documents related to this post are listed at the conclusion of the post.) Section 8 of E6 is called, “Essential Documents for the Conduct of a Clinical Trial.” In the introduction to Section 8 the Trial Master File is discussed. I consider E6 to be the authoritative document on the subject. Section 8 has a comprehensive list of Essential Documents, their location and what is necessary before, during, and after a clinical trial. When I define “TMF” I use the documents listed in Section 8 as my primary guidance. The only significant addition to this list (that I am aware of) is the FDA requirement for a Final Report, from the investigator to the sponsor. (I have an article on Final Reports at the conclusion of this post.)

However, some regulatory authorities don’t seem to be emphasizing E6 as much as they may have in the past. It has been suggested that there might be additional “Essential Documents” although no regulatory agency that I know of has published a comprehensive list that could complement E6. Also, it has been suggested that there may be a “Good Clinical Practice” standard other than E6. FDA stated this when they rewrote the requirements for Foreign Clinical Studies Not Conducted Under an IND (21 CFR 312.120). Where you can find an alternative GCP isn’t discussed.

I think that E6 gives sound recommendations for GCP compliance. We should be using it more, not less. It has been published in the Federal Register as official FDA Guidance. It is the only guidance that FDA has on the TMF.

When discussing the TMF one of the trickiest issues involves electronic records, including electronic medical records (EMRs) at a hospital or medical center. There is a lot of grey area as far as protecting privacy, access to EMRs, and the validation of an institution’s EMR system. Unfortunately there isn’t a definitive guidance document on the topic of EMRs. FDA does have a guidance document on “Computerized Systems Used in Clinical Investigations.” It is found in the Important References section on your right, along with E6. Another resource that I recently became familiar with is a document from EMEA with the clever name of REFLECTION PAPER ON EXPECTATIONS FOR ELECTRONIC SOURCE DOCUMENTS USED IN CLINICAL TRIALS. I’ve attached a PDF copy for your viewing pleasure at the bottom of the post. It contains some excellent recommendations.

The “Reflections” document discusses Assigning Responsibility for maintaining clinical trial records. FDA regulations assign responsibility to either the sponsor or the clinical investigator. The “Reflections” document notes that the clinical site needs to maintain control over source documents and not hand over the responsibility to a sponsor. Source documents are the responsibility of the clinical investigator. This includes worksheets or standardized forms that a sponsor might prepare for a site in order to conduct the study according to the protocol. Even though the worksheets are written by the sponsor, they become the Responsibility of the Investigator. Lately FDA has taken to making this point on Warning Letters. Here’s an example from a recent FDA Warning Letter to a clinical investigator on the subject of “adequate and accurate subject case histories.”

“Your site chose to use the sponsor’s standardized forms as source documents to record and document information related to the subjects’ study visits. Per the standardized form, your site was to “Complete the Inclusion/Exclusion Criteria Worksheet to evaluate for study eligibility.” In the FDA investigator’s review of 16 of 65 subject records at your site, there was no Inclusion/Exclusion Criteria Worksheet found for any of these subjects.”

Notice that FDA considers that the site “chose” to use the sponsor’s forms. These records are the responsibility of the clinical investigator. As such, if there is a problem with them 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 EMEA “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.”

Here is the E6 document:
E6_ICH_GCP

Here is the FDA guidance document on “Computerized Systems Used in Clinical Investigations.”

computerized systems in clinical trials

Here is the “Reflections” document:

REFLECTION PAPER ON EXPECTATIONS FOR ELECTRONIC SOURCE DOCUMENTS USED IN CLINICAL TRIALS

Here are four articles I wrote that relate to the TMF. The first is on Investigator Final Reports:

Investigator_final_reports_tool_fda_inspection

The second is one of my first articles, written in 2005, on Protocol Adherence & Recordkeeping. The world has changed a little since then-

Protocol Adherence and Recordkeeping

The next is on Electronic Medical Records:

http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/IT+Articles/The-Ins-and-Outs-of-Electronic-Medical-Records/ArticleStandard/Article/detail/546113

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 !!!

Blogroll Pick: Applied Clinical Trials Blog. Again I am highlighting one of the blogs that you can find on the Blogroll to your right. This is a great blog and the print edition is pretty good as well.

http://blog.appliedclinicaltrialsonline.com/

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FDA Asks For $4,030,000,000

FDA has requested $4.03 Billion, a 23% increase, for fiscal year 2011. (I hope I got all the zeros right.) Much of the increase is for the new tobacco program. The largest chunk is for food safety and we have an analysis of that by Sid Olufs, the blog’s resident book reviewer and food safety analyst. However, the issue of the FDA budget request has been lost in the light of the deficit and other news. On the Blogroll FiercePharma, but not FierceBiotech, comments as well as Gooznews on Health. Before we get to Sid’s comments I have a few short, but important items to report. First, here is the FDA press release on the budget:

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm199516.htm

This Sunday, the 7th of February, is the 10th National Black HIV/AIDS Awareness Day and February is Black History Month. Although African-Americans are only 13% of the U.S. population, they have nearly 50% of the newly diagnosed cases of HIV/AIDS. Here is a statement by Dr. Anthony S. Fauci, Director of the National Institute of Allergy and Infectious Disease that conducts AIDS research world wide:

http://www3.niaid.nih.gov/news/newsreleases/2010/BAAID10.htm

Finally there is an interesting “Frequent Flyer” column in the business section of the NY Times. It is written by a retired physics professor, Robert Kolenkow, who is a diabetic. I am a Type 1 diabetic and a very frequent flyer. I have Travel Too Much status with Alaska Airlines (They call it, “MVP Gold”). I have always found it challenging to manage my diabetes on board a packed coach cabin going across the country so I was interested in what Professor Kolenkow had to say. He participates in a diabetes mentoring group called A1C Champions. They are sponsored by Sanofi-Aventis. Since I use Sanofi insulin I am not sure how happy I am about this. However, you can take a look and judge for yourself.

Here is a link to A1C Champions:

http://www.a1cchampions.com/

Here is a link to the article:

http://www.nytimes.com/2010/02/02/business/02flier.html?ref=todayspaper

Guest Commentary by Sid Olufs:

Paying for a Difficult Job

In an earlier post I briefly described the ambitious agenda facing the new Deputy Director for Food, Michael R. Taylor (FDA Has a New Look for Food). It included these lines describing his responsibilities: “inspection and ensuring compliance with rules, coordination with state and local agencies who do much of the work of food safety, responses to “incidents” that hurt people, getting a handle on imported items that find their way into food, sponsoring and organizing the scientific and technical research needed to design a safe food system, including animal feed and veterinary care, and building the information network that helps to knit all of these together.”

Others have looked at the costs of building a food safety system that can do all of this adequately. In the most comprehensive outside analysis of FDA responsibilities and capacity, the authors concluded that the FDA is critically underfunded in its science-based regulation and decision making, so much so as to put public health at risk. (FDA Science and Mission at Risk, Report of the Subcommittee on Science and Technology, Prepared for FDA Science Board, November 2007.) The Congressional Budget Office estimate of the costs of implementing HR 2749, which falls short of the more complete goals of FDA Science and Mission at Risk, came to almost half a billion dollars a year for the first few years of transition, and about a billion dollars per year thereafter. (CBO Cost Estimate, h.r. 2749, July 24, 2009.)

The Obama administration has now released its budget for FY2011. As described in more detail in the agency budget documents submitted to Congress, FDA requested about $220 million in the form of fee-based inspections, plus additional spending over current spending which brought the total food system upgrade request to about $318 million in additional money for 2011. See the attached link for a brief summary:

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/BudgetReports/UCM199447.pdf

I spent a little time looking at the documents, and only found about $290 million in budget increases in the documents released by OMB. See their detailed HHS budget description, at:

http://www.whitehouse.gov/omb/budget/fy2011/assets/hhs.pdf

The first three pages are the FDA budget summary (the pagination starts at p. 461).) You will see the $220 million on 09.02 Food Registration and Inspection User Fee, on the third page (page # 463) of this document. The fees are “proposed.”

I found no separate discussion of the resources devoted to upgrading the FDA’s information technology, a critical resource in the needed upgrades. It could be that a separate item is included for this, but I searched in vain in the detailed agency appendices and in the Analytical Perspectives that accompany the Budget.

Judging just by the number referred to here, it does appear the Obama administration is taking food seriously, at about two-thirds to three-quarters of the resource level implied by the panel of experts that assembled FDA Science and Mission at Risk. I for one will find it interesting to read how far down that road this new budget authority will take us.

By Sid Olufs

Blogroll Pick: Gooznews on Health- With every post, I am trying to highlight one of the blogs on the Blogroll to your right. This time Gooznews has some interesting comments on the FDA Budget requests.

http://www.gooznews.com/

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Economists, Technology, & Clinical Trials

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.

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 what steps 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 medical 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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FDA Has a New Look for Food

Guest commentary by Sid Olufs.

FDA has made a major appointment to oversee food and food safety. Sid Olufs, a professor at Pacific Lutheran University, has written the first of two posts that discuss what is going on at FDA regarding food safety. Sid is also the author of a number of book reviews found on the page at the top of the Blog.

YOUR comments are always welcome!

Michael R. Taylor appointed Deputy Commissioner of Food
by Sid Olufs, 27 January 2010

The FDA has created a new position, Deputy Commissioner of Food, and has appointed Michael R. Taylor to fill it. The new office is supposed to unify a focus on food safety among the Center for Food Safety and Applied Nutrition (CFSAN), the Center for Veterinary Medicine (CVM), and the foods-related activities of the Office of Regulatory Affairs (ORA), plus other staff offices that support them.

This is a significant consolidation of FDA resources toward a mission focused on food safety. The idea has been out there for a while—for example, in May of 2009 the group Trust for America’s Health released a report advocating precisely this move, arguing it is an important interim step in the creation of a single food safety agency. Yet even if all goes well this is going to take a year to bear significant fruit. The several food-related units within FDA have many items on their now-shared plate: inspection and ensuring compliance with rules, coordination with state and local agencies who do much of the work of food safety, responses to “incidents” that hurt people, getting a handle on imported items that find their way into food, sponsoring and organizing the scientific and technical research needed to design a safe food system, including animal feed and veterinary care, and building the information network that helps to knit all of these together. The new Deputy Commissioner’s office is supposed to employ risk-based criteria for the difficult budget and other resources decisions to make all of this happen. It will be a difficult job.

Mr. Taylor clearly has the experience to take on this job, and some of the most knowledgeable people in the food safety world (like Marion Nestle and Steven Grossman) are saying this is very good news. Mr. Taylor’s published writing and congressional testimony may tell us what to expect—these will be the subject of a subsequent note.

This is all good news. But do not read too much into it. I have two reservations. First, we still have the split responsibility for food between the FDA and USDA. The FDA mission includes much less of the industry cheerleader responsibilities shouldered by USDA, but there is enough wiggle room in the mission language to let a pro-business conservative appointee take the agency in a very different direction. This is the second reservation. A food safety system should not depend on a particular party winning an election. A subsequent blog will compare different models of locking in a mission at an institution like FDA.

Mr. Taylor has written and testified about food safety issues, which provides a record that may tell us what to expect. During his time at Resources for the Future (RFF) he co-edited (with Sandra A. Hoffmann) Toward Safer Food: Perspectives on Risk and Priority Setting (RFF, 2005), and contributed a short summary chapter. The topic of risk analysis is inherently contentious—in general, advocates of a precautionary approach, as found in several western European countries, do not like it, and advocates of using the business bottom line as a factor in safety issues endorse it. [Disclosure: I personally advocate the use of risk analysis, and am convinced it needs to be part of a precautionary approach—but now seldom is.]

It makes sense to go after the biggest threats to human well-being, and to pursue the policies that produce the most improvement for scarce available dollars. Yet risk analysis comes with a technical vocabulary and measurement techniques that tend to limit participation in debates to those with the skills and experience to speak about and decipher the approach. What I saw throughout Toward Safer Food was a model of analysis that treated technical innovations as mostly exogenous variables, as the economists call them, which respond to market forces.

Take the example of concentrated animal feeding operations (CAFOs). They produce meat that costs less per pound and brings animals to slaughter many days faster. Markets gave us CAFOs. And yet, they produced public health consequences that have to be paid for through public policy and increased consumer caution—they have killed people. One of the things markets do is to allow some folks to seize the benefits of new technologies while avoiding the costs the new practices impose on others (indeed, many are created for precisely this reason). Risk analysis should include the likely effects of proposed food system technologies to vet them for things like the production of new super-germs, the need for more drugs in animals during production, and so on. None of the authors of the chapters in Toward Safer Food appear to embrace the more robust modeling needed to make risk analysis vigorously support public health.

Another important piece by Mr. Taylor is the 2007 report from Harnessing Knowledge to Ensure Food Safety, coauthored with Michael Batz (Food Safety Research Consortium, 2008). The report focuses on the food safety information infrastructure needed right now. The 9-page executive summary is available at:

http://www.thefsrc.org/FSII/Documents/FSII_Exec_Summary.pdf

It is worth reading. Briefly, we now have a chaotic cloud of food safety information, no widely shared standards for how to develop research, or how to test ideas about food safety, how to collect information at state and local government, in private industry, and in a dozen national government entities. We have to build an information system that supports public health. There are many good ideas in here, as you can see in the executive summary. One key feature of the approach advocated by Mr. Taylor is “the stakeholder model,” (TSM) in which the interested parties discuss challenges and prospects and develop approaches for improvement. Representatives from government, industry, consumer groups, and anyone else with a recognized stake get together (in this report, the gathering will be called a council) to seek consensus among their perspectives. Like the topic of risk analysis, this is a highly contentious idea. TSM has been widely adopted by state and local governments in environmental policy, to cite one example example, because of the political pressures against regulation. Plans that emerge from stakeholder committees or councils emphasize self-financing elements and voluntary compliance. Sometimes a stakeholder has a perspective that harms public health. This fact needs to be part of the institutional design. [Another disclosure: my view on this is probably influenced by personal experience, as described in

http://www.plu.edu/~olufsdw/unpleasant.htm

A third publication, Stronger Partnerships for Safer Food (coauthored with Stephanie D. David, from GWU School of Public Health and Health Services, 2009) describes the intergovernmental maze of food safety organizations we will have to integrate into an effective system. Nineteen recommendations describe the needed changes, and it is a compelling case.

See the executive summary at:

http://www.rwjf.org/files/research/20090417foodsafetysummary.pdf

Among the more difficult features are a clear congressional mandate to the Dept. of Health and Human Services (HHS), a HHS secretary committed to food safety as a main agency priority, and a significant increase in intergovernmental funding. One frequently mentioned feature of the current system is the required visual inspection of all animal carcasses, which do not detect the most dangerous sources of contamination. If they were cut out, perhaps $200 million or so could be saved—at some cost to public health. But this goes at most halfway toward funding the required changes needed at FDA alone, which needs to be supplemented by large increases in intergovernmental funding for state and local food agencies. (The budget estimates I refer to here come from sources like the Congressional Research Service and Congressional Budget Office, not the publications mentioned above.)

Observers of the health care debate over the last half year must be forgiven for their profound skepticism that these obstacles can be overcome. I don’t wish to sound entirely negative. There is much in the latter two documents that need to be put into an effective food safety agency. But more is needed, in my view. To repeat: A food safety system should not depend on a particular party winning an election. The reservations noted above are all things that can be dramatically altered by a shift in party control of Congress or the White House. A subsequent blog will compare different models of locking in a mission at an institution like FDA.

Blogroll Pick: Acronym Required In a new feature of the Blog I am highlighting one of the blogs you can find on the Blogroll each time I write a new post. Please take a look at the Blogroll as there are some interesting places to visit. Acronym Required is a recent addition to the Blogroll and discusses issues of food safety, along with other current topics.

http://acronymrequired.com/

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Clinical Trial Compliance & Checklists: The Right Approach?

Checklists and complex medical procedures: Some physicians argue that checklists can reduce infection rates during surgery and help manage an increasingly complex medical system. Also, there is a growing use of checklists in clinical trials including the use of “protocol-specific worksheets” to assist a clinical site in protocol compliance. Some QA specialists think checklists are essential. Others ask, “Is this a good thing? Are we missing something in the checklists?”

The New York Times Book Review reports on the medical part of this discussion in a review by Dr. Sandeep Jauhar entitled “One thing after another,” about the book The Checklist Manifesto” by Dr. Atul Gawande (Metropolitan Books/Henry Holt & Company: $24.50). Dr. Gawande is a professor of surgery at Harvard Medical School and a staff writer at the New Yorker. The reviewer, Dr. Jauhar, is a cardiologist and the author of “Intern: A Doctor’s Initiation.” A quick note: His review does not discuss clinical trials. However, I immediately drew a connection.

An example in the book cites “A five-point checklist implemented in 2001 virtually eradicated central line infections in the intensive care unit at Johns Hopkins hospital, preventing n estimated 43 infetions and eight deaths over 27 months.” That is a very impressive result that has been repeated at studies at intensive care units (ICUs) in Michigan, according to the review.

In clinical trials I have seen many quality assurance audit plans and monitoring procedures that rely heavily on checklists. Checklists are something that I should probably use more. I usually use the FDA Clinical Investigator Compliance Program Guidance Manual (CP 7348.811) that I was trained on when I was at FDA (see link on the right under “FDA Stuff”). However, I see a downside of checklists. Although they help make sure you review the necessary documents hey rarely assist the monitor or auditor in determining significance. I have seen cases where a monitor or auditor has hammered away about an item on their checklist that really wasn’t all that important, or maybe not even relevant for that specific study.

In addition, checklists are entirely dependent on who is writing the checklist and if their list, written in an office complex somewhere, is practical in the field where clinical trials actually are taking place. There can be some serious unintended consequences. I have seen recent FDA Warning Letters to clinical investigators that state:

“A. 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.”

The records kept at a clinical site are the responsibility of the site, of the clinical investigator, not of the sponsor or the employee that wrote them. If the site doesn’t fill out each of the worksheets, and perhaps sign and date them, then FDA will write you up in a Form FDA 483, Inspectional Observations, for inadequate recordkeeping and possibly a protocol violation. In short, the checklists and worksheets have to be practical to use at the clinical site.

Dr. Jauhar does not talk about clinical trials in his book review. But he does give concrete examples of how checklists can be a problem. For exmple he says:

“Today, insurers are rewarding doctors for using checklists to treat such conditions as heart failure and pneumonia. One item on the pneumonia checklist — that antibiotics be administered to patients within six hours of arrival at the hospital — has been especially problematic. Doctors often cannot diagnose pneumonia that quickly. But with money on the line, there is pressure on doctors to treat, even when the diagnosis isn’t firm. So more and more antibiotics are being used in emergency rooms today, despite the dangers of antibiotic-­resistant bacteria and antibiotic-associated infections.”

The book review is very much worth reading. In addition there is access to a podcast featuring Dr. Gawande. You can find a ink under “Interesting Articles” on the right as well as below:

http://www.nytimes.com/2010/01/24/books/review/Jauhar-t.html?ref=todayspaper

Blogroll Pick: Kaiser Health News. I grew up going to Kaiser in Oakland, CA. I remember how happy my mother was when she got health insurance from her job as a fiscal clerk with the federal government. They have great information in Kaiser Health News. I should read it more often. Here it is:

http://www.kaiserhealthnews.org/

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Obtaining FDA Establishment Inspection Reports- EIRs

FDA has a policy that allows an inspected organization to obtain a copy of their inspection report before it is available to the general public through the Freedom of Information Act. This policy is called FMD-145 (FMD=Field Management Directive). Since first writing about this last September, the subject continues to be of interest to visitors to the Blog. I checked the FDA website and yes, FMD-145 is still there. Here is the reprint of my original blog post. Please let me know your thoughts with a Comment.

Obtaining your establishment inspection report (EIR) under FMD-145

I frequently talk to people about the difficulties in obtaining an “establishment inspection report” or EIR after a company or clinical site has been inspected by FDA. Inspected parties can wait years before receiving an EIR, if they receive a copy at all. An FDA “Field Management Directive” – FMD 145 – states the following:

“This Field Management Directive (FMD) provides guidance and criteria for releasing a copy of the establishment inspection report (EIR) to the establishment that was the subject of an FDA or FDA-contracted inspection when the Agency determines the inspection to be “closed.”

The Agency … determined that a copy of the EIR should be routinely provided to the inspected establishment once the Agency concludes that the inspection is closed. For the purpose of this directive, the term “closed” will have the same meaning as it has under 21 C.F.R. §20.64 (d)(3).”

A “Field Management Directive” is a method by which senior management at the Office of Regulatory Affairs (ORA), the field organization that conducts FDA inspections, sets ORA policy. This means that FDA should Routinely issue a copy of the inspection report after they close an inspection. You shouldn’t even have to ask although you almost always do. If inspected by FDA you should ask the field investigator about obtaining a copy of the report per FMD 145. If it has been more than 90 days since you have had an FDA inspection and received a letter from FDA saying “no further communication is necessary,” or something like that, then you should ask for a copy of your EIR. You should contact the address listed on your FDA 482, Notice of Inspection, that was issued at the beginning of the inspection.

FDA instituted this policy so an inspected party would receive a copy of their inspection report prior to the report being released to the public at large under the Freedom of Information Act. If you have been inspected by FDA then you have a right to a copy of your inspection report and you should ask for it. FMD-145 is a tool for you to use to improve your compliance with FDA regulations. The EIR contains important information on how FDA approaches their inspections and, what they think of you. FDA states that they are committed to “Effective Enforcement.” Adhering to FMD-145 is an important component of that. Here is a link to FMD-145:

http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/ucm103299.htm

Blogroll Pick: FDA Transparency Blog. The FDA has a blog to discuss transparency by the Agency. The Transparency Blog also asks, “How Should FDA Inform the Public About Inspection Results” and has 13 comments (including one by me). Check them out and check out the other sites on the Blogroll.

http://fdatransparencyblog.fda.gov/

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Anesthesiologist Accused of Fake Drug Studies

Federal agencies including the FDA’s Office of Criminal Investigations and the FBI have joined in an investigation of Dr. Scott Reuben, the former chief of acute pain at the Bay Medical Center in Springfield, MA. Dr. Reuben was accused of faking clinical trials for pain medications including the Cox-2 inhibitors Vioxx by Merck and Bextra by Pfizer. The Associated Press reports that Dr. Rueben may have agreed to a plea bargain with the U.S. Attorney’s office in exchange for more lenient sentencing. The Journal of Anesthesia and Analgesia and the Journal of Anesthesiology have pulled 13 of Dr. Reuben’s published articles. Read more:

http://www.medicalnewstoday.com/articles/176232.php

Blogroll Pick: WSJ Health Blog where you can also read about Dr. Reuben at;

http://blogs.wsj.com/health/

Please look at the other sites on the Blogroll.

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Mountains Beyond Mountains: The Tragedy in Haiti

08 February: The New York Times Book Review reported that Mountains Beyond Mountains by Tracy Kidder was again on the paperback bestseller list for nonfiction at #14. This reflects a continued interest in Haiti and Partners in Health. The book is excellent and I would highly recommend it. Here is a link to Amazon for it:

http://www.amazon.com/Mountains-Beyond-Farmer-Random-Readers/dp/0812980557/ref=sr_1_1?ie=UTF8&s=books&qid=1265662708&sr=1-1

Remember that Partners in Health has continuing needs to help the people of Haiti. Please contribute:

www.pih.org/home.html

15 January 2010: Mountains Beyond Mountains: The Tragedy in Haiti

Given the enormity of the tragedy in Haiti it is difficult for me to write about FDA guidance documents and regulatory compliance. Instead, I am going to ask you to help with the relief efforts. When natural disasters strike it is often difficult to know just where your donations will do the most help. In Haiti I believe it is an organization called Partners in Health. They are already there and have decades of experience in helping the poorest people in Haiti, the people who are most in need Right Now. The link to their website is just below. WOULD YOU PLEASE CONSIDER MAKING A DONATION:

www.pih.org/home.html

I first learned about Partners in Health and Dr. Paul Farmer, its founder, by reading the book Mountains Beyond Mountains by Tracy Kidder. It is probably the best book on international health issues I have ever read. I strongly recommend it.

Mountains Beyond Mountains: The Quest of Dr. Paul Farmer, a Man Who Would Cure the World (Random House Reader’s Circle) (Paperback) by Tracy Kidder

From the New England Journal of Medicine: “Indeed, Farmer founded a hospital and health center, Zanmi Lasante, in Cange, Haiti, hours from the capital and at the end of a gutted road in a region destitute even by Haiti’s standards, as part of an extensive community-based health network linked to a hospital, Clinique Bon Sauveur. For more than 20 years, Farmer has spent many months every year there, often taking care of patients himself and continually improving the treatments offered by the clinic. These now include antiretroviral drugs. Lasante is supported by a foundation based in Boston called Partners in Health…”

UPDATE: You can read an update from Partners in Health here:

16 January Haiti Update

Photo UPDATE:

http://standwithhaiti.org/haiti/news-entry/photos-from-port-au-prince-david-walton/

UPDATE: 02 February: In this morning’s NY Times was an article about relief funds for the crisis in Haiti. It pointed out that when the earthquake hit, the American Red Cross (an excellent organization) had 15 people working in Haiti. In contrast, Partners in Health had 700 doctors and nurses among a staff of nearly 5,000 with one hospital and numerous clinics throughout the country. Yet the American Red Cross has raised almost $200 million for Haiti and Partners in Health about $40 million. People will donate to the best known organizations, not necessarily to the best placed ones.

A colleague of mine who has been following this blog remarked she had been donating to Doctors Without Borders The Nobel Prize winning relief organization. I also strongly support them and contribute on a monthly basis. It is important for relief organizations to have a steady flow of money after the TV cameras have left. I urge that you consider this type of support for an organization you believe is doing good work. Here is a link to Doctors Without Borders/MSF- USA:

http://doctorswithoutborders.org/

Update: Dr. Paul Farmer testifies to U.S. Senate Committee on Foreign Relations, 29 January:

http://standwithhaiti.org/haiti/news-entry/pih-co-founder-paul-farmer-testifies-at-senate-foreign-relations-committee/

Blogroll Update: Partners in Health Blog- Now you can follow the progress of relief efforts in Haiti firsthand with the Partners in Health Blog:

http://www.standwithhaiti.org/haiti/news

UPDATE 19 January: FIRSTHAND: Writer Dany Laferrière describes living through Haiti earthquake, the Le Monde interview translated by Mark Jensen:
HAITI- TESTIMONY OF WRITER DANY LAFERRIÈRE

UPDATE 18 January: Today we celebrate the birthday of Dr. Martin Luther KIng Jr.. What better way to celebrate than by helping the people of Haiti. View Katie Couric interview with Ophelia Dahl of Partners in Health on the current situation:

http://standwithhaiti.org/haiti/news-entry/ophelia-dahl-on-katiecouric/

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Analysis of Recent FDA Warning Letters to IRBs

UPDATE: Unfortunately FDA doesn’t appear to keep links to Warning Letters active. The ones inserted into this post no longer work. Thanks FDA. You can find the Warning Letters by going to the FDA Warning Letter Page and searching by company.

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm#recent

A clear pattern is emerging from the recent spate of IRB Warning Letters written by FDA. It appears that IRB registration is working. The Food & Drug Administration is learning just who is approving research in the U.S. The addition to the FDA IRB regulations, 21 CFR Part 56.106(a), requires Institutional Review Boards (IRBs) reviewing FDA research to register with FDA. It is an excellent addition to the regulations and is already paying dividends to improve clinical trials. (FDA could update a few more regulations but that’s a different story.) Formerly, FDA would only find out about an IRB’s existence if there was an application for a product approval that listed the IRB or if there was a complaint.

Here is a link to the FDA guidance document for Frequently Asked Questions regarding IRB registration:

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM171256.pdf

The ruling went into effect on 14 July 2009 and came on the heels of the Coast IRB sting where the GAO submitted a fake clinical trial that was unwittingly approved by the now defunct Coast. Since that time some very serious Warning Letters have been written citing some very serious violations of regulations designed to protect human participants in clinical trials. At least two IRBs, the Teneo IRB and the MI Hope Inc. DBA Center for Complex Infectious Disease IRB have been told to stop approving studies and to stop enrolling new subjects in existing studies until FDA approves corrective actions. Is there something seriously wrong with IRBs in this country? Reading the Teneo and MI Hope Warning Letters could lead you to think so. Take a look at MI Hope:

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm195484.htm

And now Teneo IRB:

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm191450.htm

Although both these Warning Letters are pretty bad I think that they should have been expected. Previously, FDA did not have the authority to require IRBs to register. Although the work of running a good IRB is quite difficult it amazingly easy to start an “IRB.” It takes five people, one of whom is a scientist (they are not required to be a physician), one a non-scientist, and one not affiliated with the institution. Then you toss in some administrative stuff such as a few written procedures and you’re set to go. As a result, organizations such as MI Hope and Burzynski Research Institute could start their own IRBs free from FDA oversight and with serious potential for conflicts of interest. Now that FDA has a list of these IRBs they are conducting inspections and finding a few bad actors. The same thing happened when FDA started inspecting seafood processors and home respiratory care facilities. The first time FDA comes in to conduct inspections, there frequently are problems. FDA isn’t writing Warning Letters to the many established, legitimate IRBs that have been inspected several times in the past

When I was at FDA I inspected over 30 IRBs and found that most IRB members were dedicated, hard working research professionals. Most IRB board members are volunteers, serving for no pay or a small stipend. Few people are getting rich at IRBs. Their purpose is to provide independent review of research to protect clinical trial participants. IRBs are a very good thing. Problems sometimes occur when IRBs become confused between FDA regulations and regulations enforced by the Office of Human Research Protections (OHRP). That is what apparently happened recently when a Warning Letter was written to Florida Atlantic University. They are a small academic IRB that reviews very few protocols under FDA jurisdiction. They are significantly different from Teneo, Burzynski, or MI Hope. Take a look for yourself:

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm195975.htm

As a result, there is a tendency to heap additional responsibilities onto IRBs. Some in Congress are tempted to do this and some “consumer advocates” are as well. This can lead to a stifling effect on innovative research. One principal investigator I know who conducts non-FDA regulated research, primarily through surveys or questionnaires, described IRBs as the “bane of my existence” because of the overly burdensome administrative procedures. These administrative procedures are frequently enacted because OHRP found problems in the past at some academic research institutions. The American Enterprise Institute, a very conservative policy organization, raised some interesting points last year in an opinion peace published in the NY Times (below). We should give FDA the time to wend their way through the list of newly registered IRBs and not have knee-jerk reactions to the initial results. There will be more Warning Letters in the immediate future but that should just weed out the bad actors. Most IRBs have already been inspected by FDA and are doing their work. We need to make their work easier, not more difficult.

Here is a link to the American Enterprise Institute’s op/ed piece:

http://www.aei.org/article/100868

The bottom line is we need legitimate IRBs to independently review clinical research in the United States. We also need to understand that we need research vitality. We should resist the impulse to impose too many restrictions on IRBs.

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The Blog Cleans Up Its Act

Welcome to Carl’s Blog on GxP Stuff. I’ve changed the name from “Carl’s Blog on FDA Stuff” to reflect my evolving interest in focusing on a number of issues and not being “FDA-centric.” There many other regulatory agencies in the U.S. and the rest of the world and I would like to give them some attention as well.

Also, its the new year and I’m finally figuring out how to use some of the WordPress blog features. As a result, I have cleaned up the Blogroll so that links once more make sense. I have moved many links to “Interesting Articles” and have created a new category for “FDA Stuff” that are links to the nooks and crannies of FDA’s website. Yes, I will still be discussing FDA.

This allows me to organize and highlight some of the interesting places you can go to research FDA & GxP stuff. I’ve just added Compliance Zen to the Blogroll. The author, John Avellanet, has an excellent post on communication (which I should take to heart). I’ve also moved the Blog’s very own book reviewer’s excellent website for food safety, 1 FDA, Food Safety, and Related Topics, to the top of the Blogroll. Thanks Sid. Another post worth reading is by Lisa Henderson at the Applied Clinical Trials Blog. She has some interesting things to say about when her trade publication’s sales and editorial staff started sharing the same office location.

Finally, I want to recommend some blogs/sites that are not directly related to GxP or FDA stuff. These include France 24 which is an English language news station from France. I think it is important to see things from outside the U.S. We all know about BBC but France 24 is very interesting. Also there are two blogs put out by individuals who take the time to write thoughtfully on topics that you may, or may not, find of interest. They are: Grab & Keel which focuses on current events from the author’s perspective and Monte’s Blog which takes a look at one person’s spiritual journey. Also there is Water: USGS that provides a perspective on government service and one of the most important issues we will face this century, water. Now that I am GxP I can give this issue some thought. Please scroll down and take a look at the various links. There are a number of different perspectives so you can take a look at various viewpoints. Feel free to leave a comment and suggest other sites that you find of interest.

UPDATE: This news is just in from Alan Andersen in an email to members of the FDA Alumni Association:

“FDA has announced Ralph Tyler as the new Chief Counsel. He is currently serving as the Insurance Commissioner of the State of Maryland (01/08/10 is his last day, I think) and will be joining FDA on January 19.

Tyler served as Chief Legal Counsel to Maryland Governor Martin O’Malley and as Baltimore City Solicitor. He was a partner in the international law firm Hogan & Hartson, L.L.P. Prior to that, he served in the Maryland Attorney General’s office from 1982 through 1996, holding the titles of Deputy Attorney General, Chief of Litigation and Assistant Attorney General. Acting Chief Counsel, Mike Landa, will return to his position as Deputy Director for Regulatory Affairs at CFSAN.”

ALSO: Here is the link to an article about clinical trials in the UK that I found interesting:

http://www.ft.com/cms/s/0/2b66d8ae-f570-11de-90ab-00144feab49a.html?nclick_check=1