Electronic Medical Records & Clinical Trials

March 30, 2009

An important centerpiece of President Obama’s stimulus package is to encourage electronic medical records (EMRs). Last September I made my own contribution regarding EMRs in an article for Applied Clinical Trials (“The Ins and Outs of EMRs.” I am posting it on the right under interesting articles. I am also posting a recent NPR article, “Electronic Medical Records, a Charged Debate.”

For those of us who monitor and audit EMRs for clinical trials this is a tricky issue. NPR points out it is a tricky issue for a number of other reasons. As always, I welcome your comments.

Update: See Update on EMRs under Interesting Articles for an update I wrote for Applied Clinical Trials online edition.


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The word on FDA from North Carolina

March 22, 2009

“FDA Ignores Whistleblower” the headline screamed at me as I rushed through the Raleigh Durham International Airport. However when I arrived home in Washington state my local paper hadn’t carried a word about it. Neither had the NY Times. Fair enough, the article from the News Observer, posted under interesting articles on the right, was about the safety of syringes manufactured in North Carolina. But the manufacturing problems- and FDA’s failure to address them, impact the health and safety of us all. Over 100 people became sick from bacteria laden syringes and five people died. North Carolina reader’s have commented on the article and, although most are expressions at rage at FDA, there is one thoughtful comment on the need for better quality control and quality assurance systems and how they make for good business practice.

It will be interesting to see if the new team of Hamburg and Sharfstein can solve some of the systemic problems with FDA inspections. From my review of the article it seems that at least one inspector was attempting to do a good job although she didn’t get to the whistleblower’s issue of the syringe clean room where the bacteria contaminated the syringes. It seems like a management problem to me.

You can read additional posts on FDA Commentaries here:



Acting FDA Commissioner issues a “privacy memo”

March 20, 2009

Acting FDA Commissioner Frank Torti has issued a memo to FDA staff with strong words on maintaining confidentiality of FDA documents, including e-mails and memorandums. It’s causing something of a stir although I personally think that all of the restricted areas that Torti mentions should indeed be kept confidential. However, it is very interesting that an Acting Commissioner would issue such a stern memo to agency staff. Read for yourself. The memo is listed under Interesting Articles to the right. Also under Interesting Articles is a blog entry from the In Vivo Blog. Interesting stuff.

DSI Hits Hard on Human Subject Protection

March 15, 2009

The Division of Scientific Investigations (DSI) in FDA’s Center for Drug Evaluation and Research used to be something of a joke when it came to enforcement. In fact, in Fiscal Years 2005 and 2006 they failed to issue a single Warning Letter. Not one. Well, things have changed. In the article “Bimo Warning Letters for 2008” found on the page at the Blog Top I mention that DSI has started to issue Warning Letters for clinical trials. Now, DSI has issued three Warning Letters dated 2-3 March for some very serious violations of regulations protecting the rights, safety and welfare of participants in clinical trials. Although I have questioned some of DSI’s judgement in the past few years, all three are richly deserved. They are all sent to clinical investigators (the medical doctors conducting the research).

In the first Warning Letter the clinical investigator had three lapses in approval by an institutional review board (IRB), the longest lapse in approval was for five months. IRBs are the independent ethics committees that oversee clinical trials. Not having independent review of research is a very big no-no. The Warning Letter included a citation for consenting a participant, also referred to as a “subject,” first with an English language consent form and then later re-consenting the participant with a Spanish language informed consent form. This indicates that the participant was probably only fluent in Spanish. An informed consent form must be in the language used to provide informed consent to the participant. This is another essential right of people participating in clinical trials, the right to informed consent and to not participate if they so choose.

The second Warning Letter involved pediatric trials for Zemuron, a Schering Plough drug used in relaxing muscles during surgery and mechanical breathing. This time FDA cited the clinical investigator for failing to adequately supervise “individuals to whom you delegated study tasks…resulted in inadequate informed consent documentation…failed to obtain legally effective informed consent.” There were numerous problems at this study site that involved false signatures from the study coordinator (the clinical investigator’s primary assistant) and consent forms dated by study personnel instead of the study participant.

The third Warning Letter documented that all 18 participants who enrolled in the study “received study dug prior to your review and assessment of baseline laboratory results…were infused intravenously…” The clinical investigator (again, the medical doctor conducting the study) didn’t review the laboratory results from three to 20 days after infusing the investigational drug product. This is a big deal for three important reasons.

First, you never start a clinical trial before all requirements are met. Clinical trials are experiments, not the practice of medicine. Second, the clinical investigator was dealing with very ill patients. They were having IV drug infusions. He should have reviewed their lab results regardless if they were participating in a clinical trial.

Finally, and this is the first of two points I am trying to make in this post, the clinical investigator failed to establish a clinical baseline for the participants. This is an important concept for those of us who are involved in the conduct of clinical trials as our profession. There needs to be a clearly established clinical baseline, the medical condition of the participant when the study begins. And you really want to DOCUMENT the clinical baseline. This is important to determine if the drug is safe and effective.

The second point I would like to make is that it is very disturbing that clinical research in the United States is being conducted with these ethical violations. If you have read this far you probably know that there are problems with the conduct of clinical trials, with drug safety, and the entire new drug approval process. We know that FDA needs to improve its performance if it is to adequately protect the health of the American people. The question is what needs to be done.

I would like to suggest that putting more requirements on institutional review boards (IRBs), the ethical committees that oversee research, is not the way to go. Instead, I believe that we need to modernize the clinical trial regulations that came into being in the 1970s. In particular, I believe that we should make the Consolidated Good Clinical Practice Guidelines, ICH E6, into regulations, instead of a guidance document that cannot be legally enforced. This document was written with extensive input from FDA. It is the law in Europe, Canada, Japan, Australia, and many other countries. Our regulations are outdated and don’t give researchers the necessary oversight to ensure ethical clinical trials.

Unfortunately, over the years IRBs have been criticized for not providing the necessary oversight. This isn’t the responsibility of the IRBs, it is the responsibility of FDA. FDA needs to perform more effective inspections of clinical investigators and IRBs. However, FDA does not have the resources, and until now DSI did not have the will, to enforce protections for participants in clinical trials.

Currently IRBs are being investigated by a Congressional subcommittee chaired by Representative Bart Stupak. The investigation should be discussed at a hearing later this month. I think that they may be looking in the wrong place. There are two sets of regulations for IRBs in the U.S. which is confusing to many (FDA regulations and Department of Health and Human Services, 45 CFR 46). The regulations are enforced by two different federal agencies with different approaches. Out of date, conflicting regulations just don’t help very much.

In fact, the FDA “Compliance Program” for IRBs hasn’t been updated since 1994. It was due to be updated in 1997, 12 years ago. The compliance program is the blueprint for FDA field investigators to conduct an inspection. FDA has outdated regulations, field operations, and funding.

I am also posting E6, the combined guidance for Good Clinical Practice (GCP), and other ICH documents. Finally, I am posting the link for the outdated compliance program for the inspection of IRBs. It is high time that this document was updated. As always, I welcome your comments.

Drug Safety? Good news/bad news

March 11, 2009

The good news is that the Obama Administration told Congress that it was committed to drug safety. The bad news is that Budget Director Peter Orszag delivered the news. After going without a Commissioner for half of the Bush Administration, FDA is still without a nominee for commissioner by President Obama.

An interesting article by Reuters is posted on the right under (oddly enough) “Interesting Articles” (Drug Safety…). I’m happy that Congress is concerned about drug safety for imported drugs. I am very unhappy that they aren’t discussing the issue at the same time they are confirming a new Food & Drug Commissioner. FDA needs new leadership committed to public health. Immediately.

Top choices are: Joshua Sharfstein, Baltimore Health Commissioner; Steve Nissen from the Cleveland Clinic, and Center for Drugs mainstay Janet Woodcock. My vote is for new blood (read Sharfstein or Nissen). However, and you need to trust me on this, my opinion counts for very little east of Fife, WA (the state, not the city).

The word on FDA from Tennessee

March 10, 2009

I am currently traveling through Eastern Tennessee and noticed this editorial from the Chattanooga Times about FDA failing to perform its mission of protecting the American People from unsafe food, drugs and medical devices. They are not the only ones to notice that the Bush Administration did FDA no favors when it came to supporting the Agency financially and politically. I like the fact the editorial mentions the failure of “third party” inspectors in the recent peanut crisis.

We need a strong, independent group of FDA inspectors who can do an unbiased job. Unfortunately I have seen some inspectors issue “FDA 483s” that weren’t worth the paper they were printed on. We need to rebuild FDA and we need to start immediately. However, FDA managers need to break out a copy of the regulations and do things “by the book.” Yes, the regulations are in desperate need of updating, but we need the necessary Congressional hearings and stick to the rule making process. A 483 shouldn’t be the product of an inspector’s imagination.

We’ll talk more of poor inspectional findings in the days to come. In the mean time I have posted the editorial under “Interesting Articles to the right. (FDA Woes…)

Blogs on FDA Stuff

March 8, 2009

Obviously I am not the only person with something to say about FDA. A very well organized blog with a lot of good links is Eye on FDA which I am adding to the blogroll at the right. Let me know if you have other blogs worth noting.

So I am editing this because I came across another blog on FDA stuff from another group of lawyers. This is interesting because it discusses the whole issue of FDA regulation of tobacco. The blog is called the FDA law blog and I am adding them onto the blogroll on the right. For a couple of years I was the San Francisco District Tobacco coordinator, which got me a trip to Reno, Tukwilla (Washington State), and… Honolulu. Not difficult duty. I’ll contribute soon on tobacco, because I probably disagree with everybody. Anyway, check out the blog on FDA Law. They have worked hard to put together information for us.

Another interesting blog is Grab and Keel which I have entered onto the blogroll. They discuss food safety issues (the “F” in FDA stands for food, not federal) including a house bill, H.R. 875, that would create a single food safety organization. It is a very good idea and you can check it out on the important references link to the right. Search by bill number when you get to the site.

FDA Guidance: Is anyone monitoring this?

March 6, 2009

In the 21st Century FDA has issued a lot of guidance documents, but few updated regulations. Por Quoi? In this 2008 article published in RAPS Regulatory Focus I discuss some important guidance documents to assist sponsors of clinical research “Monitor the progress of the investigations.” The article has taken on a new urgency since FDA seems to be intent on increasing enforcement on clinical trial sponsors. At least this is indicated from Warning Letters issued in the past year or two.


FDA & The Declaration of Helsinki

March 3, 2009

If this is your first or second visit to the Blog, then I should tell you that I am a former employee of FDA interested in discussing issues regarding FDA, good clinical practice (GCP), and good laboratory practice (GLP). I have posts on several issues in the past two weeks that I hope you will look through. Who knows, one or two may be of interest to you. In this post I offer my opinions on FDA’s decision to break with the ethical standards found in the Declaration of Helsinki last year. I welcome your comments on this or any other post.

Few, if any, documents carry more prestige than than the Declaration of Helsinki. First issued in 1964 by the World Medical Association it is a direct result of the atrocities committed in World War II by Nazi Germany by physicians carrying out “research” on concentration camp inmates, frequently in “studies” designed to kill the participants. It is a document that is the direct result of a critical need to establish ethicall research standards for biomedical research. It was a scientific extension of the Nuremburg Code, published in 1949, which came about as a result of the war crimes tribunals that took place in Nuremburg directly after the war.

The Declaration of Helsinki also predates the Belmont Report by 15 years, a document on research ethics that was released by the United States in 1979, that set the bases for our modern IRB regulations. The Declaration has been updated throughout the years and was referenced in the FDA investigational new drug application (IND) regulations (§ 312.120 ) until last year. At that time FDA issued a Final Rule that replaced the Declaration with “good clinical practice” or GCP as a standard for accepting research not conducted under an IND. One primary reason is a difference in policy regarding the use of placebos in clinical trials.

The Declaration of Helsinki, the Nuremburg Code, and the Belmont Report are all attached as links on the right under important documents, along with ICH E6, the original GCP document. The Final Rule for § 312.120 is attached as a PDF file at the bottom of this post.

Now, with a new administration setting international policy, is it possible that FDA will listen to criticism about severing ties with the Declaration? Is it possible that in a globalized economy and a globalized industry that FDA will try to bring itself into harmonized research ethics standards? It is an interesting question and one that the new commissioner, whomever gets the job, will need to deal with sooner or later. Who President Obama selects will give us a better idea of whether its sooner rather than later.

Last fall I participated in publishing an article (also attached to this post) discussing the Final Rule. Now I would like to pose three questions that I believe need to be reviewed in depth as we decide if FDA should embrace or reject the Declaration of Helsinki.

First, the Final Rule issued by FDA states: “The final rule replaces the requirement that these studies be conducted in accordance with the ethical principles stated in the Declaration of Helsinki (Declaration) issued by the World Medical Association (WMA), specifically the 1989 version (1989 Declaration), with a requirement that the studies be conducted in accordance with good clinical practice (GCP), including review and approval by an independence committee.”

For most of us the document that is the primary reference for GCP is a well established, internationally recognized document: E6: Good Clinical Practice: Consolidated Guidance (E6) published by the International Conference on Harmonization (ICH). There are only two small problems: although FDA recognizes E6 as a standard for GCP and in fact participated in the ICH discussions that produced E6 and even published E6 as official FDA guidance in the Federal Register, it doesn’t recognize E6 as the standard for GCP in the Final Rule, only that “the standard of GCP we propose § 312.120 was consistent with that in ICH E6 and was sufficiently flexible to accommodate differences in how countries regulate the conduct of clinical research and obtain informed consent, while helping to ensure adequate and comparable human subject protection.”

One problem is that the introduction in E6 specifically mentions the Declaration: “Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.” Now this is something that FDA has noticed as well. In fact they cite this reference in responding to one comment to the Final Rule. FDA points out that GCP is more than an operational guideline, it is an ethical standard as well. (my emphasis)

However, FDA conveniently fails to mention to this particular response that FDA is not adopting E6 as the standard for GCP. (my emphasis) So that is my second issue with the Final Rule for § 312.120. GCP is an internationally recognized standard that FDA participated in creating. However, FDA rejects the use of this internationally recognized definition of GCP in favor of one that conveniently leaves out the Declaration. It also doesn’t mention where anyone uses this new definition of GCP. The Final Rule specifically states that E6 is:

Specific incorporation of ICH E6 into § 312.120 would constrain our ability to accept data from non-IND foreign clinical studies from countries that use other comparable GCP standards. Finally, ICH E6 contains a level of detail and specificity that is not appropriate or regulations. We believe that the GCP standard in § 312.120 is appropriate because it provides sufficient flexibility to accommodate differences in how countries regulate the conduct of clinical research, while still ensuring adequate and comparable human subject protection. Therefore, we do not require that sponsors or applicants follow ICH E6”

In their new definition, shared by no one else that they cite, FDA has now defined GCP a little differently: “Under CFR §312.120(a)(1)(i), Good Clinical Practice (GCP) is defined as ‘a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected.’” FDA continues to say that GCP includes review and approval (or provision of a favorable opinion) by an independent ethics committee (IEC) prior to study initiation and continuing review of an ongoing study by an IEC. This CFR part further states the freely given informed consent of the trial subject as mandatory requirement in GCP.

It should be pointed out that the definition of an IEC is also found in E6. However, FDA’s Final Rule for § 312.120 doesn’t. The result is very interesting, on the one hand FDA counterposes the Declaration with GCP. On the other hand FDA states that GCP in E6 is based on the Declaration. Then FDA rejects its own analysis and does not allow E6, with its foundations in the Declaration, to be used as the internationally recognized standard for Good Clinical Practice. I would put forward that GCP and the Declaration are complementary to one another and both necessary for sound, ethical research.

Finally, I think we need to consider if FDA and the U.S. should conduct itself as part of an international community with internationally accepted standards. And that includes the issue of placebo controls, one of the primary reasons for the FDA severing connections with the Declaration. I’m really not qualified to discuss study design and if placebo controls are necessary. However, I do think we need international regulatory and inspection standards. I’m not at all sure that the Final Rule for § 312.120 helps in that effort.




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The FDA 483: Just what is it?

March 2, 2009

The first article I wrote after leaving FDA was a clever little piece, reflecting my own unique style, on the Form FDA 483, Inspectional Observations. I wrote it in 2005 for the Immel Report which is edited by Barb Immel. Her website is on the Blogroll. I was looking it over and it still pretty much applies today except that Turbo EIR is much more commonplace. In fact, the primary obsolete fact is that I am no longer working for my former employer and my new e-mail is: carl11anderson@yahoo.com.

If you are interested in just what a 483 is, well then here you go.


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