A “Drug Facts” Label on DTC Ads?

February 26, 2009

Should we have a simplified “Drug Facts” label used for direct to consumer (DTC) ads by pharmaceutical companies? Whenever I purchase any packaged food I always glance at the food nutrition label so I can know a little of what I am getting. It sometimes impacts my decision to buy, particularly when looking at the yuppie sausages that I have taken a fancy to. However, when FDA introduced the labels in the mid-90s they were a subject of controversy and, in the minds of some, a “burden” to industry. Now they are part of our lives and don’t seem to have caused the food industry very much harm.

Drug Facts DTC labels

Should there be drug labels for consumers?

Well, researchers at Dartmouth have come up with a suggested Prescription Drug Facts label for direct to consumer (DTC) pharmaceutical ads. The plan is spelled out in a NY Times article by Natasha Singer. There is a link below Personally, I think it is far more helpful in making a decision than floating multi-colored cartoon butterflies. The graphic was easier for me to read in the print edition if you have it available. We’ll see how FDA reacts to it all when the Dartmouth researchers present the label system to a meeting of the advisory committee on risk communication tomorrow.

Read the NY Times article:


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Interesting comments on FDA AE Draft Guidance

February 25, 2009

Here are some interesting comments on the FDA Draft Guidance “Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs – Improving Human Subject Protection” by my friend Erica Heath, President of IRC-IRB. She points out that IRBs need unexpected problems reported as well as AEs. She notes that “all AEs are problems but not all problems are AEs.” Recommended reading in all your spare time:


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FDA Warning Letter: A Weighty Matter

February 22, 2009

The most common citation on FDA Warning Letters to clinical investigators at clinical trial locations is failure to follow the investigational plan or protocol. In this January 2009 Warning Letter this is the first citation, albeit with a unique twist. The researchers based the patients’ weight based on their drivers licenses. They didn’t weigh the research subjects before calculating the investigational drug dose, which was based on the person’s weight.

Clinical trials

Patient Safety Comes First

When people are seriously ill they frequently lose weight. The weights of the patients were sometimes much lower than the weight on their driver’s license. Simply amazing. This brings up the question of qualified staff for clinical trials, a subject I’ve addressed before. See the article on Supervisory Responsibilities of Investigators on the right. And read for yourself about the drivers licenses (page 2: “ii With respect to Subject –”

No Comment From FDA on Report Concerning Medical Device Safety

February 21, 2009

I started working at FDA on January 18, 1988 answering phones in the Consumer Affairs (now Public Affairs) Office at the San Francisco District Office. Each day I would get an earful on everything from aluminum frying pans to the latest diet craze. FDA is used to people complaining about their activities. They are very good at responding, even if they have little new to say.

However, this week the Project on Government Oversight (POGO), a well known government watchdog organization, issued a report entitled, “The FDA’s Deadly Gamble with the Safety of Medical Devices” (18 February 2009). The report details the concerns of FDA scientists, professional organizations, and consumer advocates about FDA’s decision to stop requiring important medical device safety studies to be conducted under the Good Laboratory Practice (GLP) regulations (21 CFR Part 58). So far there has been no response on the FDA website.

The GLP regulations do not cover practices at most laboratories. For example, if you go to the hospital to have your cholesterol checked this would not be part of the GLP oversight. The GLPs are for safety studies that take place on drugs, biologics, and medical devices before clinical trials take place in human subjects. They are a critical part of the process that FDA uses in evaluating new health products.

One possible reason that response to the POGO report has been delayed is that it is very well researched with clear documentation of the problems. The POGO report is listed on the Blogroll on the right. Part of the documentation is “Appendix A,” a memorandum from scientists in the Division of Bioresearch Monitoring in the Office of Compliance in FDA’s Center for Devices and Radiological Health. These public health professionals make a strong case for compliance with the GLP regulations. Although there is the necessary technical writing, it is a rare glimpse into how FDA regulations are enforced, the steps FDA scientists are taking to protect public health, and is worth reading. The Blog reprints the memorandum, Appendix A, in whole in Interesting Articles on the right, “POGO Report…”

You can read additional posts on FDA Commentaries here:



FDA Hit With Yet Another Negative Report

February 20, 2009

The non-profit Project on Government Oversight (POGO) Issued a devastating report today on the failure of FDA’s Center for Devices and Radiological Health to enforce the Good Laboratory Practice (GLP) regulations. You can find the report on the Blogroll to the right. You can also read the Reuters article on the controversy. But let’s look briefly what is at stake. And you can read my take on it all right below.

I used to conduct GLP inspections. In fact, the last FDA Warning Letter to a non-clinical laboratory conducting medical device studies was issued in July 2004 as a result of my last GLP inspection. What are the GLPs and why are they so important?

The GLP regulations came into being in 1979 as a result of a series of scandals involving fraudulent data submitted to the Agency in the 1970s. As a result, regulations required non-clinical laboratories to conduct certain activities to ensure data integrity. And they required inspections to make certain the regulations were followed. Besides such obvious things such as the calibration of equipment, the GLPs offered three important elements that changed the way safety studies are conducted.

First, the regulations required a “single point of control,” i.e, a study director who had responsibilities that exceed those of an academic principal investigator. The study director is required to follow the protocol and make sure that a final report is issued according to FDA criteria.

Second, GLPs require that the data are reviewed by a “quality assurance unit” or QAU. The QAU needs to document what study activities are reviewed. Most do an excellent job and belong to professional organizations like the Society of Quality Assurance (SQA), an organization that I belong to as well.

Third the GLPs require the retention of archives so the study can be verified. There’s a lot more but these three things make the GLPs necessary for protecting the public health. So when a CDRH representative told the May 2007 annual meeting of SQA that the GLPs were no longer necessary, the place was stunned into silence. Something was very wrong.

To their credit, FDA professionals strongly objected to the policy. They did what public officials should do: Speak Up. Now it appears someone is listening. What remains to be seen is what will happen. Your guess is as good as mine.

NY Times Reports on Duke Study Regarding International Research

February 19, 2009

19 February 2009 Page B7: The New York Times misses the point on international research. Times reporter Natasha Singer uses a study published in the New England Journal of Medicine by Duke researchers led by Dr. Kevin A. Schulman, a professor of medicine at the Fuqua School of Business at Duke, to raise question regarding the validity of research conducted outside the United States. (See Blogroll on right for link to article.)

My own experience, unlike Ms. Singer or Dr. Schulman, is to actually go to clinical sites and conduct GCP audits of the research. Things look differently when you are at the research sites. I have audited studies in Beirut, Taipei, and St. Petersburg (Russia, not Florida) and found them to be conducted in an exemplary fashion. On the other hand, I have seen horrible research in Sacramento, Ft. Worth, and St. Petersburg (Florida, not Russia).

Let’s look at a few of the problems with the Duke study. First, they assume that there is some form of inherent difference between Americans and everyone else. This conveniently ignores the point that Americans are composed of everyone else. I once audited a study by an American researcher in Los Angeles. The study had difficulties with the number of subjects who were lost to follow-up. Why? Immigration authorities had deported them to Mexico and Central America.

Ms. Singer “balances” her article by citing a study by Tufts University that sees things a little differently. However, these academic studies look at numbers and don’t really give us a qualitative analysis. What about the quality of research? In many countries the study coordinators are first or second year residents with the letters “MD” after their names. By contrast, in the United States many study coordinators are unlicensed medical assistants who perform protocol-required activities including screening for eligibility and eliciting adverse events. You tell me who is more qualified. FDA is so concerned about unqualified study staff that they published the draft guidance document, “Supervisory Responsibilities of Investigators,” which you can find listed on the Blogroll on the right.

Clinical trials are a globalized industry. International trials are a reality and a good reality at that. What we need are clear international standards to govern the trials. And we need international cooperation in monitoring and auditing the trials. The obvious place to start is with the International Conference on Harmonization (ICH) and the Declaration of Helsinki. These are standards recognized by just about everybody except, at times, the FDA.

The recent Final Rule changing 21 CFR 312.120 is not helpful in these harmonization efforts. It severs FDA’s relationship with the Declaration of Helsinki in favor of “Good Clinical Practice.” This ignores the fact that in the introduction to ICH E6, the combined GCP guidance document published in the Federal Register (1996), specifically describes Good Clinical Practice in part:

“recording and reporting trials that involve the Compliance with this standard (GCP) 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.”

Ms. Singer and the Duke University researchers would be more helpful if they told us the quality of international research and the status of international research standards. Merely lamenting the lack of U.S. based trials is not helpful.


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DSI Sends Warning Letter to Florida Clinical Investigator

February 18, 2009

The Center for Drug Evaluation & Research / Division of Scientific Investigations sent a Warning Letter to a Kissimmee Florida Clinical Investigator dated 2 February 2009. It is currently posted on the FDA website and there is a link to your right. This Warning Letter looks well-deserved. The FDA Investigator spent an entire month there and looked at three different studies. This suggests that it was a directed inspection and may have been assigned to investigate a complaint.

It starts out with the failure to personally conduct or supervise the study. The study coordinator, who was not delegated the responsibility, determined study eligibility and enrolled subjects who were not eligible. This will get you into trouble every time (Scroll down to see article on Supervisory Responsibilities of Investigators a couple of posts ago).

Next there is the failure to obtain informed consent, specifically to document informed consent in relation to study related procedures.

Third is the failure to follow the investigational plan, the protocol, by violating inclusion/exclusion criteria and failing to perform basic procedures including taking the subject’s blood pressure.

Fourth the investigator failed to maintain adequate and accurate case histories. This is followed by drug accountability violations and the failure to report an SAE as required to the IRB.

All of these violations are to be expected when the investigator fails to take charge and supervise the study. It’s no wonder that FDA paid the good doctor a visit. And it seems that DSI is determined to write Warning Letters when confronted with clear and significant violations of the regulations (see article on 2008 Warning Letters on the right).

Notes to File for Clinical Trials

February 18, 2009

note to file clinical trial

Think before you write

Notes to file for clinical trials are a somewhat tricky issue. How do you maintain “adequate and accurate” subject source documents and do notes to file help? They seem to be ubiquitous these days and I am not sure it is a good thing. Here are some rules that I tend to follow for a note to file at the clinical site:

1. The source documents at the site are the responsibility of the clinical investigator (PI) and her/his staff. A clinical research associate (CRA) who is monitoring the site should not write a note to file and then instruct the PI or study coordinator to sign it. The note to file is written according to the policies of the SITE, not of the sponsor or CRO. The person signing the note to file should be the person Writing the note to file.

2. Notes to file work best when they document what you did Right, not what you did wrong. If you are attempting to document a corrective action, then document the training or measures taken. Is it necessary to duplicate that documentation in a note to file?

3. All too often a note to file is generated because someone somewhere wants to “close out” an audit or monitor visit finding. That documentation belongs to the sponsor or CRO, not the site. There is no clinical trial regulation requiring a clinical site to maintain the sponsor’s notes to file or other sponsor-specific documents.

4; Don’t write a note to file in haste. Remember that it becomes part of the official documentation of the clinical trial. If you or someone else write a note to file that says something inappropriate, it is maintained for posterity for the regulatory required length of time.

Read other posts on Good Clinical Practice:


Read the article on Notes to File from Applied Clinical Trials:


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What’s up at FDA?

February 16, 2009

This blog will attempt to discuss some of the changes that are taking place at FDA and (hopefully) helpful interpretations of regulations and guidance documents. Future posts will include an analysis of Bioresearch Monitoring Warning Letters. For example, have people been noticing the large increase in Warning Letters issued by CDER/Division of Scientific Investigations in the past two years or so? By my count DSI went from no Warning Letters issued in fiscal years 2005 and 06 to 12 or so issued in FY-2008. That’s quite an increase and it has certainly caught my attention. How about you?

In addition, I am quite curious who will be appointed the next FDA Commissioner. The lack of leadership at FDA has been hurting us all.

Finally, I wanted to share the results of a continuing conversation that I have had with colleagues and the GCP Questions at FDA regarding the preservation of e-mails for clinical trials. Here is an edited down version of the discussion:

E6 8.3.11, intends that e-mails documenting any “agreements or significant discussions…” about the study be preserved. Suggestions of keeping a protocol-specific e-mail folder and/or burning a CD at the end of the study, converting e-mails into a PDF format, or adopting a procedure to make certified copies of the e-mails, are all acceptable methods to achieve this. (FDA does not have any regulatory requirements as to the type of CD or DVD that might be used to preserve information (presumably to meet the regulatory requirements concerning clinical data/records). A company just needs to make certain that whatever media it uses does so in a manner that preserves the integrity of the original data/information.)

Please let me know what you think about it all.

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