FDA Inspections: How Long Should They Take?

May 30, 2010

how long FDA inspection

How long should an FDA Inspection take?

How long will an FDA inspection take? Three days? Three weeks? Three months? Are there any rules? The most recent FDA Warning Letter to a clinical site was released last week and it was for some rather typical violations. Failure to obtain informed consent. Enrolling subjects who met exclusion criteria. Failure to report concomitant medications. These violations were compounded by the fact the clinical investigator failed to adequately answer the Form FDA 483, Inspectional Observations. They had not specified how they were going to meet proposed corrective and preventative actions (CAPA). None of these issues really caught my attention. The Warning Letter, issued by the Center for Devices and Radiological Health, seemed entirely appropriate.

What leaped out at me, however, was the fact that the inspection had taken place over two and a half months. The inspection began September 14, 2009 and was completed on December 2nd. The Warning Letter was not that lenthy or complex. Why did it take such a long time? FDA primarily regulates clinical trials at the clinical sites. Unlike a pharmaceutical or medical device company, not all clinical sites are equipped to host an FDA inspection over a ten week period. Although some clinical sites are for-profit clinical research centers, others are busy medical clinics with limited resources to handle a ten week inspection. Is this imposing an unnecessary regulatory burden on clinical sites? Two and a half months hosting an FDA inspection can cost a Lot of time, money and resources.

How long should FDA Inspections take

What are Reasonable Hours for Inspection?

I have recently heard anecdotal evidence of one recent FDA inspection taking place over a six week period at a busy medical practice. the FDA field investigator was not at the site half of the time during the inspection while performing other duties. That can be difficult to arrange staff to assist the inspection. Another inspection lasted until 9:00 pm, a good 4 hours after the clinic’s business hours were over. Is that “at reasonable times” as specified by 21 CFR 312.68?

length of FDA inspections, how long?

Should There be Timeframes for Warning Letters?

Another item of interest is the length of time between the end of the inspection and the issuance of the Warning Letter. I worked on a temporary assignment at FDA headquarters in 2004. Then, there were strict timeframes when a Warning letter needed to be issued after the conclusion of an inspection. That evidently is no longer the case. For example, the Division of Scientific Investigations issued a Warning Letter on February 24, 2010 for a 3-day inspection that concluded on March 27, 2009. That’s almost a year. And it is hardly the only example. Is this an appropriate policy? Planning for an FDA inspection isn’t easy. knowing the approximate length might be helpful for smaller clinics.

You can read about FDA Warning Letters to clinical investigators on FDA’s Website. You can search by subject for “Clinical Investigators” for inspections assigned by the Center for Drugs and under “Investigational Device Exemptions (Clinical Investigators) for medical devices.


On the Blogroll: FDA Matters discusses The Hamburg Legacy in consideration of one year as FDA Commissioner for Dr. Margaret Hamburg.

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FDA Announces 21 Draft Proposals to Increase Transparency

May 25, 2010

FDA announced the Phase II report on their effort to increase transparency stating:

FDA Announces Transparency Report

FDA Seeks Public Comment on Transparency

On May 19, 2010, the Transparency Task Force released a report containing 21 draft proposals about expanding the disclosure of information by FDA while maintaining confidentiality for trade secrets and individually identifiable patient information. FDA is accepting public comment on the content of the proposals, as well as on which draft proposals should be given priority, on this website until July 20, 2010.

The FDA Report on the 21 Draft Proposals is available in PDF format.

The Blog will be reading the report carefully and urges you to do so as well.

UPDATE: In other news of interest FDA’s Principal Deputy Commissioner, Dr. Joshua M. Sharfstein, testified to Congress about the recall of adulterated Tylenol and other pediatric medicines. The New York Times reported that FDA is considering additional penalties including the possibility of criminal prosecution.


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German Study Finds Bias in Pharmaceutical Industry Sponsored Clinical Trials

May 23, 2010

Do clinical trials sponsored by the pharmaceutical industry show bias in research findings?

bias in clinical trials

Bias in Clinical Trials?

Public health advocates in the United States have long questioned bias and conflict of interest in industry sponsored clinical trials. Now, a recent study from Germany indicates that industry trials report out their findings with favorable findings for drugs they are sponsors of. This has certainly been the concern of American public health advocates. In this Guest Commentary Professor Gerhard Fortwengel reviews two articles regarding the German study. Gerd’s commentary certainly contributes to the discussion on pharmaceuticaal influence in publication of results of clinical trials. The articles he reviews provide a strong case for research that is independently sponsored and reviewed. The Blog certainly welcomes alternative viewpoints. Let me know what you think.

Guest Commentary

Comparison of Industry and Independent Clinical Trial Results

The results of clinical trials funded by the pharmaceutical company who is the owner of the investigational drug, are often more favorable in support of the drug under investigation compared to clinical trials with independent financial support.

bias in pharmaceutical research

Evaluation of Published Research Data

This has been confirmed by German scientists, who evaluated 57 systematic review publications with publication dates between November 2002 and December 2009. In the articles (part 1 and 2) the authors describe that published drug trials that were financed by pharmaceutical companies, or whose authors declared a financial conflict of interest, were found to yield favorable results for the drug manufacturer more frequently than independently financed trials whose authors had no such conflicts. Looking at the pure outcome figures it is also stated that the interpretation of the results was more often favorably than in independently financed trials.

The article states that evidence was found that pharmaceutical companies influenced study protocols in a way that was favorable to themselves. On the other hand the methodological quality of trials financed by pharmaceutical companies was not found to be any worse than that of trials financed in other ways. Coming back to the authors´ statement about study protocols and how they are designed to favor the drug under investigation, following ways of doing so were listed e.g. usage of lower than routine dosages in treatment arms for comparison, selection of endpoints supportive for the new drug, but not state of the art and disregarding relevant objective endpoints.

What are the consequences? Do we, as we are all somehow affected by or directly involved in drug development, want to accept this? No, never – we want to be part of a reliable business as well as we want to rely ourselves in all conscience on publications referring to new potent drugs. But what can be done?

bias pharmaceutical clinical trials

How Can We Increase Transparency in Research?

Would a higher degree of transparency help to bring some light into this and to regain credibility? What would this look like? The countries in the European Union have already implemented certain steps, such as initial regulatory approval for any type of trial and subsequently of any substantial amendment to an approved trial protocol, in addition to the worldwide implemented IRB/EC approval requirements. Of course I would expect that a regulatory approval includes the review of the scientific value of the trial and consequently “wrong” endpoints or trials with active comparators with a too small dosages should not have been approved, shouldn’t they? A (publicly) accessible clinical trial registry, including a module with trials results, mandatory to be completed by any trial sponsor (industry or academia) in a pre-defined time period after trial completion could help, particularly when the structure for the results would be clearly defined in order to avoid to focus e.g. on secondary objectives or even corollary results, instead of providing a clear result with regard to the initial study objective. At least such registries would be supportive for any agency after receiving an application for a market license to be able to check if all trials have been properly included in the package submitted and to identify missing trials with equal and negative results.

Everyone, who was ever involved in critical appraisals knows, that the reading of scientific papers requires routine and a strong background regarding the topic of the publication. So, finally this type of trial results publication channel would address more the need of the scientific community and consequently a different way must be found for the lay public.

By Prof. Dr. Gerhard Fortwengel, MPH
University of Applied Science and Arts Hannover, Germany

18 May 2010

[Schott, G; Pachl, H; Limbach, U; Gundert-Remy, U; Ludwig, W; Lieb, K.: The Financing of Drug Trials by Pharmaceutical Companies and Its Consequences: Part 1. A Qualitative, Systematic Review of the Literature on Possible Influences on the Findings, Protocols, and Quality of Drug Trials
Dtsch Arztebl Int 2010; 107(16): 279-85;

Schott, G; Pachl, H; Limbach, U; Gundert-Remy, U; Lieb, K; Ludwig, W.; The Financing of Drug Trials by Pharmaceutical Companies and Its Consequences: Part 2. A Qualitative, Systematic Review of the Literature on Possible Influences on Authorship, Access to Trial Data, and Trial Registration and Publication Dtsch Arztebl Int 2010; 107(17): 295-301]


In the United States, a leading critic of the pharmaceutical industry is Dr. Marcia Angell. Her new article is in the Boston Review is called Big Pharma, Bad Medicine.

There is more than one side in this discussion and you can read information from the pharmaceutical industry on the PhRMA homepage.

As always, The Blog welcomes Your comments.

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FDA Sends Another Warning Letter for H1N1

May 14, 2010


Tea for H1N1?

FDA has just posted a Warning Letter that was sent last July for Unapproved/Uncleared/ Unauthorized Products Related to the H1N1 virus. It is clear that problems continue from companies attempting to profit from public concern over H1Ni. It is not clear why it took FDA ten months to release the Warning Letter. What caught my eye was that this product was under the guise of traditional Chinese herbal therapy and that the instructions for use was “Flu Prevention Tea.” Many products are imported into the United States with the instructions “to make tea,” and little else. During the early 1990s I worked as a laboratory technician in the FDA San Francisco District Laboratory. We encountered many herbal products with the simple labeling “to make tea.” Some were legitimate herbal medicines and some were infested with what we casually referred to as “filth” because of insects and rodent hairs. There were also some fraudulent therapies.

H1N1 FDA Alternative Therapies

Legitimate Inquiry into Alternative Therapies

The worst case I saw was a dried mushroom known as Ganoderma lucidum that was used as an unapproved HIV/AIDS therapy, at an exorbitant price. You can still buy the stuff on the internet for $139.95, although not as a AIDS cure. There was no way you could make tea from it. Unfortunately, because of obvious scams, some people have used the opportunity to disparage all alternative therapies. There are many legitimate, licensed acupuncturists who use Chinese herbal medicines. There are legitimate organizations that advocate Homeopathy including the American Association of Homeopathic Pharmacists. And some zealots, masquerading as “quackbusters,” are targeting legitimate research to investigate alternative therapies. We need more, not less, “adequate and well controlled” research into alternative therapies conducted under the review of registered IRBs. Still, the best therapy for H1N1 is a flu shot along with soap and water to wash your hands.

Consumers have a right to access to legitimate alternative therapies. Researchers have a right to conduct IRB approved research under FDA regulations. And FDA has the responsibility to protect consumers from clearly fraudulent therapies that pop up every time we have a public health emergency like H1N1. I think this is should be a clear public health goal. There is a link on the right column to find Fraudulent H1N1 Therapies (scroll down, beneath the calendar).

On The Blogroll: There is some interesting information on the European Medicines Agency GCP Inspections website.


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The FDA 1572: What Belongs?

May 9, 2010

FDA 1572 What Belongs

What Belongs on a Form FDA 1572?

UPDATE: Final FAQ Guidance issued. See post, FDA 1572: Big Changes in FAQ…” published on June 8, 2010-

The Form FDA 1572, Statement of the Investigator, is a contract between the clinical investigator and FDA. The form is required by FDA regulations for clinical trials for drugs and biologics and is the Center for Drugs’ Division of Scientific Investigations (DSI) has paid particular attention of late. However, there have been divergent viewpoints about who should be listed as sub-investigators and other issues such as what laboratories should be included. FDA issued a draft guidance document on “Frequently Asked Questions” regarding the 1572 in July 2008. I recently gave an audio conference on the Trial Master File, or TMF, and had several inquiries afterwards regarding the 1572.

One inquiry was pretty basic. I was asked what I had meant by “accurate” and if a record needed to be accurate. I had discussed the guidance for good recordkeeping, “ALCOA.” This stand for Attribuatable, Legible, Contemporaneous, Original, & Accurate. I asked for an example and was told, “what if the investigator filled out the Form FDA 1572 with the wrong information?” You cannot submit false information to FDA. If the clinical investigator submits inaccurate information, then ask for a corrected 1572. It is as simple as that. We all know that the investigator does not like being corrected. However, in this case it is necessary. Getting necessary changes would be a lot easier if we didn’t ask for unnecessary changes. For example, you only need to ask an investigator for their CV once, at the beginning of the study. That’s it. There is no requirement for an annual updated, signed CV. None. There is no requirement for a PI to sign the informed consent form. None. So make things a little easier and keep to what IS required.

A trickier question is the criteria for including an individual in Section (Block) 6 on the 1572. Here is what the draft guidance on “Frequently Asked Questions” has to say:

FDA 1572  Clinical Trial

Who Should be Listed as Sub-Investigators On a Form FDA 1572?

The criteria for including an individual in Section #6 on the 1572 is to capture information about individuals who, as part of an investigative team, will assist the investigator and make a direct and significant contribution to the clinical data. The decision to list an individual in Section #6 depends on his/her level of responsibility (i.e., whether he/she is performing significant clinical investigation-related duties). In general, if an individual is directly involved in the performance of procedures required by the protocol and the collection of clinical data, that person should be listed on the 1572. For example, if the protocol notes that each subject needs to visit a specified internist who will perform a full physical to qualify subjects for the clinical investigation, that internist should be listed in Section #6.”

However, people I have spoken with are concerned because in a Warning Letter dated 01 October 2008, issued by the Center for Drug Evaluation and Research/Division of Scientific Investigations, it states:

“Study coordinators who administered the informed consent, determined subject eligibility and dispensed study drug were not listed on the Form FDA 1572, Statement of Investigator, for protocols (b)(4) and (b)(4). By performing these significant study activities, the study coordinators should have been listed on the Form FDA 1572s as subinvestigators.”

There are several protocols included in the Warning Letter and it is not clear which protocols are included for this citation. Later in the Warning Letter there is a citation that lists the following:

a. A blister card label for kit number 0582 was found identified as distributed to subject 747-002 instead of subject 747-004;
b. Three study medication labels for kit number 0495 was found identified as distributed to subject 747-003 instead of subject 747-002; and
c. Twelve study medication labels for kit number 0495 was found identified as distributed to subject 747-004 instead of subject 747-002.”

What belongs on 1572

Who Belongs on the 1572?

Although it is not possible to determine if this is the protocol cited for the 1572 violation, this investigational product appears to be packaged in a manner that would not require “significant clinical investigator-related duties.” It is not clear to me what activities necessitate inclusion on Block 6 of the Form FDA 1572. If, in fact, “direct and significant contributions to the clinical data” is the criteria for inclusion does that mean conducting an informed consent interview? Distributing blister cards? I am curious where the line is drawn.

This is not an insignificant issue, as researchers who are included on the Form FDA 1572 are required to submit a financial disclosure. It is also a source of different opinions between researchers and monitors. If you have a multi-center trial with 37 clinical sites, that could add up to a lot more documentation. My current inclination is to error on the side of caution. Warning Letters aren’t fun. Hopefully the final guidance on what belongs on the Form FDA 1572 will be out very soon.

You can review the draft guidance at this link (scroll down to the Federal Register notice for the PDF of the “Draft Guidance.”) Draft Guidance Documents for Clinical Trials.


In Addition: FDA released its report for PDUFA IV for Fiscal Year 2008. PDUFA is the Prescription Drug User Fee Act which is now in its fourth rendition. Read the Executive Summary

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FDA History in One Little Pill

May 4, 2010

FDA history in a little pill

The Pill that Made FDA History

An important piece of FDA history, the birth control pill, was discussed in The Science Section of the New York Times in an excellent article by Gardiner Harris. The 50th anniversary of the little pill’s approval is this month and it revolutionized more than family planning. In the words of Harris: “The pill eventually led the FDA to communicate directly with patients without going through doctors.” This was not appreciated by physicians’ groups at the time, including AMA. The little pill’s impact on FDA was overshadowed by the Thalidomide tragedy which occurred shortly after.

The pill led to FDA using panels of expert to review the safety of drug products, which is now commonplace. FDA now has numerous advisory committees for a number of therapeutic areas- and it is doing a better job of preventing conflicts of interest in their membership. It also led to epidemiological investigations that “would become the model for the future,” according to Harris. The 1960s were an important era for FDA with Thalidomide, the birth controll pill and, of course, the Kefauver-Harris Amendments that led to the modern era of clinical trials. We seldom get well-written articles that cover FDA history that can be read in a short matter of 5-10 minutes. Highly recommended reading.

The Pill That Started More Than One Revolution, by Gardiner Harris, The New York Times


Update: On 6 May FDA approved a new oral contraceptive, Natazia, a combination hormonal tablet. The FDA News Release tells the story.

Another Update: NY Times columnist Gail Collins weighs in wickedly on the topc with What Every Girl Should Know

And still another Update: Now you too can contribute to FDA history by suggesting an acronym to the Agency. I kid you not. FDA has a link where you can suggest a new acronym or abbreviation for the Agency’s use.

FDA Acronyms

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Cancer Studies: Questions… and Answers?

May 2, 2010

cancer studies questions and answers

Problems Cited for Cancer Research

Serious questions about cancer research were raised in a 25 April New York Times editorial. The editorial cites a report issued by the National Academy of Science’s Institute of Medicine (IOM) that warns about deficiencies for conducting cancer studies sponsored by the National Cancer Institute (NCI). The Times emphasized the importance of government sponsored research stating it was industry sponsored research could be more biased and that government funded cancer studies were more like to take on the rare diseases with little commercial potential. The IOM report also also stated the obvious: that government funding sometimes comes with beauracracy that hinders research. Except this time its worse. The Times states:

So it is especially worrying to hear the experts say that the system — run by the Cancer Institute at the National Institutes of Health — is so mired in cumbersome procedures that it needs to be completely overhauled.”

cancer studies answers for questions

Lively discussion on Cancer Studies

This touched off a lively discussion in the 2 May “Letters to the Editor” section of the Times. Two oncologists with the American Society of Clinical Oncology cited a shortfall in funding to NCI’s cooperative group program. Another researcher with the Massachusetts General Hospital Cancer Center states that while the cooperative group program is important, it is no longer the exclusive route to drug development. And a researcher at Case Western Reserve cited the lack of enrollment into clinical trials to be a significant barrier to research. About five years ago a reader poll in Applied Clinical Trials about 50% of the respondents cited enrollment difficulties as the primary barrier to all clinical trials- five times the number that cited regulatory burdens. Finally, a researcher argued that NCI has too strong a focus on tumors and not the immune system. He might have a point as discussed in the next paragraph. Clearly there are serious questions being asked about cancer studies.

This week wasn’t all bad news. The Dendreon Corporation received FDA approval for Provenge, a therapeutic vaccine that fights prostate cancer, and is hopefully one of the answers. Provenge is the first therapeutic vaccine (officially “autologous cellular immunotherapy”) approved by FDA to fight cancer. It uses the body’s own immune system to attack the tumor. This could spur further research and approvals of therapeutic vaccines. It also could provide more private sector funding of cancer trials.

questions and answers for cancer studies

Will Provenge's Approval Help Seattle's Biotech Industry?

Dendreon is based in Seattle, close to the home of this Blog. I certainly hope that the approval will also provide a shot in the arm for cancer studies and other clinical trials in the Pacific Northwest life sciences industry.

I have been fortunate to know some of the GxP professionals who have worked at Dendreon over the years. I know how hard they have worked and offer my congratulations for a job well done.


FDA Press Release May 3rd on safety review of commonly used prostrate cancer drugs.

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