FDA: Can This Agency Be Dangerous?

October 30, 2010

FDA Dangerous Agency

Academics Duel Over FDA & Drug Regulation

How dangerous is FDA? One of the most articulate critics of the pharmaceutical industry and FDA’s oversight of drug regulation has been Dr. Marcia Angell, the past editor of the New England Journal of Medicine and currently a Senior Lecturer in Social Medicine at Harvard University. She is also the author of the “must read” book, The Truth About the Drug Companies. She maintains that the agency has not lived up to its mission of approving safe and effective drugs. She has taken the occasion of the publication of the book Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA, by Daniel Carpenter (Princeton Studies in American Politics: Historical, International, and Comparative Perspectives), to write a scathing review in the September 30 edition of the New York Review of Books. Carpenter, a Professor of Government, is also at Harvard. Dr. Angell does not like this book and makes it very clear. And her negative review sparked a not-so-pleasant exchange between them in the October 28, 2010 edition where Angell accuses Carpenter of writing a “waspish letter” responding to her review. When Harvard academics flourish charges of being “waspish,” you know its serious.

Update: I am putting in a link for a memo by Dr. Carpenter responding to Dr. Angell’s review below.

I had been warned against tackling Dr. Carpenter’s 800 + page, rather dense history of FDA. I am leaving that to the good professor Sid Olufs, who periodically writes book reviews for GxP Perspectives (see the page at the top). However, Dr. Angell’s critique is harsh indeed. She faults Dr. Carpenter for the failure to bring out shortcomings with offices within FDA’s Center for Drug Evaluation and Research (CDER) and nine reforms that she considers important points about drug regulation in the United States and just how dangerous an agency FDA is. They are:

1. The Prescription Drug User Fee Act (PDUFA) should be repealed. I happen to agree, although I don’t think it was Dr. Carpenter’s intention to offer a polemic against the pharmaceutical industry. My experience in conducting PDUFA inspections for the agency for 10 years is that they are ineffective. We need public health inspections based on public health needs, not pharmaceutical dollars.

2. The Office of Surveillance and Epidemiology (OSE) should have more authority and independence from the Office of New Drugs. This involves Agency politics that is over my head. You can read Angell’s argument on the link below.

FDA agency dangerous

Conflicts of Interest on Advisory Committees

3. Members of CDER’s standing advisory committees should have no financial ties to drug companies (except for research support provided under carefully restricted conditions). I think that many of us are worried about the extent of drug company influence and the amount of money spent on that influence.

4. FDA should see that the post-marketing studies it requires as a condition of approval are carried out in a reasonable time period. This is a long overdue reform.

5. Approval of new drugs should be limited to three years, and during that time advertising aimed directly at the consumer should be prohibited. I’m not sure about the three years but I oppose direct-to consumer advertising.

6. FDA should review generic drugs as rapidly as brand name drugs and be adequately staffed to do so. A common sense reform.

7. In pre-marketing trials me-too drugs should be compared with an existing drug to treat the same condition, not just with a placebo. The debate over placebo controls in clinical trials is worthy of an entire book, maybe two. The Blog isn’t taking a position. Yet.

8. Dr. Angell’s eighth reform involves surrogate endpoints.
You will need to read her arguments on the link below.

9. As a condition for enrolling human subjects, all clinical trials, without exception, should be registered at inception in a public database at inception in a public database and the results shown when the research is completed. This might be easier said then done but greater transparency is a must in the future of clinical research.

FDA Agency dangerous

FDA Has a Long Ways To Go

GxP Perspective: This is a summary of Dr. Angell’s critique of FDA. I am not so sure. FDA is a very large agency and change will take time. I believe that change has been taking place incrementally and that FDA is doing a good job under difficult circumstances. While I agree with many of the points Dr. Angell raises, and highly recommend her book on the pharmaceutical industry, I think we need to look at the bigger picture. FDA is a much better agency than the one I left in January 2005. Let’s give some credit where credit is due. We’re lucky they are on the job.

The NY Review of Books Article by Dr. Angell on FDA: This Agency Can Be Dangerous

How Dangerous is FDA? An Exchange Between Daniel Carpenter and Marcia Angell

Dr. Carpenter’s Response Memo


In news from GxP Perspectives. I will be participating in the conference, Developing CAPAs in the GCP Environment on January 18-19, 2011 in Arlington, VA. (and again in January 2012)

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group


Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents. Let me know!

In the Blogosphere: The nice folks at imarc have noted Mikki O’Neal’s Guest Commentary on IRB Training. Please check out their site: imarc

FDA Issues Draft Guidance Document on Clinical Trial Adverse Events

October 25, 2010

FDA draft guidance adverse events

FDA Draft Guidance on Clinical Trial Adverse Event Reports

FDA issued a draft guidance document on adverse event reports on 28 September 2010. This opened a 90-day public comment period for FDA’s consideration on the draft guidance ending on 28 December 2010. (Comments may be made at any time but need to be made in the 90-day comment period to be included for FDA’s review as they prepare the final document.) The draft guidance, Guidance for Industry and Investigators- Safety Reporting Requirements for INDs and BA/BE Studies was issued at the same time as the final rule for re-writing 21 CFR 312.32, IND Safety Reporting, was published in the Federal Register (See previous post, FDA Clarifies Adverse Event Reports for Clinical Trials, 10 October 2010). In this final rule FDA adopted definitions from the International Conference on Harmonization, implemented new reporting requirements for bioavailability and bioequivalence (BA/BE) studies, and clarified what sponsors need to report to the FDA. One important clarification notes the following:

“The sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the drug and the adverse event”

The draft guidance document explains that FDA does not want isolate reports that may be of no use in determining the drugs safety. The document states:

“The new requirements clearly distinguish circumstances in which it is appropriate to submit individual cases and circumstances in which cases should be aggregated and compared to a control group.”

FDA adverse events

When to Report Adverse Events to FDA

The draft guidance goes on to explain the circumstances when sponsors should send safety reports to the agency. In the definitions section FDA expands on the definitions found in the final rule including for the terms “serious” and “unexpected.” The draft guidance also provides sponsors with important guidance on two important points that will undoubtedly draw a number of responses. They are:

Review of Safety Information, including the scope of possible sources of safety information, and;

Monitoring the Safety Database and Submitting IND Safety Reports. Here FDA describes a number of situations where a sponsor should report safety information to FDA. They include individual events; one or more events, and an aggregate analysis of specific events. The draft guidance also discusses reporting study endpoints and SAEs that are not study endpoints.

FDA draft guidance adverse events

How Should Clinical Trial Adverse Events be Reported to FDA?

The importance of the comment period: FDA issued the original draft rule for safety reports in 2003. There were a number of comments that suggested improvements to the draft rule. As a result, FDA significantly changed the final rule issued this September. Public comments are an integral part of the process for rule making and writing guidance documents. The input from industry, patient advocates, researchers, and GxP professionals is essential for finalizing a guidance document that will give the agency the tools it needs in determining a drug’s safety.

You can access the final rule, the draft guidance document, and information about making comments (please don’t be intimidated by the complex, lengthy title):

Draft Guidance & Final Rule

This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)

In news from GxP Perspectives. I will be participating in the conference, Developing CAPAs in the GCP Environment on January 18-19, 2011 in Arlington, VA.

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

In news from the blogosphere: Read an interview on the Biotech Blog with John Avellanet, author of the blog, Compliance Zen. John has a new book out, which I hope to review soon for the blog, Get to Market Now! Turn FDA Compliance into a Competitive Edge in the Era of Personalized Medicine.

FDA Clarifies Adverse Event Reports for Clinical Trials

October 10, 2010

FDA adverse event reporting

FDA Final Rule Clarifies
AE Reporting for
Clinical Trials

On 28 September 2010 FDA announced that it was issuing a final rule that clarifies safety reporting for adverse events during clinical trials. The final rule impacts drug and biologic regulations for clinical trials conducted under an investigational new drug (IND) application (21 CFR 312) and bioequivalence studies (21 CFR 320). The draft rule was published in 2003 and received numerous comments. These comments, combined with increased concern over drug safety, led to significant changes by FDA. The new rule defines the separation of clinical trial safety adverse event reports and post-market safety reporting. The agency is working on new regulations for post-market safety reports. FDA stated that the separation was necessary to improve the quality of safety reporting, monitor the safety of drugs and biologics, and harmonize adverse event reports internationally. There are some significant differences between the draft rule of 2003 and the final rule published on 28 September 2010 including:

Replace the defined phrase ‘‘associated with the use of the drug’’with the term ‘‘suspected adverse drug reaction (SADR),’’
• Require submission of expedited reports of ‘‘information sufficient to consider product administration
• Make it clear that safety reports of overall findings or data in the aggregate must be submitted in a narrative format,
• Permit the determination that an SADR is life-threatening to be based on the opinion of either the investigator orsponsor (as opposed to only the investigator),
• Require that the sponsor notify FDA and all participating investigators of each SADR that is both serious and unexpected, based on the opinion ofeither the investigator or sponsor (asopposed to only the sponsor),
• Require a ‘‘minimum data set’’ for each report of an SADR submitted toFDA, and
• Clarify the sources of information that sponsors must review for safety surveillance and reporting purposes.

FDA clarifies adverse events clinical trials

FDA Adopts ICH E2A Definitions

Perhaps the most significant change in the final rule is that FDA is adopting the terms and definitions in the ICH guidance document E2A that are used throughout the world. Prior to issuing the final rule FDA regulations did not specifically define the term “adverse event” although the term was referred to repeatedly in the regulations and there was a definition for “serious adverse event.” Using the ICH definitions will make it easier for clinical trial professionals to “speak the same language” when conducting research. As FDA clarifies definitions, communications between sponsors and investigators should become easier. Hopefully, researchers will now understand that it isn’t necessary to “report all SAEs immediately.” FDA is stating clearly that:

“… the revisions to the IND safetyreporting requirements will improve theoverall quality of safety reporting andthe agency’s ability to review critical safety information by ensuring that theinformation that FDA receives in an INDsafety report is relevant and useful.

Under former regulations, there may have been over-reporting of serious adverse events for which there was little reason to believe that the drug had caused the event, complicating or delaying FDA’s ability to detect a safety signal.

In this final rule, FDA clarifies definitions, provides examples of the types of evidence that suggest a causal relationship for purposes of reporting asuspected adverse reaction to the IND and participating investigators, and revises the requirements for expedited reporting of serious and unexpected suspected adverse reactions to the IND.”

The ambiguity over reporting adverse events has caused friction between many study coordinators and CRAs. Hopefully, FDA clarifying AE reporting will help researchers focus on issues of significance.

FDA Announcement of Final Rule

At the same time FDA issued a draft guidance on Safety Reporting Requirements which will be the topic of a future post. The comment period is OPEN!

Safety Reporting Requirements for INDs and BA/BE Studies

++++In news from GxP Perspectives++++

clinical trials adverse event FDA

TMF Webinar on Thursday, 14 October 2010

Special Announcement: TMF Webinar 14 October

Read the updated article on the Form FDA 1572 in:

Applied Clinical Trials “Closing Thought” on FDA 1572

ALSO: Please join me on LinkedIn at:

GxP Perspectives LinkedIn Group


TMF: Reference Model Explained

October 3, 2010

TMF Reference Model

What Documents are Necessary for a Clinical Trial?

Guest Commentary: A discussion on the trial master file (TMF) Reference Model presented to this summer’s annual meeting of the Drug Information Association (DIA). As clinical trials have evolved, regulatory authorities and GxP professionals have discussed the need for clear definitions and examples of the documents necessary for effective clinical trials. DIA began an effort to try and determine what would work in a globalized clinical trial environment. The result is the TMF Reference Model. While it is a work in progress, the TMF Reference Model has helped many clinical trial professionals determine how to record the data necessary to support a regulatory submission. This Guest Commentary by Karen Redding helps explain the concept of the TMF Reference Model.

Guest Commentary by Karen Redding

What is the TMF Reference Model?

The TMF Reference Model (TMF RM) is a single, unified interpretation of the regulations in the form of a list of TMF artifacts which would be accepted by all clinical trial stakeholders and which can be adopted or adapted by any company, institution or organization. It does not provide guidance in terms of the process by which the artifact is created or collected. It extends beyond regulatory guidance, such as ICH E6 section 8, which addresses only a sub-set of documents required in a TMF.

Who is sponsoring the reference model?

TMF Reference Model Explained

The TMF Reference Model
is a DIA Project

The initiative to create a TMF RM is supported by the Document and Records Management SIAC of the Drug Information Association (DIA). The TMF RM team consists of more than 130 representatives from 91 bio-pharmaceutical companies, contract research organizations (CROs), consultancies, technical vendors, industry groups, healthcare, academia, non-profit / NGO and regulatory agencies.

What is the structure of the reference model?

The TMF RM consists of standardized taxonomy and metadata and outlines the clear definition and organization of TMF content using consistent nomenclature. It is emphasized that this model is a reference and should not be considered mandatory, but rather as an opportunity for harmonization and alignment across the industry. The TMF RM can be adapted to an electronic or paper based TMF and by design does not endorse, nor require, any specific technology for application. The document types defined in the model are called artifacts. Version 1 .0 was released on 4th June 2010.

What are the key questions we are trying to answer in the upcoming meetings?

Collectively, the members of the TMF RM experience the same challenges, and many of these directly result in sub-groups being set up to provide a collective opinion. Current questions include:

1. How much does TMF management actually cost a company, how can we measure it, and how can we improve efficiencies?

2. What requirements need to be met to allow for a paperless environment, can we destroy scanned paper, can we retain documents in electronic form only?

3. Many studies are contracted to CROs, how much documentation needs to be maintained by the Sponsor to show oversight, and how is this oversight defined?

How do you get more information on the reference model? Is there a non-commercial website?

TMF Reference Model Explained

How To Get Involved With The TMF Reference Model?

The TMF RM group meets by teleconference every 3 weeks to discuss issues such as those above. Various sub-committees exist such as the Communications, Metrics, Paper Management and Review team, and these groups meet separately to discuss the specific aspects assigned to them. Many documents are published in the DIA Web Office. In addition, there is a LinkedIn group and a blog. You are invited to follow TMF RM activities on LinkedIn by joining the TMF Reference Model group.

The TMF blog address


Please join your industry colleagues in completing the 2012 TMF Reference Model Survey, and use results to inform your TMF best practices.


This fifteen minute survey is designed by members of the TMF Reference Model team to provide valuable insight into Trial Master File practices, both paper and electronic, to identify common problem areas, assess changes in practice and reveal opportunities for improvement. All respondents who complete the survey and provide contact information will be provided with the survey results.

Data collection closes June 1st; please join us today.


Two Important New GCP Documents: There is a new Final Rule on required elements of Informed Consent. You can read the Federal Register Announcement here that includes FDA comments in the preamble. The exact change in 21 CFR Part 50 is:

“Sec. 50.25 Elements of informed consent.

* * * * *
(c) When seeking informed consent for applicable clinical trials,
as defined in 42 U.S.C. 282(j)(1)(A), the following statement shall be
provided to each clinical trial subject in informed consent documents
and processes. This will notify the clinical trial subject that
clinical trial information has been or will be submitted for inclusion
in the clinical trial registry databank under paragraph (j) of section
402 of the Public Health Service Act. The statement is: “A description
of this clinical trial will be available on
http:[sol][sol]www.ClinicalTrials.gov, as required by U.S. Law. This
Web site will not include information that can identify you. At most,
the Web site will include a summary of the results. You can search this
Web site at any time.”

There is a Draft Guidance on Electronic Source Documentation in Clinical Investigations. The comment period is for 90 day (April 4, 2011 ?)

UPDATE: My favorite industry magazine, Applied Clinical Trials, now has a LinkedIn Group:
Applied Clinical Trials LinkedIn

++++ In News From GxP Perspectives++++

TMF Compliance Documents from FDA

GxP Perspectives on the TMF

ALSO: Read the updated article on the Form FDA 1572 in:

Applied Clinical Trials “Closing Thought” on FDA 1572

ALSO: Please join me on LinkedIn at:

GxP Perspectives LinkedIn Group


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