FDA Warning Letter on Eligibility and Informed Consent

July 30, 2010

FDA informed consent and study eligibility

FDA Warns on Informed Consent and Study Eligibility

Once again, FDA has issued a Warning Letter to a clinical investigator on the informed consent process and enrolling subjects who did not meet study eligibility criteria. The Warning Letter also cited serious record-keeping violations. This Warning Letter was issued by the Center for Biologics Evaluation and Research, which handles approximately 10% of the FDA’s Bioresearch Monitoring inspections. FDA Warning Letters in the past few years have frequently cited study eligibility and informed consent issues. They are two of the most critical areas of FDA concern. In this case 7 of 17 subjects were enrolled who did not meet inclusion/exclusion criteria. That’s pretty significant.

Seven subjects did not sign an informed consent form required by a protocol amendment and two others signed a consent form meant for HIV positive subjects. These subjects were not HIV positive. These are not minor dating errors or forgetting to get initials on page 7 of 12. They are major informed consent violations. The investigator also could not produce electronic records that were important source documents because of computer problems. Another reason to take a look at the previous Guest Commentary on Part 11 (scroll down). This is another good reason for sponsors and clinical site staff to review study eligibility and informed consent requirements. They are among the first places FDA will look.

Read The Warning Letter

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This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)


Part 11: How Will FDA Enforce?

July 25, 2010

Part 11 FDA enforce

How Will FDA
Enforce Part 11?

FDA’s announcement that it would begin inspections to enforce 21 CFR Part 11 has set of speculation on how FDA will enforce Part 11 and what they will be looking for. I’ve asked two experts, Len Grunbaum and Emma Barsky for their thoughts. They have written a Guest Commentary for the blog, one I am sure will be used as a resource by many of you concerned with Part 11 compliance. I first met Len at the last FDA training course I took, Advanced GLPs, where he was an instructor on validation. I learned a lot from him and think that he and Emma have a lot to share. Of course I welcome your comments and certainly would want to have additional Guest Commentaries on the subject.

Guest Commentary-

The FDA announced on July 8, 2010 that it will be “… conducting a series of inspections in an effort to evaluate industry’s compliance and understanding of Part 11 in light of the enforcement discretion described in the August 2003 ‘Part 11, Electronic Records; Electronic Signatures — Scope and Application’ guidance….”

So … 13 years after promulgating the regulation and seven years after moderating their enforcement model – by exercising enforcement discretion regarding selected aspects of the regulation – the agency is still not comfortable about something. What can it be? While we cannot speak on the agency’s behalf, the words “in light of the enforcement discretion” imply to us that the agency is looking to 1) understand the disparate risk-based approaches taken by companies with respect to validation, audit trails, legacy systems, copies of records and record retention, and 2) determine how effective these approaches have been in establishing and maintaining data integrity (i.e., data completeness, accuracy and validity). Perhaps FDA will revise the regulation and/or issue new guidance that will reflect its ideas of what it perceives as the “best of breed” in terms of activities that most effectively and efficiently result in compliance with 21 CFR part 11. Who knows?

part 11 enforce FDA

FDA Concern Regarding Data Integrity

We choose to focus our thoughts regarding this FDA’s initiative on data integrity because it is one of the main points that the FDA focuses on during its inspections. And it is because anything that calls data integrity into question will result in regulatory observations which, to date, have mainly been based on the predicate regulations that were put in place to promote data integrity. Therefore, enforcement discretion notwithstanding, we feel that companies will have to demonstrate the following basic quality measures to the agency:

1) All computerized systems that support regulated activities can be relied upon to operate as intended and identify all instances of incomplete, inaccurate and/or invalid data;

2) All regulated activities (e.g., changes to clinical data) can be reconstructed; and, 3) all regulated records (e.g., study data, manufacturing data) are available from the start of the respective process to the date of inspection and can be retrieved in a timely fashion. The way to do it would be to have complete, easy to follow and easy to explain documentation in support of the above-listed items; anything less may give the agency the perception that data integrity issues exist even if such may not be the case.

Listed below are some, but certainly not all, documentation pitfalls to avoid in this context:

Lack of validation documentation that focuses on systems risks (e.g., nature and complexity of interfaces, number of bug fixes) in establishing the testing strategy (e.g., nature and scope of regression testing)

• Lack of challenges to the computerized system in the area of identifying incomplete, inaccurate and/or invalid data

• In a complex database system, lack of details regarding what tables, records, etc., constitute the audit trail

• Lack of policies, and/or documented confirmation of compliance to processes regarding ensuring the retention, continued availability and easy retrieval of regulated records/data

• Lack of a complete and/or accurate record of what changes were implemented to computerized systems that support regulated activities and how they were tested and documented

• Lack of documentation regarding training of personnel who were involved with system development, validation, deployment and maintenance

• Lack of documentation regarding how compliance to 21 CFR part 11 is actually achieved (e.g., confirming required functionality through testing, confirming compliance to procedures, such as logical security, backup and recovery, through the internal audit program).

The bottom line is that documentation must stand on its own. Given that FDA may look at processes and records from several years ago and that staff who implemented computerized applications may no longer be around, it becomes imperative that you do what you must to ensure that all of your documentation for computerized applications is such that it does not raise data integrity-related questions that cannot be addressed in a timely fashion.

Emma Barsky
Len Grunbaum
Partners
The Practical Solutions Group, LLC
Practical Solutions Website

How FDA will enforce Part 11 will unfold over the next year or two. How regulated industry should prepare for upcoming inspections, according to Len & Emma, is to document your validation efforts. I think it is good advice.

Here is the original FDA announcement stating it would enforce Part 11: FDA Part 11 Announcement

Save The Date: On 4-5 November 2010 the Pacific Regional Chapter of the Society for Quality Assurance (PRCSQA) and the Organization of Regulatory and Clinical Associates (ORCA), a Pacific Northwest based organization, will co-sponsor a Fall Training on regulatory compliance topics in Seattle, WA.

The PRCSQA LinkedIn Group will update the agenda for the training. PRCSQA Fall Training workshops have traditionally been “at cost” and are an affordable training opportunity. The sessions will cover both GCPs and GLPs with speakers lined up on vendor management, quality systems, and GLP updates.

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UPDATE: My favorite industry magazine, Applied Clinical Trials, now has a LinkedIn Group:
Applied Clinical Trials LinkedIn
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New on the Blogroll: I’m not the only GxP type with a blog. Here is a well-written blog by Jackie Mardell-
Two Decades and Counting

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FOIA: Accessing Government Information

July 24, 2010

FOIA government information

How Is Government Information Made Available?

The Freedom of Information Act (FOIA) was passed to make government more transparent and information more accessible to the public. It is easier said than done. I worked as a backup FOIA Technician briefly at the FDA San Francisco District and you can’t imagine the number of requests that come in and the amount of work for an FOI Tech to redact proprietary information. It is a big job without a lot of resources committed to it. FDA anticipates request for certain documents and places them into their electronic reading room. You can access Warning Letters directly from FDA’s Home Page (scroll down on the right under “Recalls and Alerts”). The problem is they don’t anticipate many documents and, as the Government’s Attic people let us know, if it isn’t requested it isn’t necessarily produced. FDA has tried to improve that situation with the Transparency Task Force. Unfortunately it has had some mixed results. Here are two sites from FDA to look at. There is also the entertaining and informative FOIA presentation by Government’s Attic. It is information that we should all take a look at. FDA just might be one of the more accessible organizations although it still isn’t easy to access much of FDA’s information. Knowing where to look is certainly not easy.

Finally, the Washington Post has just completed a series on government secrecy, called Top Secret America,on security issues that doesn’t paint a pretty picture. Accessing government information is not becoming easier despite the FOIA.

FDA FOIA Page

FDA Transparency Task Force

Government’s Attic

Update: POGO on SEC

New on the Blogroll: I’m not the only GxP type with a blog. Here is a well-written blog by Jackie Mardell-
Two Decades and Counting

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AIDS 2010 Vienna- Protest on Funding & Hope for Prevention

July 19, 2010

AIDS Vienna 2010 protest funding

Vienna 2010 AIDS Conference Opens to Hope & Protest

The 2010 International AIDS Conference in Vienna started off with protests about the lack of funding and indifference from governmental leaders. According to a report by the Associated Press, Julio Montaner, the President of the International AIDS Society and Chair of the AIDS 2010 Conference, said that some governments with high HIV infection rates were, “irresponsible to the point of criminal negligence.” Protestors from ACT UP Paris disrupted a pre-conference meeting and a number of AIDS organizations decried the lack of funds to treat people living with HIV/AIDS and for prevention programs. There was also hope and progress reported with news of the CAPRISA Study in South Africa. A press release from the National Institute of Allergy & Infectious Diseases states:

For years, antiretroviral medicines have been effectively used to treat HIV infection. Through the successful conduct of the CAPRISA 004 study, we now have proof that an antiretroviral drug, in this case tenofovir, can be formulated into a vaginal gel that can protect women against HIV infection. Given that women make up the majority of new HIV infections throughout the world this finding is an important step toward empowering an at-risk population with a safe and effective HIV prevention tool.

Research into prevention is a positive step forward. And the conference gives the Bills of the world (Clinton and Gates) the opportunity to move AIDS research and funding forward. The HIV/AIDS protests from activists and concerns about continued funding have put the HIV/AIDS pandemic back in the headlines. You can follow bloggers at the Vienna 2010 AIDS Conference here:

AIDS 2010

A YouTube video of the AIDS protests is here: HIV/AIDS Protest and,

The NIAID CAPRISA Press Release

Day Two Update: Grim news was reported about injection drug users (IDUs) to the conference. AFP reports the following:

“Only five percent of all IDUs have access to a programme where they can swap used syringes for sterile ones, according to a study led by Louisa Degenhardt of the National Drug and Alcohol Research Centre at the University of New South Wales, Australia.

Only eight percent have safer, legal substitutes such as methadone to opiate drugs like heroin.

And only four percent of IDUs with HIV receive antiretroviral drugs, which can repress blood levels of the virus to such low levels that the risk of contaminating others can be slashed by more than 90 percent.

Another reason to stress prevention. Read the AFP Report

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Note of Blogger’s privilege: I am currently working in Washington, DC in absolutely Awful Weather. Trust me, it isn’t always easy being a freelance blogger. I can’t wait to return to the grey, cool weather in the Pacific Northwest. However, there is a Fringe Theater Festival that I hope to check out this weekend. I will spare you the details.


Part 11: It’s Back

July 14, 2010

Part 11 FDA

FDA To Resume Enforcement of Part 11

FDA has announced that “The Agency (FDA) will be conducting a series of inspections in an effort to evaluate industry’s compliance and understanding of Part 11 in light of the enforcement discretion described in the August 2003 ‘Part 11, Electronic Records; Electronic Signatures — Scope and Application’ guidance (Guidance).” This is a big deal. It has been seven years that FDA has debated Part 11 and began using “Enforcement Discretion.” The Agency announced that: “The Agency expects to begin conducting the Part 11 focused inspections soon.” Part 11, Electronic Records; Electronic Signatures has been one of the most confusing and controversial regulations FDA has ever written. I am now trying to find a Part 11 specialist to let us know the meaning of it all. Read what FDA has to say:

FDA Part 11 Announcement

UPDATE: Read the 25 July Guest Commentary on Part 11 by Len Grunbaum & Emma Barsky

The early report: The best report so far: Angie Drakulich goes into further detail on the changes including an interview with FDA in her report in the blog, PharmTech Talk

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The Blog has just been put on the expanded Top 50 Health Blogs list, which I truly appreciate. However, they constantly change their links to keep it current. Currently I am not there although there are other interesting posts. I now have two “Top Fift” links on the Blogroll.

50 Top Health Blogs


Avandia, FDA & Clinical Trials: Update- Final Wrap Up of Meeting – Diabetics: What To Do Next?

July 11, 2010

clinical trials Avandia FDA

FDA to Discuss Questions About Avandia- Update: Final Wrap-Up

Diabetics ask: What to do next? (see suggestions below)

Update 20 August 2010: The New York Times reported that GSK’s informational letter to researchers is questioned by FDA. As reported by Gardiner Harris:

NY Times Article on GSK

UPDATES: Avandia Advisory Committee, Day One and First Vote Day Two- End of Day Two: Advisory Committee votes 20-12 to keep Avandia on market

The FDA advisory committee meeting on the type 2 diabetes drug, Avandia, got off to a high profile start with Dr. Margaret Hamburg, FDA Commissioner, taking the unusual step of addressing a meeting of an advisory committee. One of the reasons is the deep divisions that exist among FDA staff. As the links to slides (below) indicate, some FDA scientists, including Dr. Thomas Marciniak and Dr. David Graham, are opposed to the drug due to safety concerns. Other FDAers don’t feel that Avandia is a risk for patients. GlaxoSmithKline remains adamant that their drug is safe and effective for treating type 2 diabetes.

Type 2 Diabetics are asking “what to do next.” On the Blogroll are several blogs with a focus on Diabetes. I have put them there as someone who is living with type 1 diabetes. Please look at each as they all have something to offer. I am recommending that diabetics and their loved ones think this through carefully. Is their physician current on treatments for diabetes? Do they have Nurse Practitioners, Diabetes Educators, and Registered Dietitians on staff? If not, you may look for a medical practice that is “full service” for the treatment of diabetes. I did that a year ago and it really made a difference in my life. Please let me know if you have additional comments, resources, or suggestions. I really want to know your comments! I am highlighting the link to:

Endocrine Today. I have found that they have the best direct suggestions to diabetics. Please let me know if there are other resources you know of in the comments section.

Here are five news articles in reverse chronological order that detail the Avandia saga: The first vote on Avandia on Day Two found that the drug increased risks for heart problems. Read Business Week on the vote to keep Avandia on market- Read the Washington Post Blog from Day two and MedPage blog from Day One:

L.A. Times: Aftermath- Diabetics Urged to Continue Avandia

NY Times: Final Wrap Up

Business Week: Advisory Committee Final Vote

Washington Post: First Vote Day Two

Avandia Day One: MedPage Today

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The FDA Advisory Committee meeting on Avandia on July 13-14 raises a number of questions about drug safety, the design of clinical trials, and FDA oversight. Three prominent critics of the popular type 2 diabetes drug Avandia, including two FDA scientific reviewers, are making presentations that will dispute the drug’s safety and whether it should keep FDA approval. However, there are a number of other presentations, including from FDA, that state the data are inconclusive or that the data from clinical trials show the drug is safe. The issue has been with us since 2007 and is complex in many ways. FDA has released the pre-meeting slides of each presentation to the upcoming advisory committee. One of the clearest reviews of the Avandia issue comes not from the press or the blogs but from the overview that will be presented by Dr. Mary H. Parks of FDA.

Avandia Pre-Meeting Slides- Overview

The Avandia critics are Dr. Steven Nissen, Chair of Cardiovascular Medicine at the Cleveland Clinic and Dr. Thomas Marciniak and Dr. David Graham, both of FDA. Dr. Nissen originally brought up safety concerns regarding Avandia in 2007 in an article he co-authored with Kathy Wolski, MPH, in the New England Journal of Medicine. Dr. Marciniak found a number of data integrity errors in his review of a post-market study ordered by the European Medicines Agency called RECORD. The RECORD study was an open-label phase IV clinical trial. Dr. Graham is an FDA scientist who testified to the U.S. Congress in 2004 that FDA was not effective in reviewing clinical trials for drugs safety.

There is strong interest in Dr. Marciniak’s presentation which calls into doubt the conduct of the RECORD clinical trial.

Dr. Marciniak’s Pre-Meeting Slides for Advisory Committee Meeting

FDA clinical trials Avandia

FDA States Difficulties in Conducting Sponsor/CRO/ Monitor Inspections

There is also a very interesting presentation to be given by Dr. Susan Leibenhaut, Medical Officer/ Division of Scientific Investigations/Office of Compliance/CDER/FDA (DSI). She will present the results of FDA inspections of the RECORD study at the sponsor, GlaxoSmithKline (GSK), the contract research organization (CRO) Quintiles and three clinical sites. The slides detail the findings listed on the Form FDA 483s issued to GSK and Quintiles. Dr. Leibenhaut slides state that there were no systemic findings but three slides list the challenges that FDA faced when conducting sponsor/CRO/ monitor inspections, specifically of Avandia. It is the first time that I am aware of that FDA has conducted a sponsor, a CRO, and a clinical site inspection for a phase IV, post-marketing study (someone please correct me if I am wrong).

FDA Inspections of RECORD Trial – Pre-Meeting Slides for Advisory Committee Meeting

GSK is making a strong defense of Avandia:

GSK Pre-Meeting Slides for Advisory Committee Meeting

I receive a weekly digest of news from FDA each Sunday by email. “What’s New on the FDA Drugs Site” didn’t mention the Advisory Committee meeting and access to the slides is not that easy to find (transparency?). Here is a link to each presentation:

Review Each of the Pre-Meeting Presentations

The issue of Phase IV clinical trials that is raised by the RECORD study is discussed in the Nature Blog:

Nature Blog: IOM Weighs In on Ethics of Post-Market Studies

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Problems With FDA: Process for Complaints

July 8, 2010

FDA complaint process

How Do You File a Complaint About FDA?

Lately I have encountered colleagues and clients who have had problems with an FDA inspection. One result is that they do not know the process to file a complaint or they fear retribution if they do complain about an FDA inspection. I discussed this briefly in a previous post on how long an FDA inspection should take. But it is more than the length of the inspections. It is that some FDA field investigators are not prepared for conducting an inspection in a clinical trial’s therapeutic area and that a few field investigators (a very small minority) use abusive inspection tactics. Fortunately FDA has a process for fielding complaints. Here is what they say, in FDA’s inimitable manner:

“If you believe an FDA employee is not following FDA’s Good Guidance Practice regulations (21 CFR 10.115) or the Office of Management and Budget’s Bulletin No. 07-02(M-07-07) Final Bulletin for Agency Good Guidance Practices (January 18, 2007), you should contact the employee’s supervisor in the issuing office or Center. If the issue is not resolved, contact the next highest supervisor or the Center’s Ombudsman. If the issue is still not resolved, contact the FDA’s Office of the Ombudsman at:

FDA Office of the Ombudsman
5600 Fishers Lane, Rm. 13B-07
Rockville, MD 20857
Phone: 301-827-3390
Fax: 301-480-8039
Email: Ombuds@oc.fda.gov

We have redesigned the FDA Web site. As a result, some Web links (URLs) embedded within guidance documents are no longer valid. If you find a link that does not work, please try searching for the document using the document title. For more assistance, go to Contact FDA.”

I would like to note that you can use the Office of the Ombudsman confidentially if you choose.

UPDATE: I have had two very good comments on this topic. You can read both, with my responses on the comments page. I welcome your comments as well. One comment is from a European colleague, Eldin Rammel, and the other is from former FDA National Expert Bob Coleman, who certainly has more experience on this than I do. I thought it should come up from the comments page. Here is Bob’s advice:

Carl, I am painfully aware that there are some FDA personnel that often overstep their authority while conducting investigations/inspections. While I was with the FDA, I often would receive information to that effect from various companies, many of the complaints for the most outrageous allegations. My response to them was that they needed to arrange for a meeting (face-to-face) with the Director of Investigations (if it was a foreign firm) or the District Director for domestic facilities to discuss the details of what happened for resolution. Unfortunately, many do not choose to do so (perhaps out of a sense of retribution – which if that ever occured would be intolerable). I have advised those impacted that unless they take their complaint directly to FDA, then nothing can or will be done.

Bob

On a different note I am going to discontinue the “Facebook Fans” site because of privacy concerns. I have started a LinkedIn Group which I hope you will join. LinkedIn is a more secure site than Facebook currently is.

GxP Perspectives LinkedIn Group

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