FDA Guidance on Risk-Based Monitoring, Part II

September 17, 2011

FDA risk based monitoring

New FDA Draft Guidance Document

FDA’s new draft Guidance for Industry: Oversight of Clinical Investigations — A
Risk-Based Approach to Monitoring (August 2011) is the subject of a great deal of discussion among clinical trial professionals. On the GCP LinkedIn group some have written about their concerns that “centralized monitoring” would severely limit a sponsor’s involvement with clinical sites. Others have pointed out that the emphasis on developing a monitoring plan should ensure that appropriate resources are tageted to where they are needed.

Two weeks ago GxP Perspectives published a Guest Commentary by Lorraine Ellis on the new draft guidance. This Guest Commentary by Judith Lynn, continues the discussion about the new draft guidance. She looks at FDA Warning Letters in developing her review and analysis.

Guest Commentary: A Risk-Based Approach To Monitoring

I reviewed the Recent Draft Guidance From FDA- A Risk-Based Approach To Monitoring with several information points in mind:

• Warning letters from FDA, including the JNJ /ICON letter of 8/10/09
• My own experiences reviewing Clinical Study Reports, conducting TMF review and mock audits
• FDA Compliance Program Guidance Manual 7348.811, Clinical Investigators

I try to view the instruction as meant to be helpful rather than another obstacle to overcome. I found that much of the draft guidance centers on managing your study, having a sampling plan, and ensuring quality. FDA mentions that both good protocol and CRF design is critically important, as well as having a monitoring plan that takes into account the specific study, and sponsors prior experience with the investigational product.

Onsite monitoring:

FDA risk based monitoring guidance

Seriously Ill or Vulnerable Populations

I am not convinced that onsite monitoring will go away. The sponsor obligation is to ensure the protection of human subjects, that sites conduct trials appropriately, and the data is auditable and accurate. Note the point in the draft guidance under section IV/ C, Factors to consider when developing a monitoring plan: that “a population that is seriously ill and/or vulnerable may require more intensive on-site monitoring to be sure appropriate protection is being provided”. This point speaks volumes as to the value FDA places in onsite monitoring.

Early phase monitoring:

The guidance states “For a product that has either a significant safety concern or for which there is no prior experience in humans, may require more intensive monitoring to ensure appropriate investigator oversight.” It is interesting that FDA specifically encourages sponsors to be onsite in earlier phase studies, when the Agency does not typically send their own investigators- remember, they investigate either for cause or pre-approval.

In my experience with both bioavailability and first in man studies, the value of being on-site to observe unexpected safety and protocol issues, and make immediate decisions regarding study conduct, has been critical. Examples:

• safety issues a healthy subject (recent army recruit) collapsed at a blood draw (was excluded); a site had urine/blood test machine not work and had to test offsite, affecting dosing times/schedules
• dose issues, a nasal sprayer malfunctioned for an intranasal product; patches expected to be study for 12-24 hours fell off almost immediately

Electronic Data

risk based monitoring FDA guidance

Electronic Case Report Forms

Using electronic CRFs is a great boon to the industry. It gives almost instant access to data that used to take months to enter, review, check for consistency and plausibility.

Data Checks that used to come only at the end of a study are available throughout: such as missing forms; out of window visits; other inconsistencies. Immediate data availability can be used to track study progress, investigator compliance (with visits, data entry, inclusion/exclusion), and detect possible troublesome data fields/labels for a single site or throughout a protocol. However, only the data entered is available for central review (remote).

Use data to identify anomalies:

FDA risk based monitoring guidance

Questions Raised During Data Review

During an audit for a sponsor preparing for an FDA inspection, I focused on 2 critical efficacy evaluations (a 20 minute physician evaluation and MRI scan, done at select study visits). I requested data management to calculate the number of procedures performed on the same day at a specific site. I found it very interesting when data management responded:

• 22 physician evaluations were performed on a single day (by the same physician)
• 15 MRI scans were performed on one day.

None of the monitoring visit reports mentioned this kind of scheduling, the requirements for calibrating MRI machines, or whether there was more than 1 machine at a site.

It may be worthwhile to spend more time during the study reviewing available study data. You may need to create customized reports to follow the metrics on your study. Consider the value of team review rather than individual review, in order to understand what your data may be indicating.

FDA warning letters often include observations that may be found during onsite monitoring:


FDA Warning Letters

• Problems with original signatures on informed consent documents. Informed consent documents are not usually submitted to sponsors/monitors, but are reviewed during onsite visits.
• Non-serious adverse events were present in source documents that were not reported to the sponsor. Without onsite review, the sponsor cannot know what is missing.
• Inadequate records, including remarks regarding inappropriate delegation (unqualified person performing procedure or not signed/dated by investigator). Many sites around the world have paper records, and without onsite review, the sponsor cannot be aware of inadequacies.
• Inadequate accountability of the test article.

Monitoring plan considerations:

You may decide to reduce the number of onsite visits. Do this wisely. Ideally the monitoring plan is another tool that helps confirm the validity of your study data. Have your monitors perform activities onsite that cannot be performed remotely.
Source data: Often, only limited source data is available remotely for centralized review.

Finally, remember what the FDA is instructing their inspectors to do, and develop your plan in anticipation. The FDA inspection manual requires inspectors to:

• review logs of onsite monitoring visits
• describe the investigators source documents for legibility and completeness
• review the informed consent process.

Ideally the sponsor will not be surprised what is found when a Regulatory agency goes to the study site.

Judith Lynn, Pharmaceutical Consultant, September 2011

Read the Draft Guidance Document


How to comment to FDA: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

The Federal Register Docket Number is FDA-2011-D-0597


Pacific Regional Chapter SQA Fall Training 10-11 November at Allergan in Irvine, CA. The training will feature a debate which should be an interesting development in training workshops: Debi Garvin, MS, RQAP-GLP and Paula Parsons: Debate: The role of CAPA in a GLP environment.

PRCSQA Fall Training


Tufts Center for the Study of Drug Development: Article on Protocol Amendments: One Third can be avoided.


Training Opportunity:

training GxP

Audits & Risk Management

GxP Audit & Risk Management Congress: 20-21 October 2011, Philadelphia, PA. This conference combines both GMP and GCP tracks to maximize the opportunity for cross training, shared best practices, and networking. Two members of the GxP Perspectives LinkedIn group, Janice Wilson and Adi Lampmann, are among the faculty. The conference is sponsored by ExL Pharma and GxP Perspectives is a media partner.

GxP Audit & Risk Management Brochure


You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives and the discussion on risk-based monitoring. I also encourage you to get an email subscription (on the sidebar to your right) or join the GxP Perspectives LinkedIn Group (below).


FDA vs. Dr. Oz: Should you be drinking apple juice? Television personality Dr. Oz says that there are dangerous levels of arsenic in apple juice. The FDA disagrees. They point out that the tests Dr. Oz conducts are for total arsenic, inorganic and organic, and only inorganic arsenic represents a danger to public health. Read the FDA press release for a detailed explanation.


On The Blogroll: PharmTech Talk discusses the Top Ten FDA 483 Observations for drug GMP inspections. Angie Drakulich reports that Numero Uno concerns Quality Control Units (QCUs).

My Perspective by Kathryn Davis, Clinical Development. In this new blog on WordPress Kathryn Davis discusses relevant issues including social media, GCP, and recruiting minorities in clinical trials.

The Dark Daily Laboratory and Pathology News


FDA Clinical Investigator Course,
7-9 November 2011, Silver Springs, MD


clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the Draft FDA Risk-Based Monitoring guidance document and on protocol deviations. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

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GxP Perspectives on twitter: @GxPPerspectives

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Please comment on the new draft guidance on Risk-Based Monitoring.

FDA Releases Draft Guidance for Monitoring Clinical Trials

September 4, 2011

FDA releases draft guidance document for monitoring clinical trials

FDA Draft Guidance Offers New Methods of Monitoring Clinical Trials

At long last, FDA has released a new draft guidance document for monitoring clinical trials. The previous FDA guidance document, Guideline for Monitoring Clinical Investigations (1988/1998) was withdrawn earlier this year. The new draft guidance document, FDA Guidance for Industry- Oversight of Clinical Investigations– A Risk-Based Approach (August 2011), discusses the changes in the way clinical trials are conducted and new methods of monitoring clinical trials. There is a 90-day comment period where members of industry, professional organizations, and the public can submit written commments to the agency for review and consideration.

In this Guest Commentary veteran monitoring specialist Lorraine Ellis gives her perspective on the new draft guidance for monitoring clinical trials.

Guest Commentary by Lorraine D. Ellis, MS, MBA

When I started monitoring, the Investigators completed CRFs from the source documents and there were few Clinical Research Coordinators (CRCs). Usually an office nurse or staff member would complete the forms when they had “free” time. Three decades later, sites, studies, and monitoring have changed significantly. Investigator sites must have significant study infrastructure (SOPs and facilities, etc) and trained/experienced staff to complete the complex trials of the 21st century. So it is significant that the 1988 Guidance document has been retired and the new guidance on monitoring describes FDA’s view on applying 21st century technology and methods to monitoring.

There are several key advances in this guidance. The guidance describes the term “centralized monitoring” for the many practices of using technology to review data off-site. This term and other FDA comments describe using “off-site” monitoring as one of the acceptable methods of monitoring data quality and study conduct. This guidance will intensify the discussions of “why do we need monitoring every 4 to 6 weeks with 100% source document verification” and “what is the best monitoring procedure for this study”. Also, FDA outlines more detailed monitoring plans as the risk based approach requires that monitoring approaches should be tailored to the trial.

clinical trial monitoring fda guidance document

Poorly Designed Protocols, CRFs, or Trial Instructions

FDA suggests a multi-factor approach to ensure data integrity, compliance and patient protection since there are many trial factors that can affect these trial elements besides monitoring. For example, poorly designed protocols, CRFs, or trial instructions could cause fatal trial errors despite extensive monitoring. Inadequate, incomplete or poor training of all involved in the trial, Investigators, staff, monitors etc., could also decrease study quality. The guidance encourages using various methods of study conduct review to assess these study elements as well as data quality.

The second half of the guidance provides information on monitoring plans and their expected content. Currently monitoring plan content and quality vary among Sponsors so this detailed section should increase monitoring plan quality and detail as it describes methods appropriate to the study. Since this guidance promotes custom monitoring plans based on variables of the study such as scope and complexity, these sections will assist Sponsors in designing and implementing those monitoring practices appropriate to the study.

FDA clinical trials guidance

"Greater Reliance on Centralized Monitoring"

One sentence will probably be surprising to some veteran monitors and Sponsors. “FDA encourages greater reliance on centralized monitoring practices than has been the case historically, with correspondingly less emphasis on on-site monitoring”. Many Sponsors that have instituted EDC and other technologies for data collection/review, have not decreased on-site monitoring time they continue to rely on the “gold standard” of visits every 4 to 6 weeks and 100% SDV. FDA does advise that at least one on-site monitoring visit should be done to ensure processes and procedures are in place at the site to ensure data quality. FDA continues that to use centralized monitoring properly, Sponsors need to develop methods and standard operating procedures so that site records, data entry, and data reporting follow well-defined procedures.

FDA guidance on clinical trials monitoring

Risk-Based Approach

FDA recommends that the monitoring plan is developed based on a risk assessment of the study complexity, study endpoints, disease complexity, geography, Investigator experience, EDC capabilities, Investigational product safety, study stage and quantity of data. After risk assessment, the Sponsor prepares a tailored monitoring plan for each study that will address that risk and outlines the multi-faceted approach to the trial. The plan, that includes monitoring procedures, monitoring responsibilities, and trial requirements, should be in sufficient detail so monitors and others involved can carry out their respective tasks correctly.

The plan should also include: monitoring methods, communication of monitoring findings, resolution of issues, training topics, training evaluation, and monitoring plan amendments.
It will be interesting to read the comments sent to FDA in the next 90 days. Some Sponsors will say “it’s about time” monitoring will be optimizing 21st century technology. Others may struggle with the changing of the “gold standard” of monitoring. In any case, this guidance may be the catalyst the industry needs to optimize monitoring methods and effectiveness.

FDA Guidance for Industry: Oversight of Clinical Investigations– A Risk-Based Approach

Visit Lorraine’s Website


How to comment: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

The Federal Register Docket Number is FDA-2011-D-0597


You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives and the discussion on risk-based monitoring. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).

Please take a short 3-question survey to help GxP Perspectives improve! Survey begins 22 SEP 2011

On the Blogroll: Chromosome which features an excellent post on, “The Site’s Side,” by Jae Chung, founder of goBalto, Inc., located in San Francisco. The post discusses some of the problems clinical sites face with monitors.

On The Blogroll: On Biostatistics and Clinical Trials– Finally a blog on biostatistics that I can almost read:) It is written by Dr. Deng, 邓春勤 A Medical Doctor turned into Biostatistician in Clinical Trial and Drug Development Industry
clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the draft guidance document. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

GxP Perspectives LinkedIn Group

The FDA, Center for Drug Evaluation and Research (CDER) is announcing an industry workshop entitled ‘‘CDER Small Business Assistance – Clinical Trials and Electronic Submissions.” This two day event will be held in two California locations consecutively. The first workshop will be held in Los Angeles, CA, on September 26-27, 2011, followed by a second in San Francisco, CA, on September 28-29, 2011.
This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)
GxP Perspectives has returned to twitter: @GxPPerspectives

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FDA Commissioner Margaret A. Hamburg’s Statement on the Passing of Dr. Charles Edwards 

September 1, 2011

FDA Commissioner Margaret A. Hamburg’s Statement on the Passing of Dr. Charles Edwards

FDA repeat violations warning letter

Former FDA Commissioner
Dr. Charles Edwards

The death of Dr. Charles Edwards is a great loss to the Food and Drug Administration and to Americans who enjoy the safest supplies of food and medicine in the world, thanks to his leadership. During his tenure as FDA commissioner, Dr. Edwards was one of the country’s most ardent drug safety advocates, ordering the extensive review of over-the-counter drugs for safety, effectiveness, and accuracy in labeling. In addition, he ordered that one of the first mandatory package inserts be included with oral contraceptives to warn patients about the possible risks.

Dr. Edwards led FDA from December 1969 to March 1973, taking the reins in a time of great change at the agency. Under his leadership, FDA’s budget doubled from 1970 to 1972 as the commissioner steered the agency towards a greater regulatory role. During these years FDA began regulating biologics and radiological health.

From FDA, Dr. Edwards continued serving his country as assistant secretary for health in the Department of Health, Education and Welfare. There he proposed major reforms in health care and gave greater standing to the Centers for Disease Control and Prevention.

In 1990, long after Dr. Edwards had left government service, Health and Human Services Secretary Louis Sullivan named him head of the Advisory Committee on the FDA to review the agency’s mission, structure, priorities, staffing, and budget.

In a warning that seems a foreshadowing of current concerns about FDA resources, the Edwards committee warned: “An agency charged with such a broad array of vital health protection responsibilities, yet one that lacks the tools to carry out those responsibilities, is in serious danger. And hence, so is the American public.”

While he was still commissioner, Dr. Edwards wrote in a journal article, “I firmly believe that the FDA today represents the soundest and most effective approach to carrying out the vital public functions with which it is charged. I also believe that we are constantly challenged to do a better job, and I can assure you that we intend to meet that challenge.”

His words echo today.

Serving during the turbulent Watergate years, Dr. Edwards was confronted with myriad crises and a skeptical public, but he met each with an integrity and dedication that did honor to his office, the agency, and his country. It is this dedication that I strive to emulate each day as I follow in his footsteps as commissioner. He will be greatly missed.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

I was just a wet behind the ears scientist when Dr. Edwards made the transition from FDA to being the ASH. I remember years later, he was the first ASH to whom I made a presentation (and wouldn’t you know it, I can’t remember the topic – probably laser safety). FDAAA alumni member Phil White worked for him as his special assistant in the OC in the early 70’s. Phil’s take is straightforward: “My favorite Commissioner.”

Read the New York Times Obituary

FDA Warning Letter Cites Repeat Violations

August 28, 2011

FDA Warning Letter Repeat Violations

FDA Cites Repeat Violations on Reporting Adverse Events

A recent FDA Warning Letter to a clinical investigator shows the importance of implementing the corrective actions promised from previous inspections. FDA states; “Given that you have not implemented the corrective actions promised in response to the August 2008 inspectional observations, we have concerns about whether the corrective actions that you have currently outlined will be properly implemented and executed in a manner that will prevent the recurrence of this and similar types of violations in the future.” In this case the previous inspection had cited the clinical investigator for the failure to report adverse events and serious adverse events, the same violations that the 2011 inspection documented. The violations, combined with the failure to implement corrective actions from the previous inspection, earned the investigator a Warning Letter.

It is important to remember how an FDA investigator prepares for an inspection. First, they receive an assignment from the Center for Drugs, The Center for Devices, or the Center for Biologics to conduct the inspection. Then there is a review of the file that includes the previous inspection reports. Each inspection report notes the violations at the previous inspection, or if it is the initial inspection, and if the violations are ongoing or resolved. The fastest way from a Form FDA 483, Inspectional Observations, to a Warning Letter is if there are ongoing violations from the previous inspection.

repeat violations

Review of Previous Inspection Reports

Promising corrective actions is all well and good. However, it is important to note that FDA will actually check up on your proposed corrections the next time they conduct an inspection, even if the inspection is three years later.

The Warning Letter has an interesting feature as it is signed by “Leslie K. Ball, M.D., Acting Director, Office of Scientific Investigations, Office of Compliance, Center for Drug Evaluation and Research.” Up until recently this had been the Division of Scientific Investigations. At FDA an Office is a higher organizational unit than a Division (all emphasis by GxP Perspectives). Evidently there has been some form of reorganization. However, this hasn’t been reflected on CDER organizational charts. The most recent “CDER Key Officials List,” dated August 22, 2011, listss the following:

Division of Scientific Investigations (DSI)

Leslie Ball, M.D., Director
Joseph Salewski, Deputy Director
CT Viswanathan, Ph.D., Associate Director
Chris Howard, Project Management Officer (Acting) (co-located)
Tanya Clayton, Project Management Officer (co-located)
Kevin Prohaska, Human Subject Protection Team (Acting)
Alex Gorovets, International Policy Team (Acting)
Constance Lewin, M.D., Good Clinical Practice Branch I
Sherbet Samuels, Good Clinical Practice Team I (Acting)
Tejashri Purohit-Sheth, Good Clinical Practice Branch II
Jean Mulinde, Good Clinical Practice Team II (Acting)
Sam Haidar, Good Laboratory Practice and Bioequivalence Investigations Branch (Acting)
Martin Yau, Bioequivalence Team (Acting)
Jackie O’’Shaughnessy, Good Laboratory Practice Team (Acting)
Thomas N. Moreno, Information and Informatics Team (Acting)

Evidently there are some significant changes taking place. Perhaps we will learn more later.

Read the Warning Letter

Also: Read the recent Warning Letter from CBER to a Clinical Trial Sponsor


You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).


On The Blogroll: Applied Clinical Trials Blog discusses Facebook.


FDA warning letter

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Your comments are welcome!

FDA Issues Draft Guidance on Medical Device Clinical Trials

August 15, 2011

FDA clinical trial medical device

FDA Seeks Comment on Draft Guidance Document

FDA has issued two new draft guidance documents on medical device clinical trials to support a Pre-Market Approval application (PMA). Approximately 30% of FDA regulated clinical trials are for medical devices and are regulated by the IDE regulations (21 CFR 812). The remaining 70% are for drugs and biologics and are regulated by the IND regulations (21 CFR 312). The majority of guidance documents, including ICH E6 for good clinical practice, and the majority of clinical trial vendors address drug products, not medical devices. Although Good Clinical Practice is relevant to all clinical trials there are unique aspects for device studies as opposed to drug studies. This is one reason that FDA issued a device-specific guidance document.

The draft guidance document, Draft Guidance for Industry, Clinical Investigators, and Food and Drug Administration Staff – Design Considerations for Pivotal Clinical Investigations for Medical Devices (August 15, 2011), addresses therapeutic and aesthetic devices and diagnostic devices. Areas the document address include; Regulatory Framework for Level of Evidence and Study Design, The Importance of Exploratory Studies in Pivotal Study Design, Clinical Outcome Studies, Diagnostic Clinical Performance Studies, and Sustaining the Level of Evidence of Clinical Studies. The guidance states that its scope is:

clinical trials FDA medical device

Design Considerations for Pivotal Studies

“This guidance describes principles that should be followed for the design of premarket clinical studies1 that are pivotal in establishing the safety and effectiveness of a medical device. Practical issues and pitfalls in pivotal clinical study design are discussed, along with their effects on the conclusions that can be drawn from the studies concerning safety and effectiveness.”

The Agency also released the draft guidance document; Draft Guidance for Industry and Food and Drug Administration Staff – Factors to Consider when Making Benefit-Risk Determinations in Medical Device Premarket Review (August 15, 2011). The Agency states:

FDA clinical trial medical device

Benefit-Risk Determination

“This guidance document explains the factors that FDA considers when making benefit-risk determinations in the premarket review of certain medical devices. The processes discussed in this guidance are applicable to devices subject to premarket approval (PMA) applications and, in limited cases, devices subject to premarket notification (510(k)) requirements. This guidance applies to both diagnostic devices and therapeutic devices.

Although guidance is not binding, the concepts and factors described herein generally capture how benefit-risk determinations are made by FDA during the premarket review process.”

Read the Guidance Document on Design Considerations

Read the Guidance Document on Benefit/Risk Determinations


ALSO of interest: FDA is currently accepting comments on the IVD Draft Guidance Document on In Vitro Companion Diagnostic Devices.

The draft guidance was issued 14 July, Bastille Day. I wish that I could explain it to you as well as Jamie K. Wolszon at the FDA Law Blog, but I can’t so I recommend taking a look over there:


FDA Law Blog on IVD Companion Devices


You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).


Required Summer Reading: Essex IRB Warning Letter. Earlier this year FDA warned of a fictitious submission to central IRBs. Essex took the bait and approved the fictitious submission.


On The Blogroll: On Biostatistics and Clinical Trials– Finally a blog on biostatistics that I can almost read:) It is written by Dr. Deng, 邓春勤 A Medical Doctor turned into Biostatistician in Clinical Trial and Drug Development Industry


FDA warning letter

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What are your thoughts? Please share your comments on Medical Device Clinical Trials.

Major Reorganization at FDA

July 14, 2011

Dr. Margaret Hamburg

Dr. Margaret Hamburg, FDA Commissioner

Every organization needs to take stock of personnel and responsibilities, including FDA. The world of FDA regulaton is changing rapidly and in an effort to keep current Commissioner Margaret Hamburg has announced a major reorganization in an FDA-wide announcement reprinted below. She announced a new position, stating “I am establishing a new Deputy Commissioner for Medical Products and Tobacco.” The position will be filled by Dr. Steven Spielburg (no not That one) the former Dean of Dartmouth Medical School to fill the position. There are a number of other changes at the top. Here’s what the announcement said:

From: A Message from the Commissioner
Sent: Wednesday, July 13, 2011 3:41 PM
To: FDA-Wide
Subject: A Message from the Commissioner

Dear Colleagues,

I am writing today to let you know about some changes that I will be making to the agency’s management structure. As you probably recall, back in January, I told you that I was initiating a review of the Office of the Commissioner. As I explained at that time, this review was driven by the expanding and rapidly changing nature of the Agency’s responsibilities, and the need for a management structure that reflects these changes and best supports your efforts.

I consulted with former Commissioners, as well as with HHS Secretary Sebelius, and considered many options before arriving at the structure that I am announcing today.

The most important thing driving my consideration of this is the changing nature of both the Agency and the job of Commissioner. Today, the Agency faces several key challenges:

First, we are a very large agency, with an incredibly broad span of responsibility. We regulate products that account for between 20 and 25 percent of every consumer dollar spent in the U.S. and that total more than a trillion dollars annually. For the most part, these are products that people rely on in fundamental ways every day.

Second, as technology and science continue to evolve, we are faced with the challenge of making sure that new ideas translate into the products and opportunities that people need and count on to protect their health. Innovative products that are truly transformative create unique scientific and regulatory challenges, and FDA must be a consistently powerful catalyst for innovation.

FDA Change

The Challenges of Globalization

Third, we have seen the dramatic transformation of globalization – more products, more countries, more access by consumers and companies to global supplies – and this presents an enormous challenge to FDA in ensuring the safety and quality of the products we regulate.
Finally, we continue to be faced with administrative challenges. In these difficult economic times, our agency’s budget requires constant attention. And, simply providing the support and services for our 12,000 plus employees – everything from phones to IT to office space on our beautiful, growing White Oak campus – is a daunting job.

I take very seriously my responsibility to lead FDA along a path that will meet these challenges. One crucial part of this responsibility is to create a structure in the Commissioner’s Office that best supports your efforts and reflects the changing nature of the Agency.

FDA reorganization

'The structure of the Office of the Commissioner that I inherited was created in 1970'

The structure of the Office of the Commissioner that I inherited was created in 1970, when the FDA consisted of three Centers and a field office. By 2011, we had grown to seven Centers, and a Commissioner’s Office with more than 1,600 staff. Over the years, as Congress created new programs that cut across Center responsibilities, those programs were placed by default in the Office of the Commissioner.

The new organizational alignments more accurately reflect the agency’s responsibilities, subject matter expertise and mandates in an ever more complex world, where products and services do not fit into a single category. Let me begin by saying that, for most of the FDA, this organizational alignment will likely not have a significant impact on you or your day-to-day work.

The most obvious change you will see is that the Agency’s programs, in terms of a reporting chain to me, will be divided into “directorates” that reflect the core functions and responsibilities of the Agency. This new management structure will enable the Office of the Commissioner to better support the agency’s core scientific and regulatory functions, and help tie together programs that share regulatory and scientific foundations. I will rely on the leadership of these directorates to help provide the necessary direction and coordination needed by an Agency of this scope.

FDA changes

Dr. Steven Spielberg

I am establishing a new Deputy Commissioner for Medical Products and Tobacco, who will provide high-level coordination and leadership across the Centers for drug, biologics, medical devices, and tobacco products. The Centers will, of course, remain as discrete management entities under their current expert leadership. In addition to this strategic role with the Centers, this position will oversee our Special Medical programs.

I am pleased to announce that Dr. Steven Spielberg, former Dean of Dartmouth Medical School and currently Director of the Center for Personalized Medicine and Therapeutic Innovation at Children’s Mercy Hospital in Kansas City, has accepted this position. In this role, Dr. Spielberg will serve as both advocate and a support for Center Directors in their important work for FDA.

I will also be creating a directorate focused on grappling with the truly global nature of today’s world — food and drug production and supply, as well as the science that undergirds the products we regulate — so that the FDA can move from being a regulator of domestic products to one overseeing a worldwide enterprise.

fda reorganization

Global Regulatory Operations & Policy

To oversee this transformation, I have asked Deborah Autor, now Director of CDER’s Office of Compliance, to take on the role of Deputy Commissioner for Global Regulatory Operations and Policy. In this position, Deb will provide broad direction and support to the Office of Regulatory Affairs and to the Office of International Programs, with a mandate from me to make response to the challenges of globalization and import safety a top priority in the years to come. Dr. Murray Lumpkin, who has served with dedication and accomplishment as Deputy Commissioner for International Programs and Director of the Office of International Programs, will take on a new role as Senior Advisor and Representative for Global Issues. In this role, he will be charged primarily with special projects that draw on his expertise working with counterpart regulatory agencies on issues of global regulatory harmonization, governance and capacity-building.

The third directorate is the previously established Office of Foods, which we created to make our oversight of FDA’s food and feed program a more seamless enterprise. That task is even more important today as Mike Taylor leads the implementation of the Food Safety Modernization Act.

fda reorganization

Office of Operations

The fourth directorate will be a new Office of Operations, headed by a Chief Operating Officer. The COO will oversee the agency’s administrative functions, such as human resources, facilities, information technology, finance, and other activities that provide support to your organizations. Within this Office, I am bringing the budget formulation and budget execution functions together under a CFO position. We have initiated a search to fill the Chief Operating Officer position.

The Office of the Chief Scientist, charged with our important efforts to improve FDA’s science and address issues of cross-cutting scientific concern, will continue to do so. The National Center for Toxicological Research will report to the Chief Scientist, Dr. Jesse Goodman, and, like the other Centers, will remain a discrete management entity within this new directorate model.

fda reorganization

John Taylor

Within the new, smaller, immediate office of the Commissioner, John Taylor will remain as Counselor and will have the additional responsibility to oversee the policy and planning functions, the Office of Legislation, and the Office of External Affairs. I want to thank John for serving as acting Principal Deputy these past months, in addition to his duties as Counselor. He has tirelessly supported me and the Agency with enthusiasm, energy, expertise, and good humor.

You can find revised organizational charts, reflecting this realignment at http://inside.fda.gov:9003/AboutFDA/FDAStaffInformation/OrgCharts/default.htm. (This org chart could not be accessed at time of publication. You can also try here for Office of the Commissioner) In addition, I will share a video message of this announcement shortly. Your managers will be available to answer any questions you might have in the coming days.

In closing, I want to take a moment to thank you so much for all that you do. FDA is an extraordinary place, with so many highly-dedicated professionals and support staff who are committed to promoting and protecting public health. You accomplish a tremendous amount every day and I am grateful for all of your work. These organizational changes are intended to help further your important work and the mission of this remarkable Agency.

Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs

(Information from FDA Alumni Association)


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FDA Issues New Guidance for Sponsor & CRO Inspections

March 19, 2011

FDA guidance sponsor CRO inspections

FDA Issues Updated Guidance on Sponsor & CRO Inspections

FDA is increasing their emphasis on Sponosr and CRO inspections with the release of an updated version of the Compliance Program Guidance Manual, CP 7348.810, Sponsors, Contract Research Organizations, and Monitors (CPGM). This FDA guidance document gives instructions to FDA personnel on how to conduct an inspection of a sponsor or CRO involved in FDA regulated research.

It significantly modernizes the previous CPGM, released over 10 years ago, introducing new sections and deleting sections that were obsolete or irrelevant.

There are new sections on the Registration of Studies on ClinicalTrials.gov; Review of Site Records; Financial Disclosure; Electronic Records and Electronic Signatures; Emergency Research; International Data; and GLP Studies. Other sections, such as Medical Devices, are substantially updated and clearer. The new CPGM should professionalize FDA’s approach to sponsor and CRO inspections and ensure closer review of a sponsor’s regulatory responsibilities. It is long overdue. I have done a brief analysis of Section III, Inspectional, of the new CPGM. There are also some helpful links to documents in Section VI, References and Contacts including several documents that I had never heard of before.

FDA inspection guidance on sponsors and CROs

Sponsor and CRO Inspections Usually Will be Scheduled

The first significant change is right at the beginning of Section III, Inspections, “under this program will be pre-announced unless otherwise instructed in the inspection assignment.” This formalizes a policy that began a few years ago under the Medical Devices Initiative. In addition, the new CPGM makes a point of emphasizing a statement routinely included in FDA inspection documents: Approaches that differ from those described in FDA’s Guidance documents should not be listed on the (Form FDA) 483 (Inspectional Observations) unless they constitute deviations from the regulations.” There are also instructions that the new CPGM “provides only the minimum scope of the inspection” for the field investigator to “expand the inspection as the circumstances warrant.” There are also specific instructions on how to document a violation:

“Any deviations from regulations should be thoroughly documented. For example, if the sponsor failed to review monitoring reports in a timely fashion and/or failed to bring non- compliant clinical investigators into compliance, monitoring reports, report review dates, and evidence of clinical investigator continued non-compliance should be documented and copied.” (original emphasis)

There are specific instructions that stem from FDA’s increased vigilance regarding falsification of data:

FDA sponsor inspection

Increased Emphasis on Falsification of Data

“Discuss potential violations involving fraud subject to Title 18 of the United States Code (18 U.S.C.) with your supervisor, District Compliance Officer, and assigning Center contact for appropriate referral to the Office of Criminal Investigations (OCI).” Reader’s should note that Title 18 violations are the ones that can put you into prison. Here are the new sections of the CPGM:


“ClinicalTrials.gov is a website maintained by the National Library of Medicine (NLM). Its establishment was mandated by the 1997 FDA Modernization Act (FDAMA) to provide a public resource for information on studies of drugs, including biological drug products. The FDA Amendments Act of 2007 (FDAAA) mandated expansion of this data bank and included enforcement provisions to help ensure compliance.” There are specific guidance instructions in this section including a discussion of the Form FDA 3674, which we all will be paying closer attention to. Among the additional instructions to FDA field investigators are:

“6. Determine whether primary and secondary outcomes measures are listed on ClinicalTrials.govfor the study/studies. Determine if the outcome measures, if any, listed on ClinicalTrials.gov are generally consistent with the primary and secondary outcomes in the sponsor’s study protocol(s).

7. When examining informed consent documents related to an applicable clinical trial registered on ClinicalTrials.gov, determine if the appropriate required statement referencing ClinicalTrials.gov is included6. 21 CFR 50.25(c). The statement is:

‘’A description of this clinical trial will be available on http://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.’’’

For the section on Monitoring Procedures and Activities there is one significant change in recognition of the changes in the conduct of clinical trials: “With the prevalence of multisite clinical trials, traditional monitoring techniques – early and frequent on-site visits at all clinical sites – have become resource intensive. Regulations do not prescribe a specific monitoring technique, simply stating that sponsors are required to select monitors qualified by training and experience to monitor the investigational study (21 CFR 312.53(d), 511.1(b)(8)(ii), and 812.43(d)).”

FDA sponsor CRO inspections guidance

Monitoring of Clinical Trials is Evolving

In part, this statement recognizes that 100% source/CRF verification might not be practical or necessary, that sponsors may need to adapt new techniques, sometimes described as “Compliance Monitoring,” where monitoring records and reports are reviewed to determine outlier data. This could include no adverse events reported at a specific site. The CPGM goes on to state: “Determine if all CRFs are verified during monitoring visits. If a representative sample was selected, determine how the size and composition of the sample were selected.”

Financial Disclosure is discussed for the first time by FDA in a CPGM. Financial disclosure violations are very rarely cited by FDA during sponsor/CRO inspections. This may change with these instructions:

“1. Determine if the sponsor obtained financial disclosure information from each investigatorbefore his/her participation in the clinical trial, as required by 21 CFR Part 54 and 21 CFR 312.53(c)(4) and 812.2(b)(5) and 812.43(c)(5).

2. Determine if the sponsor received prompt updates regarding relevant changes in financialdisclosure information from investigators during the study and for one year after study completion.

3. Determine if the sponsor reported to FDA (on Form FDA 3454 and 3455, respectively), allpertinent investigator disclosures and certifications of financial information as required by 21 CFR 54.6.

4. Determine if the sponsor retained the documentation to support the certifications anddisclosures of investigators’ financial information that was reported to FDA.”

FDA inspection of sponsor

Updated Section on
Part 11

There is an updated section on Electronic Records and Electronic Signatures. The FDA guidance document, “Guidance for Industry Part 11, Electronic Records; Electronic Signatures – Scope and Application” (Part 11 Guidance) is discussed at length confirming that this document currently represents FDA’s enforcement policy regarding Part 11.

The CPGM emphasizes issues including the Scope of Electronic Records & Signatures; Procedures; Data Collection; & Security.

Finally there are new sections on Emergency Research; International Data; & Nonclinical Laboratories reflecting new regulations, guidance documents, or inspection policies. It is important to note that although FDA will not inspect GLP studies at every sponsor/CRO inspection, the possibility exists. The new CPGM gives the field investigator specific instructions on what to look for in non-clinical studies. (UPDATE: Read the recent Sponsor Warning Letter on Preclinical Studies on the link below.)

The new CPGM will significantly change how Sponsor/Contract Research Organizations, and Monitor inspections are conducted. It confirms a shift to review of sponsor responsibilities by FDA’s Bioresearch Monitoring program managers. It is a very important document for sponsors and CROs to review.

Read the New CPGM

Guidance for Industry on Financial Disclosure

Guidance on Certifications Required By FDAAA (including clinicaltrials.gov)

Compliance Policy Guide on Fraud and Untrue Statements…

Part 11: Scope & Application Guidance

Sponsor Warning Letter on Preclinical Studies from CDRH


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