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New FDA Draft Guidance Document

FDA’s new draft Guidance for Industry: Oversight of Clinical Investigations — A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Two weeks ago GxP Perspectives published a Guest Commentary by Lorraine Ellis on the new draft guidance. This Guest Commentary by Judith Lynn, continues the discussion about the new draft guidance.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I reviewed the Recent Draft Guidance From FDA- A Risk-Based Approach To Monitoring with several information points in mind: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 I found that much of the draft guidance centers on managing your study, having a sampling plan, and ensuring quality.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 Note the point in the draft guidance under section IV/ C, Factors to consider when developing a monitoring plan: that “a population that is seriously ill and/or vulnerable may require more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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Please comment on the new draft guidance on Risk-Based Monitoring.

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.

FDA Guidance Documents on GCP: Periodic Review

June 26, 2011

FDA Comment Period Proposed Guidance

FDA Comment Period for Proposed Guidance on Financial Disclosure

The FDA has released a number of guidance documents in the past few years that gives the Agency’s current thinking on Good Clinical Practice and other regulatory issues. Some of these documents change the “conventional wisdom” on conducting clinical trials. One document: “FAQs on the Form FDA 1572, Statement of the Investigator,” changes the way we look at putting research coordinators on the FDA 1572. Another document, “Adverse Event Reporting to IRBs,” changes the old rule of thumb to Always report a serious adverse event (SAE) to the IRB within 15 days (or less). Currently, FDA is soliciting public comment on the Draft Guidance Document, “Financial Disclosure by Clinical Investigators.” The comment period is the opportunity for the public, researchers, and regulated industry to comment on FDA’s guidance on financial disclosure and compliance with 21 CFR Part 54.

FDA guidance document periodic review

Periodic Review of SOPs

Why am I bringing up the issue of guidance documents?
Every organization that writes standard operating procedures (SOPs) to maintain compliance with FDA regulations should have a policy in place to perform Periodic Review of those procedures. Any periodic review should include a review of guidance documents from FDA and other regulatory agencies. There have been more than one Form FDA 483, Inspectional Observations, that have listed the failure to perform Periodic Review of SOPs. Look at the “Reference” section of your SOPs. Is it current? Are you keeping up with what FDA and EMA are saying?

Here are several documents that have been released of late that I think should be on any periodic review of SOPs:

Draft: Financial Disclosure by Clinical Investigators

FAQs on the FDA 1572

Supervisory Responsibilities of Investigators

Adverse Event Reporting to IRBs

MHRA: Clinical Laboratories

EMA: Pharmacovigilance and Risk Management

Finally, I think it is important to return to a final rule and look at the “preamble.” This is the discussion of a proposed rule (regulation) and the public comments on it during the rulemaking process. Here is the lengthy preamble to the 1987 rewrite of the IND regulations, 21 CFR Part 312. In part 3 of the preamble, you have to scroll all the way down to access part 2 and then scroll all the way down to get to part 3, you can see what FDA said about transferring responsibilities to a CRO. Very interesting reading:

Part 312 Preamble

(Graphic on upper left is “Freedom of Speech,” by Norman Rockwell.)

8 July UPDATE: There is an interesting FDA Press Release regarding new anti-smuggling measures and a new Draft Guidance Document on dietary supplement ingredients.

On The Blogroll: FDA Matters discusses the new FDA import initiative

The Medicine Show on Forbes discusses the decline in drug approvals.


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Please Leave Your Comments on Regulatory Guidance Documents

FDA Releases Draft Guidance on “Artificial Pancreas” to Fight Diabetes

June 21, 2011

FDA diabetes artificial pancreas

FDA Guidance for "Artificial Pancreas"

FDA released a draft guidace document for development of an “artificial pancreas,” a highly anticipated step in the fight against diabetes. At one time the onset of type 1 diabetes, where the body stops producing insulin, was always fatal. Then, in 1922, scientists from the University of Toronto gave the first injection of insulin to a 14 year old boy with type 1 diabetes. The experiment was a success and one of the major achievements in the history of medicine. However, this would be the first of many steps in fighting diabetes mellitus. Two of the scientists, Dr. Frederick Banting and Professor John Macleod won the 1923 Nobel Prize for Medicine which they shared with two other members of their team, Charles Best and Bertram Collip. And a new Nobel Prize winner may be working on an artificial pancreas right now.

The concept of an artificial pancreas or a “closed loop” system is that a diabetic could automatically have their blood sugar analyzed and in real time inject insulin to maintain a normal glycemic level.

artificial pancreas FDA

Researchers are Focusing on the "Artificial Pancreas"

Although there have been many advances with insulin pumps and continuous glucose monitors, the devil is in the details on how to regulate the amount of insulin supplied to the diabetic. It is hardly an easy matter.

Most diabetes researchers are looking into the concept of an artificial pancreas as opposed to replacing the islet cells in the diabetic’s pancreas that create insulin. It is the destruction of a diabetic’s islet cells that causes type 1, insulin dependent, diabetes. The Toronto researchers originally called their discovery “isletin.” Type 2 diabetes, once referred to as “adult onset” diabetes, is currently in epidemic proportions in the United States. It impacts the body differently than type 1 diabetes.

The development of an artificial pancreas requires the use of sophisticated medical devices, many of which are already approved. However, it requires the devices to communicate with each other and the development of an algorithm to measure the right amount of insulin to be administered at the right time. No easy task.

FDA guidance artificial pancreas

Draft Guidance Discusses Clinical Trials & Applications for Approval

It is also a difficult issue to regulate. FDA is responsible for ensuring that any artificial pancreas system is safe for the user. The new draft guidance lays out a step-by-step approach for researchers through the regulatory process, for “The Content of Investigational Device Exemption (IDE) and Premarket Approval (PMA) Applications.” The FDA press release states:

“Our goal is to provide a clear pathway for artificial pancreas development so that people with diabetes can benefit from innovative medical devices,” said Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health. “Getting a safe and effective artificial pancreas system to Americans with type 1 diabetes is an FDA priority.”

The draft guidance is for an “early version of an artificial pancreas system.” There is a 90 day comment period from the date the guidance is issued (22 June 2011). A seperate guidance on more autonomous artificial pancreas systems is expected to be released by FDA by the end of 2011.

FDA Press Release

Draft Guidance…Low Glucose Suspend (LGS) Device Systems


On the Blogroll: Top 40 FDA-Related Websites (and tweeters)


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Please Leave Your Comments & Experience on Diabetes and the Artificial Pancreas in the Leave a Comment section below

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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On the Blogroll:

Marc Stecker’s Photos


On the Blogroll: FDA Matters once again discusses the importance of FDA’s contributions to public health. Please read Steven Grossman’s post on Change Takes Time.

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New FDA Guidance Documents Planned for 2011

January 9, 2011

FDA Guidance Documents 2011

FDA Plans New Guidance Documents in 2011

FDA just issued a new draft guidance document for Electronic Source Documents in Clinical Investigations (see below) and has more in the works. In this Guest Commentary, John Avellanet, founder of Cerulean Associates LLC, takes a look at what is in store for 2011 as far as FDA Guidance Documents with a focus on new documents for postmarket surveillance. The article is excerpted from a lengthier article in John’s newsletter SmarterCompliance. John forecasts new guidance documents every year in his newsletter. There is a link to John’s website below.

Guest Commentary by John Avellanet:

FDA postmarket surveillance is the emphasis of at least six different guidance documents planned for publication in 2011. And these are in addition to the new International Conference on Harmonization (ICH) and Global Harmonization Task Force (GHTF) documents expected, including a GHTF guidance on the handling of recalls and field safety corrective actions (see below).

The list of FDA postmarket surveillance guidance documents includes:

1. Chemistry, Manufacturing, and Controls (CMC) – Postmarketing Plan
2. CMC Postapproval Changes Reportable in an Annual Report
3. Pharmaceutical Manufacturing Statistics and Trend Analyses
4. Best Practices for Conducting Pharmacovigilence Studies Using Electronic Healthcare Data (remember that since FDAAA of 2007, the term “study” explicitly means postmarket nonclinical study)
5. Medical Device Reporting for Manufacturers
6. Postmarket Surveillance and the National Competent Authority Report Exchange Criteria and Report Form
7. Types of Submissions for Postapproval Changes to Combination Products

FDA Guidance Documents

Expect New REMS Guidance from FDA

I also expect the agency to release a revised risk evaluation and mitigation strategies (REMS) guidance, at least in draft form, by year’s end. Part of this release will be the creation of a pilot program to test what a standard REMS could like as a default part of any new drug or biologic submission. This means one more step toward pushing the industry to create some type of REMS for every single new drug or biologic developed. The agency will maintain an approach to a standard REMS that will be harmonized with other regulatory member agencies in the ICH. And while such a revised draft REMS guidance may come as a separate document, I suspect the agency may take a newer tact: “guidance by FAQ.”

guidance documents

EMA is Also Releasing New Guidance & Clarifications

Both the European Medicines Agency (EMA) and the UK’s health agency (MHRA) have begun publishing clarifications and revisions to guidance documents and regulatory interpretations using question and answer formats posted on agency webpages. The FDA adopted this approach most recently in its “guidance” (for Buildings and Facilities) on avoiding moldy or musty odors in drugs. Might the agency harness the “guidance by FAQ” approach for its upcoming standardized REMS draft and pilot?

The standard REMS template – while seeming to add more requirements to drug development – will actually provide manufacturers and developers more flexibility, something already known to readers of Get to Market Now! Turn FDA Compliance into a Competitive Edge. While I do not expect the REMS guidance and template to be finalized until after the pilot program is complete, consider developing a high-level REMS as part of any late stage development today. Expect to be able to talk intelligently to FDA reviewers of your plans for a postmarket surveillance program. A high-level draft REMS strategy (you need not share the actual document with the agency) will only help.

Finally, be aware that in 2011, the HHS Office of Inspector General (OIG) will examine the FDA’s postmarket surveillance activities, with a report expected to be published in 2012. This will inevitably result in more postmarket guidance, and may give the FDA the backing it needs to make a basic REMS part of any new drug or biologic submission by 2014.

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

Global Harmonization Task Force focuses on medical devices

International Conference on Harmonization focuses on drugs and biologics

SPECIAL ANNOUNCEMENT: From the FDA Alumni Association (FDAAA): The WHO is seeking a pharmaceutical technical officer to work in China ondrug policy. The position looks very interesting. Please forward to anyone you think might be interested. Please contact WHO directly if you have questions. For info contact <a href="Florence Houn “>Florence Houn at FDAA. or view the WHO AnnouncementWHO Announcement


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Special Notice: The Blog was published in the Journal of Diabetes Science & Technology on the topic of Supervisory Responsibilities of Investigators with my colleagues Ann Berenbaum and Patti Young.

Access the Abstract Here


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:

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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 Guidance: FAQ for In Vitro Diagnostic Devices (IVDs)

September 27, 2010


FDA Guidance: FAQ for
In Vitro Diagnostic
Medical Devices

In Vitro Diagnostic medical devices (IVDs) have long occupied a poorly understood sector of clinical trials. Now, a recent FDA document, Guidance for Industry and FDA Staff: In Vitro Diagnostic (IVD) Device Studies- Frequently Asked Questions (June 25, 2010) clears up many questions. The FAQ offers resources including the definition of many basic IVD and medical device terms. Examples include the FDA definition of the difference between Invasive and Non-Invasive and the difference between a Significant Risk and Non-Significant medical device. The FAQ gives FDA contact information for IVD review divisions and the conduct of clinical trials. Most importantly, the FAQ discusses how IVDs meet the criteria for exemption from most requirements under medical device clinical trial regulations.

The FAQ discusses the requirements for the emergency use of investigational IVDs. It also discusses the differences in informed consent requirements between FDA and the U.S. Department of Health and Human Services which funds NIH studies. Frequently researchers think that if a study is exempt under DHHS regulations (Title 45 Part 46) that the study is exempt from FDA informed consent regulations found in 21 CFR Parts 50 and 56. FDA requires IRB and informed consent even if studies are exempt from most requirements of 21 Part 812.

The FAQ also discusses use of data collected from studies conducted outside the United States. The FAQ gives the following guidance:

… the PMA regulation, 21 CFR Part 814, allows foreign data to be used as the sole support of a marketing application but only if (1) the data are applicable to the U.S. population and to U.S. medical practices, including laboratory practices, (2) the studies have been performed by clinical investigators of recognized competence, and (3) the data may be considered valid without the need for an on-site FDA inspection or, if necessary, FDA can validate the data through an on-site inspection or other appropriate means (21 CFR 814.15(d)).

For IVD devices, FDA would consider differences in population demographics, disease prevalence, disease presentation, laboratory practices, and medical standards of care. If the sponsor plans to submit an application based solely on foreign data, FDA recommends that the sponsor consult with the reviewing division prior to submission of the application.


ICH Good Clinical Practice Can Also Apply to Medical Device Studies

The FAQ endorses ICH E6: Consolidated Guidance on Good Clinical Practice as a sound guidance document with sections applicable to medical devices as well as pharmaceuticals. It also discusses the draft ISO 14155 document:

Although the ICH document was written for studies of pharmaceuticals, sections of the guidance address study issues common to all investigational products. Thus, these sections of the ICH GCP provide a useful reference regarding the proper conduct of studies.

The draft ISO document specifically states that it does not apply to IVD devices. The draft ISO document is an international document intended to reflect basic practices appropriate to clinical trials worldwide. It does not include all of FDA’s specific requirements for clinical studies and is not presently a standard that FDA has officially recognized; therefore, we do not recommend that you rely on it.


Appendix 2 Shows Requirements for IRB Approval and Informed Consent

The FAQ has two charts, Appendix 1 and Appendix 2, that clear up decision making for IVD exeption criteria as well as informed consent requirements. And in keeping with current FDA clinical trial policy the FAQ emphasizes the use of quality systems for IVDs. The FAQ and two other relevant FDA guidance documents are below:

FAQs for In Vitro Diagnostic Devices

FDA Guidance on Informed Consent for IVDs Using Leftover Human Specimens

Comparison of FDA (21 CFR 50 & 56) and DHHS (45 CFR 46) Regulations

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

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

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:

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FDA 1572: Big Changes in FAQ Information Sheet Guidance

June 8, 2010

FAQ FDA 1572

Most Study Coordinators Belong on the FDA 1572

FDA has made some big changes in the final version of their Frequently Asked Questions (FAQ), Statement of the Investigator (Form FDA 1572) Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs (May 2010). The FAQ states that research coordinators (study coordinators) should “usually be listed in Section #6 of the 1572.” This is a significant change from the draft FAQ Information Sheet Guidance that came out in July 2008. Many clinical sites do not list study coordinators on the FDA 1572. It means that most study coordinators will need to file financial disclosure information. It will be a significant change in the way FDA inspects clinical sites. Specifically the FAQ document states:

Generally, a research coordinator has a greater role in performing critical study functions and making direct and significant contributions to the study data. For example, a research coordinator often recruits subjects, collects and evaluates study data, and maintains study records. Therefore, the research coordinator should usually be listed in Section #6 of the 1572.”

You can review this in Section 33, page 14 of the Final FAQ on FDA 1572s. This is a big change from the July 2008 draft FAQ:

If a research coordinator is performing critical study functions and collecting and evaluating study data, the coordinator should be listed on Block #6.

This is a very significant difference and not just because they changed “Block #6” to “Section #6.” FDA is saying that a study coordinator “generally” performs critical study functions. And FDA says that recruiting subjects is one of those functions. Obtaining informed consent, although not stated in the FAQ, is also regarding as a critical function. FDA made that clear in a Warning Letter issued October 1, 2008. The Warning Letter states:

FDA 1572 FAQ Change

FDA Makes a Clear Statement on 1572 Requirements

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

Although the 1572 FAQ, like all FDA Guidance Documents, states that it “Contains Nonbinding Recommendations,” the Warning Letter makes it crystal clear that “nonbinding” only goes so far. My advice?

Put your study coordinators on the 1572 pronto.

UPDATE: Remember that the FAQ does not need a CV for subinvestigators, just financial disclosure. It’s in the FAQ

UPDATE 6 January 2011: Two Important New GCP Documents:

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

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.”

Another update: Read an updated version of this article in
Applied Clinical Trials


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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.



For some reason WordPress isn’t showing comments for this post:


Just discovered your blog and find it rather helpful. Our site is looking at the new 1572 guidance and will be implementing changes soon. I am not happy with the guidance for Sub-Investigators (VII, Section #6, #31) because it still leaves the interpretation wide open as to who provides “direct and significant contribution to the data.” We do oncology research and the nature of the care and treatment of these patients means that dozens of staff are involved. An auditor could intrepret that each of those staff members has a significant contribution to the “data.” I am not comfortable that Section #6, #32 protects us.

I know the Delegation of Authority log was never an official FDA document but it seemed a much more efficient means of informing Sponsors of who was conducting procedures for their studies. For me the 1572 should be reserved for those who make the decisions that a clinical trial is appropriate for given research subjects and for whom financial (or other) incentive could bias the enrollment and outcome of a trial . In our situation, that would be the physians who order the treatment for their patients. Staff assist in that process, but a study coordinator is never the one who decides that a treatment is appropriate. What brought about the need to expand the definition of who is a “sub-investigator?”

Thanks for your comment:

I basically agree with you about the study delegation log. It was in the guidance “Investigator Responsibilities” (October 2009) and I thought that it was a good vehicle for this type of situation. I do not have a clue why this has been emphasized at this time. Please make sure you look at section 32 of the FAQ where it addresses residents:

“Concerning staff residents on rotation, it may be difficult to prospectively identify those individuals who might perform specified protocol procedures or collect clinical data. Specific names of the rotational staff do not have to be listed in Section #6. Instead, to successfully address this scenario, the names of rotational individuals and the procedures they are expected to perform should be included in the clinical study records.”

This paragraph is at the top of page 14 in the FAQ.


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The FDA 1572: What Belongs?

May 9, 2010

FDA 1572 What Belongs

What Belongs on a Form FDA 1572?

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

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

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

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

FDA 1572  Clinical Trial

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

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

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

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

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

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

What belongs on 1572

Who Belongs on the 1572?

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

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

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


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

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