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New FDA Draft Guidance Document

FDA’s new draft Guidance for Industry: Oversight of Clinical Investigations — A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Two weeks ago GxP Perspectives published a Guest Commentary by Lorraine Ellis on the new draft guidance. This Guest Commentary by Judith Lynn, continues the discussion about the new draft guidance.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I reviewed the Recent Draft Guidance From FDA- A Risk-Based Approach To Monitoring with several information points in mind: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 I found that much of the draft guidance centers on managing your study, having a sampling plan, and ensuring quality.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 Note the point in the draft guidance under section IV/ C, Factors to consider when developing a monitoring plan: that “a population that is seriously ill and/or vulnerable may require more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

GxP Perspectives LinkedIn Group

GxP Perspectives on twitter: @GxPPerspectives

Follow GxPPerspectives on Twitter
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 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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GCP Protocol Deviations & Violations: Determining the Root Cause

March 6, 2011

protocol violations and deviations GCP

GCP Protocol Violations: Determing the Root Cause

The top violation cited during FDA inspections of clinical sites has consistently been the failure to follow the investigational plan- Protocol Deviations & Violations. Coupled with recordkeeping violations the failure to follow the protocol has been the mainstay of the Form FDA 483, Inspectional Observations, issued by FDA field investigators to clinical sites for decades. However, FDA has recently been pointing out that the root cause can just as easily be poorly designed protocols as noncompliance by a clinical investigator. In the previous post on GCP CAPA plans I note that at least two root causes that should always be investigated. This is particularly true when you find systematic protocol violations. Two areas that should always be reviewed are:

Protocol Design: Frequently you will find a Note to File in a clinical site’s regulatory binder saying that the study coordinator had been “retrained” in the importance of subject compliance. However, if subjects are routinely missing visits or protocol-required procedures you need to take a look at how well designed the protocol is. Were clinical sites consulted when the protocol was written? Is the visit schedule practical? Are the tests easily performed or do they require special efforts by research staff at a busy medical practice? And just how many protocol amendments do you have anyway? It is the clinical site that will receive an FDA 483 but the root cause very well might be found at the sponsor.

GCP Violations and protocol deviations

Protocol Violations are the Top GCP Violation at Clinical Sites

Protocol Adherence: Sometimes the clinical site is the cause of the deviation. There is a significant difference between the practice of medicine and the conduct of a clinical trial. I can’t count the times that I have been told, condescendingly, that “We’ve been doing this type of medical procedure for quite some time.” That’s all well and good but have you been reading the protocol for quite some time? A clinical trial is an experiment, and frequently requires activities that are not the usual practice of medicine. You may need to order a second blood test, or change the dose of the investigational product.

In cases like this a follow-up letter from the monitor to the clinical site might not be enough. If the root cause is the failure to understand the responsibilities of a clinical investigator then the issue may need to be escalated to someone with the letters “MD” after their name. Sometimes you need a physician to explain the protocol to another physician. Seldom does the “re-education” of support staff work as an effective corrective action.

Determining the root cause of systemic protocol deviations and violations isn’t always easy. However, if you don’t follow the investigational plan you can jeopardize your application. And remember, always investigate at least two possible causes of protocol violations.


In a recent FDA Warning Letter protocol violations are discussed at length.

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

On the Blogroll: Cancer Sucks

Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.
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SPECIAL UPDATE: 18MAR2011: FDA has released an updated version of the Compliance Program Guidance Manual 7348.810, Sponsors/Contract Research Organizations/Monitors. There are new sections on registration of clinical trials on ClinicalTrials.gov, Financial Disclosure, the Part 11 Scope & Application Guidance Document, and other issues. If you work for a sponsor, a CRO, or are a contract CRA you MUST read this document. Review Section III, Inspectional.

I am in the process of writing an analysis of this updated compliance program. Please let me know if you have questions or suggestions for points to consider. Thanks!


Clinical Trial Protocol Deviations & Violations- Part II

April 12, 2010

GCP protocol deviation and violations in clinical trials

The Dilemma of Protocol Deviations in Clinical Trials

Protocol deviations or violations are the most common FDA 483 citations by FDA during clinical trial inspections. Recently the Blog featured a guest commentary on Keeping Protocol Violations in Check, in a Guest Commentary by Judith Lynn. Now we have another GxP Perspective by Sarah Wilson, a GCP auditor I have had the chance to work with on several audits over the past few years. Sarah discusses the pitfalls when protocol deviations or violations become practice during a study. She also explains the difference between a “deviation” and a “violation.” I am putting a link to Judith’s commentary at the end of the post so you can compare GxP Perspectives between two excellent professionals.

And now, here’s Sarah:

When Protocol Deviations Become Practice During Clinical Trials
by Sarah Wilson, BS, MS, CCRP

The Food and Drug Administration and the International Conference on Harmonization (ICH) do not distinguish between “deviations” and “violations”. If you take a quick look at the FDA Inspectional Manual, the term “Protocol Deviation” is defined as “A protocol deviation/violation that is generally an unplanned excursion from the protocol that is not implemented or intended as a systematic change” The keywords in the definition should be “not implemented or intended as a systematic change”. Therefore, in this article, protocol deviation and protocol violation are synonymous.

When a clinical investigator agrees to conduct a clinical study under GCPs; he or she typically signs an agreement such as Form FDA-1572. By signing this agreement, the investigator commits to conducting the study in accordance with the approved protocol and that changes to that protocol will only be made as precedence to protect the safety, rights, or welfare of the subject (Title 21 CFR 312.53). Likewise, when the investigator agrees to conduct the study using International Conference on Harmonization (ICH) Guidelines, he or she agrees to “conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favorable opinion by the ethics committee” (ICH E6, Section 4.5.1).

clinical trial violation GCP

All Clinical Trials Will Have Deviations from the Protocol

Very seldom, if ever, will you find a clinical study without deviations. Subjects do not always return for visits during the protocol allotted time and doctors do not always enroll eligible subjects or perform all of the tests required by the approved protocol. These are all deviations from the protocol and the objective should be to ensure the deviation is not routinely repeated. When deviations occur on a routine basis, it becomes a rule – not an exception and is therefore no longer just a deviation but a “practice”.

Good Clinical Practices dictate that protocol deviations be thoroughly documented, explained and reported to the sponsor. To simply document that the deviation occurred is not enough. When possible, researchers should also document what will be done to prevent reoccurrence, a type of corrective action plan. For example, if site personnel forgot to schedule a subject’s follow-up visit or to order the investigational product in time to dispense to the subject; there should be processes implemented to prevent this from becoming a routine protocol deviation.

protocol clinical trial violation

Good Clinical Practice

Serious deviations/violations, such as failure to follow-up with a subject or an adverse event may also require a report be sent to the approving Institutional Review board (IRB). Many IRB’s tell clinical sites not to send them protocol deviations unless they affect the welfare or rights of the subjects. Documentation showing protocol deviations were reported to the sponsor and IRB (if required) should be available at the site.

Protocol deviations may also occur due to poor protocol development. A sponsor may piggy-back off another protocol and fail to remove components that was important to that particular clinical trial investigation and yet, do not apply to the current investigational therapy. In this case, the author suggests a protocol amendment is the correct course of action, however, many will not submit an amendment. Is there another acceptable means of handling this error that will undoubtedly end up as a protocol deviation?

Test Your Knowledge. Using the Case studies below, decide how you would handle the different scenarios.

Case Study 1
For a psychological study investigating a treatment for bipolar disorder, the protocol requires Dr. X to perform a physical examination that includes a rectal and genitourinary exam. These exams are not typically performed by Dr. X and he therefore, did not do the exams. Dr. X has enrolled 125 subjects and the rectal and genitourinary exam was omitted for each. Is this a protocol deviation and should it be reported to the sponsor? The IRB?

protocol violations clinical trials

Two Case Studies

The example presented in the above case study clearly demonstrates a repetitive protocol deviation. This is no longer a protocol deviation but practice. A conscience decision has been made to omit this part o the physical exam. However, in this particular example, it would not be sensible to issue an amendment to the protocol to omit the exams only because the investigator repeatedly fails to perform them. The sponsor should not use boiler-plate physical exam criteria but ensure the physical exam requested is typical for the specialty under investigation. If such an error occurs, the sponsor should consider issuing a formal document excusing the examination and IRB approval or acknowledgement should be obtained.

Case Study 2
The criteria in many protocols specify acceptable ranges for certain laboratory tests. Let us assume that for this Case Study, Inclusion Criteria require the subjects’ Body Mass Index (BMI) to be 18-35; systolic blood pressure 90-140, diastolic pressure 50-90 mmHg and vital signs taken after 3 minutes rest in supine position. The clinical investigator enrolled 8 out of 11 subjects with a BMI of 36. The clinical investigator felt the number was close enough to the target range that the subjects could be enrolled. Did these protocol deviations become practice?

clinical trial protocol violation FDA

Repeated Protocol Deviations

It would not be uncommon for the investigator to overlook the 1unit difference in the target value and enroll the subjects. However, if the Investigator enrolled several subjects outside the approved inclusion criteria, then this has now become a practice and the sponsor should consider bringing the investigator into compliance or amending the protocol to allow “investigators discretion of clinical significance”. It’s possible that the investigator knows enough about the subjects to know that they will suffer no harm by participating in the study, however, in addition to patient safety, ranges are also often created for statistical evaluations. It is imperative that sponsors and study monitors ensure data is obtained based on approved criteria for subject safety and data integrity.

In conclusion,
we accept that protocol deviations inevitably occur in nearly any given clinical trial. This means the action taken was inconsistent with the Food and Drug Administration (FDA) and Institutional Review Board (IRB) approved protocol. Sponsor and clinicians should remember that deviating from or violating a clinical trial protocol presents many opportunities for failure. Consistent deviations, in my opinion, are a blatant disregard for Good Clinical Practices (GCP) and can potentially affect the rights and safety of the subjects participating in the clinical trial. It can also jeopardize the quality and reproducibility of the research data. Routine deviations from an approved clinical trial protocol are unacceptable and mandates an amendment to that protocol or investigational plan because routine protocol deviations are no longer just a protocol deviation – it is practice.

Thanks Sarah! Check out Sarah’s Blog, “QA Talk” on the Blogroll and right here:



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).

SPECIAL UPDATE: 18MAR2011: FDA has released an updated version of the Compliance Program Guidance Manual 7348.810, Sponsors/Contract Research Organizations/Monitors. There are new sections on registration of clinical trials on ClinicalTrials.gov, Financial Disclosure, the Part 11 Scope & Application Guidance Document, and other issues. If you work for a sponsor, a CRO, or are a contract CRA you MUST read this document. Review Section III, Inspectional.

A new feature from FDAzilla on FDA 483s

Read the Press Release on 483s



Protocol Violations: Root Cause Analysis

GxP Perspectives LinkedIn Group

You can also read what Judith Lynn has to say on the subject:


Keeping Protocol Deviations in Check: Part 1

March 17, 2010

protocol deviations

Keys to FDA Compliance

Recent FDA Warning Letters have shown serious concern about protocol adherence and the number of deviations documented. I am hearing the same things from colleagues monitoring sites. My fried Chris wrote me last night, “It is unbelievable how much this is still occurring even as we speak.” A clinical research associate confided in me Monday that “They had never heard of GCP!” Clinical sites have been experiencing their own issues regarding protocols which I will discuss in future posts. The only person who seems non-plussed by this is my colleague Judith Lynn. She has been writing protocols and monitoring sites for many years and offers us some sound advice. Needless to say, she begins with some very basic sponsor responsibilities.

Guest Commentary by Judith Lynn-

Manage your study

Recent warning letters from FDA remind us of a fundamental truth about running trials: Sponsors need to manage their studies.

We might do well to consider FDA guidance as a helpful guide, not another obstacle or checkbox. A monitoring plan is a useful exercise for the study manager, to help define critical timepoints, help predict manpower requirements, and data flow. Good monitoring helps ensure reliable data. This in turn helps sponsors make better decisions, either for the next study or for a marketing application. Hiding or ignoring safety or study conduct trends only builds in problems later.

Monitor the study

• Have a communication plan, if your monitor finds something of concern, make sure there is a mechanism to escalate concerns
• Expect monitors to look not only at each subject individually, but also pay attention. Electronic data collection, and review of lab reports over time help with this

Review monitoring visit reports.

protocol deviations FDA

Regular Review of Monitor Reports

Keeping current with review of reports helps the sponsor. If you don’t have time, consider asking for help. If nothing else, for financial reasons (if there is no report, why should you have an expense report)? Issues I have found, both during study conduct or during file audit, include:

~ Reports are delinquent or missing
~ Frequency of visits does not match monitoring plan
~ Different monitor each time (this can affect the ability to track issues over time, and site’s understanding of the protocol)
~ Protocol deviations at sites, pay attention to the number and type of deviations noted

Protocol Deviations

I have recently seen exhaustive notes and lists of protocol deviations at sites. While tabulation of numerous deviations can be tedious, deviations can be an indicator of problems with a site or with the protocol.

~ Inclusion/exclusion criteria are not realistic (if too many subjects enrolled, with sponsor approval, that don’t meet criteria)
~ Site does not understand the study (Retraining?)
~ Study is complex
~ Site may not have appropriate facilities (if procedures often not done, there may be an offsite laboratory or X-ray facility that is difficult for subject to get to)

I have worked in both large and small sponsor companies. Often we have a lot to do and limited time and budget. I encourage you to make the time, and dedicate the resources to manage your study. It will pay off.

Judith Lynn, 17 March 2010

Judith Lynn is a Pharmaceutical Consultant based in Redwood City, CA. Watch for future Guest Commentaries including Protocol Deviations: Part 2 by Sarah Wilson

Protocol Violations: Root Cause Analysis

A Head’s Up for Sponsor-Investigators:

FDA has just issued a Warning Letter for GCP violations to a “sponsor-investigator” someone who both initiates a clinical trial and conducts it. In this case the Warning Letter was sent to the researcher for Sponsor responsibilities as they had passed on the investigator role to another researcher. All of the same responsibilities Judith mentions hold true for academic research and “Investigator-Initiated Research.” Read for yourself:


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Reflecting on the Trial Master File, the TMF

February 5, 2010

Post updated 28 January 2011: Just what is a trial master file or TMF? What are “Essential Documents?” How does FDA expect to see researchers document a clinical trial? Are there differences between FDA and EMA, the European Medicines Agency in TMF requirements? UPDATE: Read the Final version of the “EMA Reflections” Document on EDC, released after this post was originally published.

Reflecting on TMF

Documentation Requirements for Clinical Trials

It is interesting to note that although “TMF” is a standard industry term in the United States and is used by regulators around the world, the FDA doesn’t actually have a TMF inspection and rarely uses the term. FDA regulations are vague about the exact documents required for a clinical trial. In a response to an inquiry about documents answered by “GCP Questions,” a program within the Office of the Commissioner, FDA stated on 02 November 07:

“FDA’s regulations are intentionally pretty general, the reason for this is that the agency believes that sites and sponsors should have the necessary flexibility to adopt procedures that will comply with the regulatory requirements, and make sense (given the complexity of the study and available staff), without being unnecesarily burdensome.”

While this may be a commendable intent, it isn’t particularly helpful. I understand that regulations and guidance documents can’t be overly specific, but vague guidance on regulatory compliance leads to what I call, “regulation by rumor.” People will use an anecdote they have heard about what they think an FDA investigator wants in order to determine what documents FDA considers essential to a clinical trial. This can cause real problems between a clinical site and a monitor or auditor. There are genuine differences on how to document protocol deviations and other issues.

trial master fileThe term “trial master file” comes from the ICH E6 Guidance Document on Good Clinical Practice (E6). (Links to E6 and other documents related to this post are listed at the conclusion of the post.) Section 8 of E6 is called, “Essential Documents for the Conduct of a Clinical Trial.” In the introduction to Section 8 the Trial Master File is discussed. I consider E6 to be the authoritative document on the subject. Section 8 has a comprehensive list of Essential Documents, their location and what is necessary before, during, and after a clinical trial. When I define “TMF” I use the documents listed in Section 8 as my primary guidance. The only significant addition to this list (that I am aware of) is the FDA requirement for a Final Report, from the investigator to the sponsor. (I have an article on Final Reports at the conclusion of this post.)

TMF Trial Master File

ICH E6 Sets the Standard for Essential Documents

However, some regulatory authorities don’t seem to be emphasizing E6 as much as they may have in the past. It has been suggested that there might be additional “Essential Documents” although no regulatory agency that I know of has published a comprehensive list that could complement E6. Also, it has been suggested that there may be a “Good Clinical Practice” standard other than E6. FDA stated this when they rewrote the requirements for Foreign Clinical Studies Not Conducted Under an IND (21 CFR 312.120). Where you can find an alternative GCP isn’t discussed.

I think that E6 gives sound recommendations for GCP compliance. We should be using it more, not less. It has been published in the Federal Register as official FDA Guidance. It is the only guidance that FDA has on the TMF.

When discussing the TMF one of the trickiest issues involves electronic records, including electronic medical records (EMRs) at a hospital or medical center. There is a lot of grey area as far as protecting privacy, access to EMRs, and the validation of an institution’s EMR system. Unfortunately there isn’t a definitive guidance document on the topic of EMRs. FDA does have a guidance document on “Computerized Systems Used in Clinical Investigations.” It is found in the Important References section on your right, along with E6. Another resource that I recently became familiar with is a document from EMEA with the clever name of “Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials.” I’ve attached a PDF copy for your viewing pleasure at the bottom of the post. It contains some excellent recommendations. (Also attached is the final document released after this post was originally written. It is very similar: See “EMA Reflections”)

TMF electronic records

Electronic Medical Records

The “Reflections” document discusses Assigning Responsibility for maintaining clinical trial records. FDA regulations assign responsibility to either the sponsor or the clinical investigator. The “Reflections” document notes that the clinical site needs to maintain control over source documents and not hand over the responsibility to a sponsor. Source documents are the responsibility of the clinical investigator. This includes worksheets or standardized forms that a sponsor might prepare for a site in order to conduct the study according to the protocol. Even though the worksheets are written by the sponsor, they become the Responsibility of the Investigator. Lately FDA has taken to making this point on Warning Letters. Here’s an example from a recent FDA Warning Letter to a clinical investigator on the subject of “adequate and accurate subject case histories.”

“Your site chose to use the sponsor’s standardized forms as source documents to record and document information related to the subjects’ study visits. Per the standardized form, your site was to “Complete the Inclusion/Exclusion Criteria Worksheet to evaluate for study eligibility.” In the FDA investigator’s review of 16 of 65 subject records at your site, there was no Inclusion/Exclusion Criteria Worksheet found for any of these subjects.”

TMF FDA warning letters

Notice FDA's Wording in Warning Letters

Notice that FDA considers that the site “chose” to use the sponsor’s forms. These records are the responsibility of the clinical investigator. As such, if there is a problem with them during an FDA inspection, then the problem belongs to the clinical site. In this case, the problem was significant enough to result in a Warning Letter. Having solid documentation of a clinical baseline, including recording the Inclusion/Exclusion Criteria are Very Essential Documents. It should be noted that this clinical investigator had a lot of additional problems, not just the sponsor’s standardized forms, or worksheets.

The EMA “Reflections” document gives some good advice for clinical trial recordkeeping. They use the old FDA guidance ALCOA- Attributable, Legible, Contemporaneous, Original, and Accurate and add four additional elements. They are Complete, Consistent, Enduring, and Available When Needed. The last point is particularly important. If you can’t show the document to a regulatory inspector, then for the purposes of the inspection, it doesn’t exist. I would add one additional element; QUALITY. People sometimes place importance on fax coversheets, which are not Essential Documents, instead of the quality of the source documents that document a clinical baseline and protocol-required activities.The quality of the documents used to support an application for a new drug or medical device is sometimes overlooked, to the detriment of Good Clinical Practice. These are the documents used to protect human subjects in research and ensure data integrity. Their quality should allow them to “stand alone.”


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Updates posted 28 JAN 2011- Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

UPDATE 28 JAN 2011: There is a very interesting Important Notice to IRBs that is on the FDA website. Sort of a Coast IRB redux.

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.”


Update: Read the Final Reflections Paper from the European Medicines Agency on Electronic Data Capture:

EMA Reflections

Also: There are a couple of very good comments to this post by experienced professionals. They are well worth reading.

Here is the E6 document:

Here is the FDA guidance document on “Computerized Systems Used in Clinical Investigations.

Here are some links that will be of use in researching original data and certified copies:

Compliance Policy Guide 130.400 (equivalent to 7150.13)

Applied Clinical Trials: CDISC Clinical Research Glossary

And finally on Notes to File:


Please remember, your comments, questions, complaints, and advice are always welcome !!!

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

Announcement: The 18th and 19th of January 2011 I will be at the conference for Developing CAPAs in the GCP Environment, Arlington, VA. And Again in 2012!

2012 CAPAs in the GCP Environment

Read the updated article on the Form FDA 1572 in:

Applied Clinical Trials “Closing Thought” on FDA 1572

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Read additional posts on Good Clinical Practice- GCP:


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