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New FDA Draft Guidance Document

FDA’s new draft Guidance for Industry: Oversight of Clinical Investigations — A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Two weeks ago GxP Perspectives published a Guest Commentary by Lorraine Ellis on the new draft guidance. This Guest Commentary by Judith Lynn, continues the discussion about the new draft guidance.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I reviewed the Recent Draft Guidance From FDA- A Risk-Based Approach To Monitoring with several information points in mind: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 I found that much of the draft guidance centers on managing your study, having a sampling plan, and ensuring quality.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 Note the point in the draft guidance under section IV/ C, Factors to consider when developing a monitoring plan: that “a population that is seriously ill and/or vulnerable may require more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

May 10, 2011

FDA Warning Letter

One of the Many Exhibitors at the
ACRP Conference

FDA Warning Letters, and some thoughts on critical and creative thinking, conclude my reporting from the Global Conference for ACRP – the Association of Clinical Research Professionals – held last week at the Washington State Convention Center in Seattle. During the conference it became apparent that many people, including FDA employees, have a difficult time searching for Warning Letters on FDA’s website. The Warning Letter section is an absolute mess. So I thought I would provide a few simple search tips to help find Warning Letters for GCPs. Unfortunately cGMP Warning Letters are more difficult, but the tips still help. Then I would like to tell you about an interesting session I attended on critical and creative thinking.

When searching for FDA Warning Letters, the link is below, scroll down and choose to “Browse Warning Letters by SUBJECT.” You will be presented with the alphabet. Click on “C” and then scroll down past all the “cGMP” categories until you reach “Clinical Investigator” where you will find the majority of GCP Warning Letters.

FDA Warning Letters

Searching for FDA Warning Letters

They will be listed in alphabetical order. There is a “Sort by:” option. Choose “Letter issued DESC” from the drop down menu. You will then have most of the GCP Warning Letters with the most recent listed first. You can also choose as subjects: Clinical Investigator – Sponsor; Bioresearch Monitoring; IRBs; Sponsor Obligations; and “IDE….” for medical device Warning Letters. There are several ways of listing for each category. You can sort by “Letter Issued DESC” for each category. There are five GLP categories plus Good Laboratory Practices. Go figure.

FDA Warning Letters

There were a number of interesting sessions that I attended at the ACRP meeting. I wanted to tell you about Critical Thinking in a Regulated Environment, because it can be so darn difficult. Kirk Mousley described critical thinking as producing ideas and then evaluating ideas. Citing Iris Verdi he described creative thinking as original, imaginative, and uncommon. He discussed that creative thinking comes through different avenues: it is often a revisement of something that already exists (evolution); a combination of two or more ideas (synthesis); or just a different way of looking at things, asking yourself, “how else can I look at this?”

FDA Warning Letters

How Can I Look at This Differently?

Mousley also discussed the barriers to creative thinking including “not part of an approved process” (SOPs). He noted that the regulatory process itself discourages critical thinking by imposing a “process mentality.” He countered that by suggesting that you build into a process the encouragement of critical thinking. And he pointed out the myth that “every problem can only have one solution or one right answer.” One of the points that I emphasize when doing a root cause analysis of a problem identified during a CAPA process is that you should Always Look for More Than One Root Cause.


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: The FDA Lawyers Blog discusses a variety of interesting issues including bioequivalence data, litigation tactics, and Victory for Embryonic Stem Cell Researchers.

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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.
Please join GxP Perspectives on LinkedIn at:

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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!


FDA Inspections: How Long Should They Take?

May 30, 2010

how long FDA inspection

How long should an FDA Inspection take?

How long will an FDA inspection take? Three days? Three weeks? Three months? Are there any rules? The most recent FDA Warning Letter to a clinical site was released last week and it was for some rather typical violations. Failure to obtain informed consent. Enrolling subjects who met exclusion criteria. Failure to report concomitant medications. These violations were compounded by the fact the clinical investigator failed to adequately answer the Form FDA 483, Inspectional Observations. They had not specified how they were going to meet proposed corrective and preventative actions (CAPA). None of these issues really caught my attention. The Warning Letter, issued by the Center for Devices and Radiological Health, seemed entirely appropriate.

What leaped out at me, however, was the fact that the inspection had taken place over two and a half months. The inspection began September 14, 2009 and was completed on December 2nd. The Warning Letter was not that lenthy or complex. Why did it take such a long time? FDA primarily regulates clinical trials at the clinical sites. Unlike a pharmaceutical or medical device company, not all clinical sites are equipped to host an FDA inspection over a ten week period. Although some clinical sites are for-profit clinical research centers, others are busy medical clinics with limited resources to handle a ten week inspection. Is this imposing an unnecessary regulatory burden on clinical sites? Two and a half months hosting an FDA inspection can cost a Lot of time, money and resources.

How long should FDA Inspections take

What are Reasonable Hours for Inspection?

I have recently heard anecdotal evidence of one recent FDA inspection taking place over a six week period at a busy medical practice. the FDA field investigator was not at the site half of the time during the inspection while performing other duties. That can be difficult to arrange staff to assist the inspection. Another inspection lasted until 9:00 pm, a good 4 hours after the clinic’s business hours were over. Is that “at reasonable times” as specified by 21 CFR 312.68?

length of FDA inspections, how long?

Should There be Timeframes for Warning Letters?

Another item of interest is the length of time between the end of the inspection and the issuance of the Warning Letter. I worked on a temporary assignment at FDA headquarters in 2004. Then, there were strict timeframes when a Warning letter needed to be issued after the conclusion of an inspection. That evidently is no longer the case. For example, the Division of Scientific Investigations issued a Warning Letter on February 24, 2010 for a 3-day inspection that concluded on March 27, 2009. That’s almost a year. And it is hardly the only example. Is this an appropriate policy? Planning for an FDA inspection isn’t easy. knowing the approximate length might be helpful for smaller clinics.

You can read about FDA Warning Letters to clinical investigators on FDA’s Website. You can search by subject for “Clinical Investigators” for inspections assigned by the Center for Drugs and under “Investigational Device Exemptions (Clinical Investigators) for medical devices.


On the Blogroll: FDA Matters discusses The Hamburg Legacy in consideration of one year as FDA Commissioner for Dr. Margaret Hamburg.

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FDA Warns Pfizer After Children Receive Overdoses in Clinical Trial

April 20, 2010

FDA Pfizer Warning Letter

FDA Warns Pfizer

FDA took on the largest pharmaceutical company in the world, Pfizer, after FDA documented that as many as 13 children were overdosed with the drug Geodon, being studied to treat bipolar disorder. In a one month inspection an FDA field investigator, accompanied by a physician from the Center for Drugs, Division of Scientific Investigations (DSI), reviewed Pfizer’s conduct. It took FDA 11 months to write the Warning Letter, dated April 13, a delay that would not have been permitted a few years ago. However, in the past three years FDA has cited three of the largest pharmaceutical companies for failures as a sponsor of clinical trials.

All three were cited for the failure to monitor the progress of the investigation, an activity that is more likely than not contracted out to CROs- Contract Research Organizations. The other two large sponsors, Sanofi-Aventis and Johnson & Johnson, used CROs to monitor their studies. It is not clear from the Warning Letter if Pfizer used a CRO for the audited studies. There were other dosing errors of concern to FDA in the Warning Letter. Pfizer was also cited for informed consent issues and failure to have cardiologists available to read safety ECGs.

FDA had this to say about Pfizer’s conduct on monitoring:

FDA regulations require that sponsors ensure proper monitoring of clinical investigations. Our investigation found that Pfizer failed to properly ensure monitoring of the study referenced above. As a result of inadequate monitoring, widespread overdosing of study subjects at multiple study sites was neither detected nor corrected in timely manner.”

Pfizer responded to FDA as reported by the Associated Press, in an article by Matthew Perrone.

Pfizer Warning Letter

Pfizer Responds

Pfizer spokeswoman Kristen Neese said many of the problems cited by the FDA were first pointed out by the company itself more than four years ago.

‘Pfizer has communicated with the FDA about our conduct of clinical trials and, over the next two weeks, will provide an outline of new and existing processes for preventing similar issues with Pfizer clinical trials,’ Neese said in a statement.”

It is important to note that FDA had cited Pfizer in the past regarding the failure to monitor clinical trials. Repeat violations are more likely to result in an enforcement action. However, all three of these sponsor Warning Letters indicate that if something goes wrong at a clinical site, such as overdosing children, then the sponsor will be held responsible.

In Pfizer’s defense, it should be noted that Pfizer is the organization that caught the overdosing. The Warning Letter cites Pfizer for not determining that the subjects received incorrect dosages of study drug through their monitoring of the site. However, Pfizer data managers determined the overdose occurred. It seems that Pfizer may have been “monitoring the progress of the investigation” in more than one way, through monitoring visits AND through review of the data by their data management department. It seems harsh to me to cite a sponsor for violations that the sponsor found themselves. Something to think about.

This is the first Warning Letter that Pfizer has received for clinical or other research. They have received Warning Letters in the past for labeling or promotional claims, most recently in 2008.

Read the Warning Letter here:



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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

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


GCP Training on Informed Consent: The Basics for Compliance

March 29, 2010

GCP Informed Consent Training

Informed Consent: Protecting Participants in Clinical Trials

The most serious GCP compliance concerns in a clinical trial are frequently regarding informed consent. FDA recently issued several Warning Letters about clinical sites failing to appropriately consent a clinical trial participant. Training that informed consent is a Process and not just a form to fill out is essential to a quality clinical trial. FDA looks closely at the Qualifications of research staff obtaining informed consent. In this guest commentary Mikki O’Neal discusses the importance of informed consent training from the perspective of a clinical site.

Guest Commentary:

By Mikki O’Neal, CCRP, CCRC
Regulatory Compliance Manager
Houston, Texas

Informed Consent Training: A Site Perspective

Lack of {adequate} training frequently seems to be a standard hot topic in research circles. What constitutes solid training? By what measures should a researcher be deemed qualified to obtain informed consent? While I feel that online training modules provide a good basic foundation, institutions are often relying on them as the sole requirement to satisfy the training process of a researcher. I like to refer to this as theory-based training. While online modules and classroom training do give a researcher a good grasp of how research evolved into what it is today, what is often missing from these training methods is application training. How do you take what you have learned in a module and apply it to every day research activity? Informed consent training is a perfect example. You can speak about informed consent theory until you are blue in the face, but until a researcher is able to see an actual consent process applied, how can they truly grasp the relevance of “it’s all in the details”? This is one of the first steps that foster the communication gap between a poor consenter and a well informed research subject.

More and more you see non-research clinical staff being burdened with the additional responsibility of consenting a subject for a trial while they are performing their basic job functions. Not only does it add extra responsibility to their plate, but obtaining proper research informed consent is typically not even a topic that gets entertained because they don’t understand the reasons, importance, or implications.

GCP Training

GCP Training for Informed Consent Compliance

What is more surprising is that very often these observations occur with “experienced” research personnel, which begs to question the methods in which they were trained. One of the largest mistakes that I think a site manager can make is to hire a researcher based on experience listed on paper and then assume that because of said experience, training will not have to occur (or that very minimal training will suffice). Taking it “back to the basics”, in my opinion, is a critical factor with this topic. It is very easy to start cutting corners and minimizing the importance of a true informed consent process when a study seems simple or the researcher is rushed.

Food for thought: Should researchers be required to demonstrate informed consent ability with an annual practical assessment? Would it be beneficial for sites to implement random “audit” shadowing of researchers during an informed consent process? Is there a “one size fits all” solution to solving informed consent issues? A vital piece of the puzzle is oversight. Know what is going on at your site. Assess the capability of your research personnel. Standardize your training so that all personnel are trained in the same manner regardless of experience. Require continued education. And most of all, never assume that someone is adequately trained just because they have worked in the field of research for an extended amount of time.

Please read other Guest Commentary on the page at the top of the Blog.

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.”


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