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).
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.
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?
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?
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.
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:
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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.
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: