Pitfalls in Good Clinical Practice
By Robert Schiff, PhD, RAC, CQA, FRAPS
A pitfall can be defined as a potential and usually unanticipated disaster or difficulty.1
When we perform clinical studies we try to anticipate unforeseen pitfalls before they arise.
However, other occurrences are clearly foreseeable, yet we permit them—or cause them—
to happen.
Good Clinical Practice (GCP) refers to international standards of quality for the performance of clinical studies with human subjects. These standards aim to ensure the data
generated are honest (data integrity), the subjects are protected and the clinical protocols
are followed.
This article is based upon years of auditing clinical study sites, CROs and sponsors
and review of FDA Warning Letters.
Consent Form Problems
Monitors routinely check study participants’ consent forms for appropriate signatures and
dates. Sometimes the study manager, such as the principal investigator (PI) or coordinator, neglects to sign the consent form at the time the subject signs and dates it. This is a
violation of GCP.
If a subject needs to undergo some type of screen, such as a blood test, before qualifying for the study, investigative sites may delay the consent process until after the results
come back. This is done to reduce the time to consent and documentation. This is unacceptable under GCP. The subject needs to sign the consent form before anything is done.
According to 21 CFR 812.100, “An investigator is responsible for ensuring that an
investigation is conducted according to the signed agreement, the investigational plan and
applicable FDA regulations, for protecting the rights, safety, and welfare of subjects under
the investigator’s care, and for the control of devices under investigation. An investigator
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is also responsible for ensuring that informed consent is obtained in accordance with part
50 of this chapter.”2 The last sentence creates a potential pitfall.
If a clinical coordinator or subinvestigator obtains consent from a subject, must the PI
review the form? GCP suggests that the PI who has not performed the consent process at
least initial and date the review. However, 21 CFR 312.603 indicates that an “investigator”
must consent the subject. ICH E6 notes that a designee of the PI can consent subjects.
According to 21 CFR 50.27 (b)(1), Documentation of Informed Consent, “A written
consent document that embodies the elements of informed consent is required by 21 CFR
50.25. This form may be read to the subject or the subject’s legally authorized representative, but, in any event, the investigator shall give either the subject or the representative
adequate opportunity to read it before it is signed”4
The key word here is “investigator.” Is it acceptable for a clinical coordinator to obtain
consent from a subject?
As defined in 21 CFR 50.3, “Investigator means an individual who actually conducts a
clinical investigation, i.e., under whose immediate direction the test article is administered
or dispensed to, or used involving, a subject, or, in the event of an investigation conducted
by a team of individuals, is the responsible leader of that team.”5 Under this strict definition, only the PI qualifies as the investigator and thus is the only person permitted to
obtain consent under 21 CFR 50.27. However in the United States it is accepted for the
subinvestigator, clinical coordinator, other designee to consent the subject.
According to ICH E6, Good Clinical Practice: Consolidated Guidance, an investigator
is “A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader
of the team and may be called the principal investigator.” The subinvestigator is ”Any individual member of the clinical trial team designated and supervised by the investigator at a
trial site to perform critical trial-related procedures and/or to make important trial-related
decisions (e.g., associates, residents, research fellows).”6
The E6 guidance, section 4.8.57 does permit the investigator, or a person designated
by the investigator, to inform or obtain consent from the subject. The designee must be
under the direct supervision of the investigator. Therefore, there must be some type of evidence that the PI, if not directly obtaining consent from subjects, confirms or verifies that
the consent process is correct and appropriate.
The next pitfall is backdating of signatures. This is falsification.
As can be surmised from the situation with delegation of consent form duties to subinvestigators or clinical coordinators, the PI simply may not have the time to “personally
conduct or supervise the described investigation(s).”8 Further, the PI may not document
the delegations.
Failure to fulfill the requirements of 312.56 can be seen in Warning Letters. These
can be found on the FDA website (http://www.accessdata.fda.gov/scripts/warningletters/
wlSearchResult.cfm?subject=Clinical%20Investigator).
Lack of active involvement in a study by the PI is a common problem. The reason is
well known. PIs are chosen not only for their ability to oversee a study but also for their
professional reputation. Thought leaders can influence sales of new products. Large
pharmaceutical and medical device companies choose these thought leaders to run their
clinical studies. It is not uncommon for PIs of this caliber to lead 10 to 20 studies at the
same time. In some cases these PIs also have a medical practice. The challenge for the
sponsor is how to ensure these busy professionals meet the requirements of 21 CFR
312.56 or 21 CFR 812 and ICH E6 for direct PI participation.
The answer lies in the qualification visit of the clinical site. Following are key questions the sponsor and or designee should ask at the visit:
• Are the investigator’s obligations understood as noted in Form FDA 1572, GCP requirements, and other country-specific and/or local regulatory guidelines?
• Does the potential PI have adequate training and experience with clinical trials and
GCPs? (Please comment on relevant study experience.)
• Does the clinical site staff have adequate training and experience to participate in this
study?
• Is the PI or staff involved in other clinical studies that may affect participation in this
study? (If yes, please comment.)
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• In how many studies is the person involved as PI?
• Do the PI and staff have sufficient time to start, conduct and complete the study?
• Does the PI plan to use subinvestigators? (If so, how many and for what activities?)
If the sponsor is concerned that the PI has too many other responsibilities, it can suggest
that the individual become a subinvestigator. The other possibility is to require a weekly
meeting, depending upon the subject accrual rate and the nature of the clinical study, of
the PI and appropriate staff that is documented with minutes. This indicates active management of the study.
I recall one particular qualifying visit at a major institution, attended by the sponsor,
representatives from FDA and another government agency and some of my staff. The
investigative staff consisted of the PI and two coordinators. We were not concerned with
parts 50 and 56 because this site was used in other studies for the sponsor. However,
they did not involve this PI. Having performed qualifying visits many times before, we did
not want to embarrass anyone. We notified the head clinical coordinator beforehand of the
questions and also enclosed parts 312 and 812 and pertinent parts of ICH E6 to reinforce the PI’s knowledge.
Apparently, none of the materials or the affiliations of the qualifiers were relayed to
the PI. When asked for how many studies he was involved as the PI, he could not answer
and had to be reminded by his coordinator: 17 studies. He also had a private practice. We
asked if subinvestigators were involved. He had not thought through how the study would
be managed, even though he had received the protocol and case report form prior to our
visit. He appeared disinterested and therefore was not recommended for the study. This
did not bode well for the sponsor because it had selected the PI and one of the government agencies was funding the study.
Protocol Violations and Deviations
The difference between violations and deviations tends to be blurry. Some sponsors
and monitors consider all deviations to be violations. There is, however, a distinction.
Violations arise from failure to follow regulations such as in the CFR. For example, failure
to report serious adverse events violates 21 CFR 312.32. The citation reads: “Unexpected
fatal or life-threatening suspected adverse reaction reports. The sponsor must also notify
FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as
possible but in no case later than seven calendar days after the sponsor’s initial receipt of
the information.”9
Another violation, specified under 21 CFR 312.66, Assurance of IRB Review, is failing
to notify the IRB when there are changes to the protocol.10
“An investigator shall assure that an IRB that complies with the requirements set
forth in part 56 will be responsible for the initial and continuing review and approval of
the proposed clinical study. The investigator shall also assure that he or she will promptly
report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that he or she will not make any changes in the
research without IRB approval, except where necessary to eliminate apparent immediate
hazards to human subjects.”
ICH E6, as noted above, is a guidance that does not have the force of law and reflects
the same requirement as 312.66 for IRB/Ethical Committee review. According to ICH E6
section 3.3.7, “Specifying that no deviations from, or changes of, the protocol should be
initiated without prior written IRB/IEC approval/favorable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when
the change(s) involves only logistical or administrative aspects of the trial (e.g., change of
monitor(s), telephone number(s)).”11
Deviations tend to be less critical and do not violate a specific regulation. For example, an “out of window” situation where a drug is given a day late is a deviation if it is not
permitted in the protocol. Usually the clinical site will request permission from the sponsor to deviate from the protocol. The sponsor then determines if the deviation can result
in a data-confounding issue. The approval or disapproval is always documented in writing.
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Data Discrepancies and Concerns
Source documents and their transcription to case record forms (CRFs) present a major
area for error. Some data can be directly transferred to an electronic system through discussion with or by the subject where there is no apparent data or audit trail. However, FDA
has made it clear that certain critical information—a subject’s status as a diabetic, for
example—must be traceable.
Some of the areas of mismatch between source documents and the CRF can be
found with adverse event notation, complete and appropriate medical history, inclusion
and exclusion criteria, listing of all concomitant medications, etc. There are times when
the PI is in need of subjects because of slow recruitment. The age of subjects may be outside the inclusion criteria. The motivation may be financial because investigators are paid
based upon number of subjects in the study.
Let’s take a look at two examples where the CRF information raises questions. The
first concerns reporting of adverse events. A study is conducted to evaluate a new contrast agent used during an MRI procedure. The subject lies flat on the carrier for the MRI
equipment and the contrast agent is administered via IV. Upon completion of the MRI
procedure, as the subject gets up from the carrier, is somewhat ataxic and dizzy and has
to be held to prevent a fall. This is certainly an event, but is it reportable? Getting up from
a reclining position under any circumstances can result in these symptoms. Although it is
reportable on the CRF, too often investigators consider this normal and do not report the
adverse event.
The second example can be found in certain international studies where the equipment may not necessarily be the most modern available. The following is cited in Barnett’s
book on Good Clinical Practice12 and has been observed by me. Review of subject data by
an auditor during the study showed all subjects had blood pressure readings in multiples
of 5 (i.e., 135/75, 125/90). There were no intermediate scores. Upon questioning, the PI
revealed that these blood pressure readings resulted from equipment limitations: blood
pressure could only be read in multiples of 5. The equipment was eventually replaced.
A pattern in the data such as blood pressure that remains the same over multiple visits or compliance of all subjects with the drug regimen is unusual and needs investigation.
Data trends can be missed when the monitors don’t visit the sites often enough or there
is a high monitor turnover.
The final topic has motivated FDA to maintain a disbarment list of investigators who
have demonstrated misconduct or fraud. This section discusses an example and how misconduct and fraud were detected.
First, misconduct does not encompass honest differences of opinion or error. Instead,
it means fabrication or falsification of data in proposing, designing, performing, recording
or reviewing research, or in reporting it. A form of misconduct can also occur because of
repeated errors and inaccuracies by employees caused by inattention to detail, lack of
training, experience or education and tolerated by management. When management knowingly permits the continuation of poor performance, for whatever reason, its deliberate
lack of action can be interpreted as misconduct.
Fraud is defined as knowingly, willfully and repeatedly submitting false information in
documents that have been (or are intended to be) submitted to the federal government.
Fraud includes backdating of documents or creating them retrospectively or just simply
making up data. This constitutes fraud. Title 18 of the United States Code 1001, Making
False Statements, and 1341, Mail Fraud, make the falsification a criminal federal offense.13
If you are a sponsor, the best way to uncover misconduct is to identify the original
source documents and look for inconsistencies in the data (times, dates, progress notes,
attendance records, etc.), handwriting, etc. There are also areas to question: uncompleted
CRFs, minimal PI involvement, understaffed and overworked staff, missing documents,
inadequate source documents, etc.
The following example shows how misconduct was discovered. On a routine monitoring visit to a clinical site in the southwestern US, we found many discrepancies. The site
had been reporting back to the managing CRO that 17 subjects had completed the study.
The monitor could not find any source documents to support 17 subjects, much less 17
completions. One subject had a completed CRF and two were listed in source documents
with no CRFs. The PI had very little involvement in the study and, prior to the arrival of the
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monitor, the coordinator was terminated for using the PI’s prescription pad illegally. When
the PI was informed of the monitoring visit, he rehired the coordinator to reconstruct the
study. Nothing was reconstructed. After a thorough investigation by the CRO, FDA was
notified and a complete file and accounting were sent to the agency. The PI received a
Warning Letter.
Conclusion
There are many potential pitfalls in the performance of clinical studies. Most errors are
sins of omission and the best way to reduce errors is through excellent monitoring and
auditing of clinical studies, assessing compliance with regulations, verifying the data,
evaluating trial conduct, determining involvement of the PI, interviewing staff and remaining vigilant to the unexpected.
References
1. Encarta Dictionary
2. 21 CFR 812.100 General Responsibilities of Investigators
3. 21 CFR 312.60 General Responsibilities of Investigators
4. 21 CFR 50.27 (b)(1) Documentation of Informed Consent
5. 21 CFR 50.3 Definitions
6. ICH E6 Good Clinical Practice: Consolidated Guidance, April 1996
7. Ibid paragraph 4.8.5, April 1996
8. 21 CFR 312.56 Review of Ongoing Investigations
9. 21 CFR 312.32 IND Safety Reporting
10. 21 CFR 312.66 Assurance of IRB Review
11. ICH E6 paragraph 3.3.7, July 2002
12. Mathieu MP. Good Clinical Practice: A Question and Answer Guide. Needham, MA: Barnett International; 2011. USC Title 18
sections 1001 and 1341, June 25, 1948
Biography
Robert Schiff, PhD, RAC, CQA, FRAPS is CEO of Schiff & Company, a regulatory affairs, compliance and clinical research organization established in 1982. He has held senior positions in Hoffmann LaRoche and Warner Lambert. Dr. Schiff has authored more
than 60 publications. He received his bachelor’s degree from the City College of New York, his master’s degree from Iowa State
University and his doctorate from the University of California at Davis. He serves on the boards of several companies, is a member of the editorial board of the Regulatory Affairs Professional Society (RAPS), a RAPS Fellow, and is listed in Marquis’ Who’s
Who in America, Who’s Who in the World, Who’s Who in the East, Who’s Who in Science & Engineering, and American Men of
Science. Dr. Schiff is a certified quality auditor. He can be reached at [email protected].
© 2012 by the Regulatory Affairs Professionals Society. All rights reserved.
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