In every clinical trial there are study subjects who are very close to meeting one or more inclusion or exclusion criteria,
but for one reason or another don't.
The inclusion criterion may be:
- A screening creatinine of <2 mg/dL is required, and the subject has a creatinine value of 2.2 mg/dL.
- Subjects must be >18 years old, but the volunteer is 17 years and 10 months old.
- A screening hemoglobin of >10 mg/dL is requited, but the subject has a hemoglobin value of 9.8 mg/dL.
- Dosing is to occur within 14 days of the screening visit, but the subject is dosed on day 15.
Oftentimes, the scenario goes like this: The principal investigator identifies a subject who does not meet one or more of
the inclusion/exclusion criteria and contacts the sponsor to request a waiver. The sponsor provides the waiver. The subject
is enrolled into the clinical trial. The principal investigator notifies the Institutional Review Board (IRB)/Independent
Ethics Committee (IEC) that the sponsor has provided a waiver, and a subject who did not meet inclusion/exclusion criteria
was enrolled into the trial.
To many readers, this scenario makes sense, is appropriate, and it is what they do. The purpose of this paper is to remind
these readers that this scenario is not GCP-compliant. GCPs require the IRB/IEC to approve the enrollment of a subject, not
meeting inclusion/exclusion criteria, prior to that subject's enrollment into the trial. This article will review the regulations
and guidelines when a sponsor provides a protocol waiver to enroll a subject who does not meet one or more inclusion/exclusion
criteria; the FDA's apparent position on sponsor-provided waivers (based on warning letter references); the IRB/IEC's responsibility
regarding these waivers; and the risks to the subject, investigator, sponsor, and clinical trial when protocol-ineligible
subjects are enrolled into a clinical without the prior approval of the IRB/IEC.
Implications of protocol waivers
The principal investigator. Before the trial begins, the principal investigator signs the FDA 1572 and, typically, signs the sponsor's protocol signature
page. By signing, the principal investigator has documented his/her intention, commitment, and obligation to conduct the trial
in compliance with GCPs, the applicable regulations and guidelines, and the protocol. In the absence of a life-threatening
situation, US regulations and ICH guidelines stipulate that changes to the protocol are only permitted if the sponsor has
alerted the IRB/IEC, and the IRB/IEC has granted prior approval.
For clinical trials involving drugs:
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. (21 CFR 312.66:
Assurance of IRB Reviews)1
The investigator should not implement any deviation from, or changes of, the protocol without agreement by the sponsor and
prior review and documented approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to eliminate
an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the
trial (e.g. change of monitor(s), change of telephone number(s)." (ICH E6: Section 4.5.2)2
For clinical trials involving medical devices:
An investigator shall notify the sponsor and the reviewing IRB (see 56.108(a) (3) and (4)) of any deviation from the investigational
plan to protect the life or physical well-being of a subject in an emergency. Such notice shall be given as soon as possible,
but in no event later than five working days after the emergency occurred. Except in such an emergency, prior approval by
the sponsor is required for changes in or deviations from a plan, and if these changes or deviations may affect the scientific
soundness of the plan or the rights, safety, or welfare of human subjects, FDA and IRB in accordance with 812.35(a) also is
required. (21 CFR 812.150)3
Most protocols restate this requirement for further emphasis. A sponsor's waiver for inclusion/exclusion criteria, in the
absence of IRB/IEC approval, does not supersede the FDA 1572, the protocol signature page, the regulations or guidelines,
or GCPs. A waiver of inclusion/exclusion criteria granted by the sponsor does not grant permission to the principal investigator
to enroll ineligible subjects without prior approval by the IRB/IEC.
The clinical trial: homogeneous population. A fundamental principle of conducting multi-center clinical trials is the ability to pool data from various clinical settings,
allowing the sponsor to draw statistical and clinical conclusions based on the patient population defined by the entry criteria.
This principle is only valid, however, if another fundamental principle of GCPs occurs. The protocol must be conducted in
the same way at each multi-center site; a homogeneous patient population (based on criteria defined in the protocol) is treated
and followed the same way (per protocol).
The ability to pool data is compromised if individual sites follow a different treatment regimen: treating subjects with a
different dose, or enrolling subjects who are different from the proscribed and IRB/IEC-approved inclusion/exclusion criteria.
The validity of statistical and clinical conclusions regarding safety and efficacy rests on the premise that a defined patient
population was treated with the study drug and followed the evaluation schedule.
The study subjects. The trial cannot begin without documented approval for the protocol by the IRB or IEC. Per this approval, the IRB/IEC has
reviewed the risk/benefit profile of the protocol, and has granted approval for the trial to begin based on this assessment
and for a particular patient population (described by the inclusion/exclusion criteria). Enrolling a subject who does not
meet the IRB-approved inclusion/exclusion criteria is putting the prospective patient at risk; the subject is different from
the IRB/IEC-approved patient population meant to be eligible for enrollment. The informed consent form may not accurately
reflect the risks/benefits for the subject, since the consent form was designed (by the sponsor) and approved (by the IRB/IEC)
for the patient population described by the protocol's inclusion/exclusion criteria.
The sponsor. When the study is complete, the sponsor will need to justify and explain why ineligible subjects were enrolled into the trial.
If many subjects were enrolled who did not meet inclusion/exclusion criteria (and who did not receive IRB/IEC approval prior
to enrollment), the FDA (or another regulatory agency) may conclude that the intended population was not treated, as designed.
Once the data is submitted to the regulatory agency, the regulatory authority reviewing the data can request the data set
be re-run to exclude the ineligible subjects from the efficacy tabulations and conclusions; after all, those patients were
not intended to be treated in the protocol. The exclusion of even small numbers of subjects from this data set may have devastating
effects on the trial, and may even result in the trial being conducted again because the loss of these subjects has reduced
the statistical power of the trial. Sponsors should be aware that each protocol waiver for inclusion/exclusion criteria might
result in the data for that subject being used only for safety evaluations and conclusions, and excluded for efficacy evaluations and conclusions.
Also, when the trial is complete and the data submitted, the enrollment of a large number of ineligible subjects might confound
the conclusions of the trial and negatively affect the efficacy claims and the label text. Sensitivity analyses, for example,
may reveal that outcome measures are different for subjects receiving waivers than those not receiving waivers, putting the
results at risk. The regulatory agency may conclude that the data are unreliable and reject the trial.