Improving Inclusion/Exclusion Criteria

in Clinical Trials

Jack

Mod

ell,

MD,

Sen

ior

Med

ical

Offi

cer • Dr. Modell is a board-certified psychiatrist with 30 years of

experience in clinical research, teaching, and patient care including 10 years of experience in clinical drug development (phases 2 through 4), medical affairs, successful NDA filings, medical governance, drug safety, compliance, and management in the pharmaceutical industry.

• He has authored over 50 peer-reviewed publications in addiction medicine, anesthesiology, psychiatry, neurology, and nuclear medicine. Dr. Modell is a key opinion leader in the neurosciences, has served on numerous advisory and editorial boards, and is nationally known for leading the first successful development of preventative pharmacotherapy for the depressive episodes of seasonal affective disorder.

Purpose• To provide recommendations to clinical teams

on the approach to formulating inclusion and exclusion criteria in clinical trials: – to enhance the quality of subject selection– to simplify and expedite the enrolment process– to minimize protocol violations and amendments

to protocols

General PrinciplesInclusion/exclusion criteria define the study population to which results of the clinical trial can reasonably be generalized.• Population may or may not be a good

representation of the entire population with the disease or condition of concern.

Deviations from inclusion/exclusion criteria (“waivers”) are not allowed because they potentially jeopardize the scientific integrity of the study, regulatory acceptability, and subject safety.• Therefore, adherence to the criteria as

specified in the protocol is essential.

General Principles (2)• Inclusion criteria contain only those items that

define the target population desired for study.– Within limits of known safety coverage, should

generally allow inclusion of the broadest representation of the population for intended use, but usually not beyond.

– For each and every inclusion criterion written, the study team should have justification for why that criterion, exactly as written, is necessary to define the desired study population.

General Principles (3)• Exclusion criteria shape the desired,

“included” population by defining which subsets need to be excluded for other reasons, such as safety.– For every exclusion criterion written, the study team

should have justification for why that criterion, exactly as written, is necessary to prevent subjects, in some cases who may otherwise be qualified, from participating in the study.

General Principles (4)• Inclusion and exclusion criteria need to be

written as clearly and unambiguously as possible.– There should also be considerable forethought

into the• necessity, • desirability, & • potential unintended consequences

of each criterion and any associated parameters.

General Principles (5)

• Care should be taken to write the fewest number of inclusion and exclusion criteria sufficient to describe the population to be studied.– Duplicative, overlapping, and potentially

contradictory criteria should be avoided.Challenge yourself to determine whether all of the

inclusion criteria are truly required to define the target population, and all of the exclusion criteria are truly required for safety or other limitations to the target population.

General Principles (6)Inclusion/exclusion criteria should not be copied indiscriminately from one protocol to the next. • Criteria should be selected anew for

each protocol, though previously written criteria can be used for reference.

The same applies to labs & other clinical exams.• “I have no idea how to interpret it or

why it’s there – Oh, wait, it was in the last protocol we did!”

General Principles (7)• Think about inclusion/exclusion criteria in

terms of where you want to draw the line between sensitivity and the “false positive exclusion” rate;– there is usually a reciprocal relationship between

the two.

Falsepositive

rate

Detection sensitivity

Example: No hypertensive subjects please!• Approach #1: Exclude all subjects with a

systolic blood pressure > 120 mmHg– This will likely exclude nearly all subjects with at

least moderate hypertension. • The criterion provides extremely high sensitivity for

detecting hypertension.– It will also inappropriately exclude a very high

percentage of subjects who do not have hypertension.

No hypertensive subjects please (but don’t falsely exclude any subjects either)• Approach #2: Exclude all subjects with a

systolic pressure of > 180 mmHg– A small proportion of all patients with

hypertension would be excluded. • The criterion provides extremely low sensitivity for

detecting hypertension.– But no non-hypertensive subjects would be

excluded

No hypertensive subjects please! (3)• No matter where a criterion is set, there will

be a trade-off between subjects who are unnecessarily excluded and those who probably should be excluded but do not meet the specified criterion.– It is up to the study team to consider this for each

criterion selected and to decide how best to optimize this inherent trade off. there is no absolute or perfect solution to this problem.

Investigator EducationStudy teams should be diligent in reviewing I/E criteria with investigators to help ensure that:

• the protocol-specified details are completely understood • investigators understand that inclusion and exclusion criteria must

not be violated

To aid in understanding the I/E criteria, explanatory footnotes in the protocol should be considered for any criteria for which the rationale may not be evident

Phase of Development• Early in development when limited safety

information is known, more conservative inclusion/exclusion criteria may be needed to ensure patient safety.

• Once the safety profile begins to be established, less restrictive criteria can usually be applied. – Allows broader inclusion of patients into late-stage trials,

which provides more “real-world use” safety profile. – Helps define appropriate labeling for this target

population.

Target Population & Individual Subject Characteristics• Generally healthy subjects can have physiologic or

laboratory values outside of the defined “normal range,” yet still be very healthy;– for example an athlete or runner with a resting heart rate

of 45.

• Yet in a cardiac patient, bradycardia often signals significant underlying pathology or drug effect. – The study team (and protocol) need to be able to

differentiate between normal physiology that may produce a testing abnormality and a truly pathologic condition.

Disease Area• Exclusionary values/ranges need to be adapted to

the population under study – In some diseases, lab values that would be considered

abnormal in healthy populations may be acceptable, such as low hemoglobin in patients with chronic disease; or rapid heart rate & hypertension in anxiety.

– If there is intent to exclude a specific medical problem, for example, serious cardiac arrhythmia, the exclusion criterion needs to refer specifically to the excluded rhythm

– and not, in the case of this example, to something more general like “cardiac arrhythmia,” which could include several benign rhythm disturbances.

Demographics and “Standard I/E Criteria”• Conventional demographics or labs such as age, BMI,

renal function, etc. should not be routinely included in I/E criteria without any consideration. – Do you actually need BMI, age, or the specific laboratory

criteria? If so, for what reasons?– Could the criteria instead be written with regard to co-

morbid conditions; e.g., a healthy 80 year-old versus a 50 year-old in poor condition?

– Can a more general criterion be used e.g. “no major illness or debility that in the investigator’s opinion is likely to jeopardize subject safety or interfere with the subject’s ability to comply with study requirements”

– but…

Flexible vs. Fixed Inclusion/Exclusion Criteria

– The use of more flexible criteria requires strong assurance that these decisions can and will be properly made, and that variability or errors in investigator judgment are not likely to skew the intended population or jeopardize patient safety.

“…that these decisions can and will be properly made…”

“I’m a psychiatrist: how was I to know the subject had pneumonia?”

“I knew his liver enzymes were elevated but I’ve seen much worse and he really wanted to be in the study.”“The rating forms didn’t show it, but in my clinical opinion he had it, so I put him in the study.”“It said, ‘no current major medical illnesses,’ and her colon resection [for cancer] was seven months ago.”

“Beta thalassemia is a major illness?”

Actual quotes from investigators

Fixed Exclusion Criteria• It is also permissible, and often desirable, to use fixed

(“rigid”) exclusion criteria, e.g., “serum Na < 130 or > 150”; “systolic BP < 60 or > 160”

• If there is clinical justification for why it is desirable to exclude these subjects and the values chosen are intended to be unequivocal.– The advantage: It sets absolute standards for subject

participation that are not open for opinion or debate. – The disadvantage: If the criteria are too stringent, they

may unnecessarily exclude some subjects who are not at a particular risk that the criteria are intended to prevent.

Studies of Long Duration• Many studies are now requiring data

collection over many years.• Since guidelines and prescribing information

change over time, this should be taken into account by using wording such as, “contraindications as per the prescribing information,” to allow label and guideline changes to be incorporated without modifications to the protocol.

Regulatory & Ethical Considerations• In later stage development, I/E criteria may have

regulatory implications. – The population under study may affect product labeling;

this needs to be considered carefully. – Regardless of potential labeling considerations, I/E criteria

are always written to optimize the benefit-risk for patients.• Prospective subjects should never be “groomed” to

meet I/E criteria for the primary purpose of study participation prior to obtaining informed consent.

Operational Issues• Subjects are sometimes inappropriately

randomized before investigators receive all information relevant to I/E criteria, often due to delayed lab results.

• Check-steps should be considered in the programming of the randomization such that randomization cannot occur until all I/E criteria have been entered and noted to be consistent with protocol specifications.

Discussion• Using no more than four inclusion and six

exclusion criteria*, define a study population for late phase II testing of: – a drug for depression (n = 150 per arm), – which in a healthy volunteer study was well

tolerated,– and although prolonged QTc interval was observed

in 4 of 30 on drug compared to 2 of 30 on placebo (p ≈ .7), no dysrhythmias were observed

*A table of lab values – if you’d like to use one – can count as one criterion; just have a few examples of any values you think might be particularly important.

SummaryInclusion/Exclusion Criteria:

define the study population to which results of the clinical trial can be generalized – waivers not appropriate

need to be written clearly and unambiguously, with consideration of “unintended consequences”

must be highly study specific; avoid “copying” establish the line between sensitivity and “false positive

exclusion” rate that are “flexible” often lead to “flexible populations” and

“flexible results” may have regulatory implications must always written to optimize the benefit-risk for

patients