1. Inclusion and Exclusion Criteria (Defining the Study Population)
General considerations
Run-in periods (enrichment)
Regression toward the mean

2. Some Issues in Selecting Patients for Clinical Trials
Broad or narrow criteria
Recruitment and patient logs
Nature of clinical sites (patient to research or research to patients)

3. Relationship of Study Sample to Study Population and Population at Large
Population without Condition
Definition of Condition
Population with Condition
With Condition but Ineligible
Entry Criteria
Study Population
Eligible but not Enrolled
Enrollment
Study Sample
Source: Friedman, Furberg and DeMets.

4. Internal and External Validity
Internal validity – can you attribute the differences among treatment groups to the treatments studied
Randomization
Blinding
Sample size
Random and systematic errors minimized
External validity – can you generalize the results to patients outside the trial (the same or larger target population); to whom to the results apply?
Inclusion criteria
Characteristics of those randomized
Setting of trial
Outcomes assessed and duration of follow-up

5. The Study Population is Defined by Inclusion and Exclusion Criteria
Eligibility Criteria:
Should be defined in advance
No exceptions should be made unless a priori stated
Characterize population (e.g., labeling indication for a new drug/device)
Impact of results (assessment by others)
Replication of study

6. Considerations in Developing Eligibility Criteria
1. Enroll patients who have potential to benefit from intervention
2. Enroll patients for whom there is a high probability of detecting results of intervention
3. Do not enroll patients to whom intervention is potentially harmful
4. Do not enroll patients at high risk of conditions which preclude ascertainment of endpoints
5. Do not enroll patients who cannot comply with protocol
Friedman, Furberg, DeMets: Fundamentals of Clinical Trials, Chapter 4

7. Selection of Patients for a Trial
Yusuf et al., Stat Med, 9:73-86, 1990.
Drug clearly indicated based on current knowledge Exclude
Drug effect unknown:
But likely to be beneficial to certain patients Include*
And outcome uncertain in certain patients ? Include
But theoretical possibility of harm or little hope ?? Include* of benefit
Special exclusions (competing risk, poor Exclude compliance, inability to ascertain endpoint)
Drug contraindicated based on current knowledge Exclude
* Include such patients with explicit prior statement of a subgroup hypothesis

8. Advantages and Disadvantages of Opposing Selection Strategies
Highly restrictive selection criteria
Advantages
Provides more precise comparison of the test and control treatments
Results of the trial less likely to be affected by population variability
Disadvantages
Increases the cost and time required for patient recruitment
Limits the generalizability of the study findings
Minimally restrictive selection criteria
Makes patient recruitment easier
Provides base for wider generalization of findings
May obscure treatment effects because of variability in composition of study population
Results of the trial may be confusing, especially if an observed effect appears to be associated with a subgroup of patients in the study and the subgroup is too small to yield a reliable treatment comparison
Meinert C., Clinical Trials. Design, Conduct and Analysis.

9. Usually Favor Minimal Restrictions for Large Outcome Trials
A priori, often not clear who will do best
Rare that there are large subgroup differences of a qualitative nature
Faster answer to question
With few restrictions, risk stratification after the trial is completed can be performed (more information to formulate treatment guidelines; cannot assess consistency of results in a subgroup if they were excluded)

10. Does it Work? “Practical Clinical Trials: Increasing the Value of Clinical Research for Decision Making in Clinical and Health Policy”
Treatments that mimic use in practice
Diverse patient population; minimal exclusions
Many clinical sites; heterogeneous practice settings
Multiple, easily ascertained, clinically relevant endpoints
Tunis SR et al, JAMA Center for Medicare and Medicaid Services and Agency for Healthcare Research and Quality

11. Explanatory and Pragmatic Trials
Explanatory (“laboratory” conditions)
Strict selection criteria aimed at creating a homogenous patient population
Pragmatic (“normal” conditions)
Heterogeneous patient population, one where might expect more non-adherence
Schwartz & Lellouch J Chronic Dis 1967)

12. Recruitment Considerations
Always more difficult than anticipated (need a backup plan to the backup plan)
Easier with broad eligibility criteria (e.g., large simple trials)
Yield not 100%
Eligibility criteria (age, prior history, prior treatment, etc.)
Exclusion criteria
Physician refusal
Patient refusal
MRFIT screened 361,662 men to identify 12,866
Must closely monitor to ensure target is met

13. Patient Logs Should You Count Those Not Included?
Possible Advantages
May provide insights on how to improve slow enrollment
May allow more reasonable recommendations concerning findings – generalizability
Allows an assessment of how many eligible patients are being enrolled
Disadvantages
Time-consuming
Often uncertain where the counting starts
Issue of generalizability usually cannot be addressed with logs alone

15. Randomized Trial of Extracranial-Intracranial Arterial Bypass
Patients Undergoing Randomization versus Patients Operated on Outside of the Trial in 57 of 71 Participating Centers
No. of
Centers
Surveyed/Total
Randomized
to Medical
Treatment
Operated
on Outside
the Trial
Randomized
to Surgery
Location
no. of patients
United States 30/
Europe 15/
Japan 12/
Canada 5 * ?
TOTAL
* These centers were not surveyed; randomization was assumed to have been complete.
Sundt, TM. N Eng J Med 316:814-16, 1987.

16. MRFIT Recruitment 22 centers (specially funded to carry out the study)
Sources of 12,866 participants (no. centers using source)
Census tract listings (door-to-door) (3)
Industry/government (15)
HMOs (2)
Union lists (10)
Churches (7)
Shopping centers (10)
Civic clubs (8)
Other (14)

17. ESPRIT HIV – IL-2 ELITE II CHF – Losartan
243 clinical sites
25 countries
4,150 patients
288 sites
45 countries
3,152 patients
Some trials require many sites and different types of sites

18. Advantages of Multi-Center Trials
SAMPLE SIZE!
Faster enrollment and therefore faster answer to the research question
External validity (generalizability)
diversity of patients
convenience to patients
diversity of clinical sites
Credibility (each site is a replicate)
More clinicians involved in research
3rd, as a consequence of exciting advances in the basic sciences, there is a growing pool of clinical research questions. This is one of the reasons why the Director of NIH wants to reengineer the clinical research enterprise. With our current system we have not been keeping pace; it is only going to get worse.
4th, unfortunately public confidence in biomedical research is not high. With the exception of a few diseases, like breast cancer and HIV, we have not done a good job of engaging the community in the research process. Instead, the community reads about fraud, about commercial interests, and unsafe treatments.
5th, we have tp figure out a way to do trials cheaper. We need to minimize what I call unnecessary defensive documentation and ancillary data. The “what if” game. You must have witnessed that. We need to collect this because what if this happened?.

20. Run-in Periods Def. A period before randomization in which patients are given a treatment (active or placebo) to establish eligibility.
Run-ins involve compromises between internal and external validity and are often considered for reasons of efficiency.
Pablo-Mendez A, JAMA 1998

21. Rationale for Run-In Periods
May be active or placebo; generally considered when:
1. Expected compliance is low;
2. Substantial behavior change is required (SNaP);
3. Contact with participants is infrequent (Physician’s Health Study);
4. Possibility of side effects to experimental treatment;
5. A large number of “placebo responders” are expected (e.g., pain study);
6. It is necessary to assure disease status is stable (or washout);
7. Efficacy of treatment on intermediate response variables is required, thereby enhancing clinical applicability (CAST).

22. ITT and Run-Ins
If the primary interest (primary estimand) is the difference in outcome between treatment and control groups among patients who can tolerate the treatment, it is better to use a run-in period and ITT analysis than to try and estimate this estimand using only the patients who tolerated the treatment after randomization.

23. Run-In Periods in Trials - Examples
To enhance clinical applicability (CAST)
To screen for placebo response (pindolol + fluoxetine versus placebo + fluoxetine for depression)
To assess tolerability of active treatment (carvedilol for the treatment of heart failure)
To screen for non-adherence (Physician’s Health Study used carotene placebo and open-label aspirin during run-in)
All have the potential to increase power or reduce sample size requirements

24. Potential Problems with Run-In Periods
Carryover effects
Blinding jeopardized
Interpretation of results have to be qualified
Strategy for enrichment wrong
Leber PD and Davis CS, Cont Clin Trials 1998

25. Enrichment Designs
Enrichment designs refers to studies that aim to increase power by choosing patients that are more likely to show benefit than a broader population (personalized medicine).
In heart failure and hypertension – initial studies were in more advance patients
Active run-in periods (e.g. CAST) or randomized withdrawal studies
Biomarkers and genetic traits that predict response (e.g., expression of HER-2 in tumors in women with metastatic breast cancer)
Temple R, Commun Statist Theory Meth, 1994

26. An Example of Enrichment That Backfired
Tacrine for the treatment of Alzheimer’s disease (N Engl J Med 1992;327: )
Patients first randomized to 2 doses of tacrine (10 or 20 mg four times a day) or placebo (titration or enrichment phase) for 6 weeks (crossover).
Following 2 week placebo washout period, responders in first phase randomized to their best dose or placebo for 6 weeks (parallel group).
This was followed by an active treatment phase (uncontrolled).
Concerns: Carryover effects, withdrawal effects, maintenance of blind, and generalizability
See also Leber and Davis, Cont Clin Trials, 1998 and Encyclopedia of Biopharmaceutical Statistics

27. Factors Influencing Efficiency of Targeted Therapy (Enrichment) Design
Heterogeneity of effect across subgroups (e.g., test positive patients expected to do much better than test-negative patients)
Prevalence of factor describing responder group
Sensitivity and specificity of test to define the responders
There is often uncertainty. Thus, may first have to determine efficacy of
treatment in both test-positive and test negative patients.
Maitournam and Simon, Stat Med 2005

28. Summary
In most trials eligibility requirements are too restrictive (an opinion)
Arguments concerning logs versus no logs arise because of restrictions
Trial entry procedures are simplified with broad inclusion criteria
Study design teams should carefully consider reasons for exclusion
Exemptions should not be granted
We need to determine way of efficiently involving more clinicians in the community in research
There are advantages and disadvantages to run-ins and enrichment designs. The latter are being actively pursued as part of a “personalized medicine” research agenda.