PubH 7420 Clinical Trials: Supplemental Notes for Lectures 9 and 10
Supplemental Reading References
1. Prentice RL. Surrogate endpoints in clinical trials: definition and operational
criteria. Stat Med 8:431-440, 1989.
2. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being
misled? Annals of Int Med; 125; 605-613, 1996.
3. Sargent DJ, Wieand HS, Haller DG, et al. Disease-free survival versus survival
as a primary end point for adjuvant colon cancer studies: individual data from
20,898 patients on 18 randomized trials. J Clin Oncol 23:8664-8670, 2005.
4. Neaton JD, Wentworth DN, et al. Considerations in choice of a clinical endpoint
for AIDS clinical trials. Stat Med 13;2107-2125, 1994.
5. Neaton JD, Gray G, Zuckerman BD, Konstam MA. Key issues in endpoint
selection for heart failure trials: composite endpoints. J Card Fail 11:567-575,
2005.
6. Montori VM, et al. Validity of composite end points in clinical trials. BMJ
330:594-596, 2005.
7. Kelly PJ, LIM lly. Survival analysis for recurrent event data: an application to
childhood infectious diseases. Stat Med 19:13-33, 2000.
8. Rogers JK, et al. Analyzing recurrent hospitalizations ion heart failure: a review
of statistical methodology, with application to CHARM-Preserved. Euro J Heart
Fail 16:33-40, 2013;
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Endpoint (def) - the outcome of the study; principal criteria of response. The choice of
the endpoint defines the question under study. Sometimes the occurrence of an
endpoint leads to termination or alteration of the patient's treatment.
Primary endpoint (def.) - that event on which the sample size of the trial was based and
which is considered to be of primary importance in evaluating the treatment.
Secondary endpoint (def.) - an outcome variable used in addition to the primary
endpoint to evaluate the effect of treatment.
Co -primary endpoint (def.) - a trial with two or more primary endpoints considered
"equally" important. For example, if there are two co-primary endpoints, the design and
analysis plan may require that both endpoints achieve a specific level of significance for
the new treatment to be considered a "success" ("and" rule), or may require either
endpoint to reach a specific significance level for the treatment to be considered a
"success" ("or decision rule).
Example #1: Multiple Risk Factor Intervention Trial (MRFIT)
Primary endpoint - death from CHD after 6 years
Secondary endpoints - all cause mortality after 6 years; CHD death or
non-fatal MI after 6 years (combined endpoints)
Example #2: CPCRA TOXO Study
Primary endpoint - toxoplasmic encephalitis (TE)
Secondary endpoint - TE or death from any cause
Note: For the primary endpoint an important assumption was made -- namely, that
deaths unrelated to TE would occur at the same rate in the treatment (pyrimethamine)
and control (placebo) group.
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Most primary prophylaxis studies for specific AIDS defining infections, e.g. TE, PCP,
MAI, and CMV have chosen the primary endpoint as the development of a specific
infection and have made the rather anti-conservative assumption stated above.
Example #3: EPHESUS Trial
Co-primary endpoints - 1) all cause mortality; and 2) cardiovascular morbidity or
mortality. The new treatment (eplerenone) was considered a success if it was
superior to placebo for all-cause mortality at the 0.05 level of significance or was
superior to placebo at the 0.01 level for cardiovascular morbidity or mortality.
Most trials have multiple endpoints. Some are used to evaluate the safety and
tolerability of the treatment and some to evaluate the efficacy of the treatment. The
following are some general considerations in the choice of an endpoint:
1.
Relevance; prior experience with the endpoint
2.
Reliability of measurement
3.
Ease of measurement; cost
4.
Objective and completeness of ascertainment
5.
Assessable in all patients
6.
Rate of occurrence
7.
Stated a priori
Friedman, Furberg, and DeMets give 5 rules to follow for defining response variables:
1.
Define primary and secondary response variables in advance of the study and
write them down.
2.
The primary response variable must be capable of being assessed in all patients
and must be measured the same for all patients.
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3.
Generally, patient participation in the trial end when the primary response
variable occurs.
4.
Response variable should be capable of unbiased assessment.
5.
It is important to have response variables than can be ascertained as completely
as possible.
Pocock states 4 factors to consider related to frequency of evaluation for major
response variables (see p.49):
1.
Amount of contact required to assure effective medical care.
2.
Inconvenience to patients.
3.
Clinical center resources.
4.
Number of visits required for adequate treatment comparisons.
Other related issues:
1.
The frequency of visits should be the same if possible for each treatment group.
2.
Adequate controls should be established to assure that events are reported. This
is less of a problem if events are determined at regularly scheduled visits.
3.
The National Death Index is now used in most large clinical trials to verify that all
deaths have been ascertained.
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Combined or Composite Endpoints
In some trials the combination of different events is used as the primary endpoint. Such
endpoints are frequently referred to as combined or composite endpoints.
Examples:
1)
Coronary Primary Prevention Trial - primary endpoint was fatal or non-fatal MI.
Patients who experienced a heart attack and died later during the follow-up
period were only counted as a single event. Deaths from other causes were not
counted as endpoints.
2)
TOMHS - a combination of several cardiovascular endpoints is planned. Multiple
occurrences of endpoints will be tabulated but the primary endpoint will be based
on the first endpoint which occurs.
3)
ddI-ddC - a combination of infections and malignancies (AIDS) or all-cause
mortality is being used to define "progression of disease".
4)
ACTG 384 (study or different HAART regimens for patients with HIV) - a
"regimen termination" endpoint was used which was a combined endpoint of
virologic failure, permanent treatment discontinuation, AIDS or death, or
withdrawal from the study.
Neaton et al. in (Stat Med 13; 2107-2125, 1994) and in (J Cardiac Failure 11:567-575,
2005) discuss the advantages and disadvantages of combined endpoints and uses
progression to AIDS to illustrate some possible problems with use of combined
endpoints.
The main advantage of using a combined endpoint is that often fewer patients are
required to conduct the study. The disadvantages are that events that constitute the
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combined endpoint may differ in terms of severity and in most trials events after the first
one a patient experiences are ignored.
Currently, methods for using all the major outcomes a patient experiences during a
study to compare treatment groups is an active area of research. Some methods for
handling recurrent hospitalizations in heart failure trials are summarized in the paper by
Rogers et al. Neaton et al compare methods for summarizing multiple AIDS-defining
events in HIV treatment trials. Kelly et al summarize statistical methods for comparing
treatment for the same recurrent event and for different event types.
Surrogate Endpoints
Temple (In: Nimmo WS, Tucker GT, eds. Clinical Measurement in Drug Evaluation.
New York, John Wiley, 1995) defines a surrogate endpoint as "a laboratory
measurement or a physical sign used as a substitute for a clinically meaningful endpoint
that measures directly how a patient feels, functions, or survives. Changes induced by
a therapy on a surrogate endpoint are expected to reflect changes in a clinically
meaningful endpoint."
A surrogate endpoint in the strict sense is an endpoint for which a test of the hypothesis
of no association between the surrogate endpoint and treatment is equivalent to testing
the hypothesis of no association between the "true" endpoint and treatment. One
assumes that the only pathway whereby the treatment affects the "true" endpoint is
through the surrogate. Some examples of surrogate markers are: 1) blood pressure
change for coronary heart disease and stroke; 2) CD4+ cell count change for
progression to AIDS or death; 3) serum cholesterol change for coronary heart disease
incidence. Many investigators advocate the use of surrogate endpoints in order to carry
out trials with smaller sample sizes. Several interesting examples where we have been
misled by surrogate markers are given in the paper by Fleming and DeMets.
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To establish that a disease marker or a risk factor is a surrogate for a clinical endpoint,
one must show that: 1) the disease marker is a predictor of the clinical outcome; 2) the
treatment modifies the surrogate; and the 3) the disease marker fully captures the effect
of treatment on the clinical outcome. The 1st two criteria are met for many markers; the
3rd criterion is the most difficult to establish.
The experience of the Cardiac Arrhythmic Suppression Trial (CAST), (NEJM, 324:781788, 1991), highlights the difficulty in using intermediate or "surrogate" endpoints to
evaluate interventions. In that trial, 2 approved drugs for the treatment of arrhythmias
(encainide and flecainide) were associated with substantially higher death rates than
placebo. The drugs were approved because they had a pronounced effect on the
suppression of ventricular premature beats considered pre-cursors to arrhythmias and
sudden death.
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