Sequential multiple assignment randomized trials (SMART) (Lavori and Dawson, 2000
, 2003; Ten Have et al., 2003
; Murphy, 2005
) are intended to be used in the building and refinement of adaptive treatment strategies. In these trials, subjects are randomized multiple times. A number of SMART trials have been, or are being, conducted. These include the CATIE trial for antipsychotic medications in patients with Alzheimer's (Schneider et al., 2001
), STAR*D for treatment of depression (Rush et al., 2003
; Lavori et al., 2001
) and phase II trials at MD Anderson for treating cancer (Thall et al., 2000
In order to make the discussion of the SMART trial design concrete, consider the following simple example modeled after a SMART trial, which includes a number of the interventions described in Example 1 above, and which is currently underway by one of us (Oslin). This trial was designed to address two questions related to the development of a strategy for treating alcohol dependent patients with the opiate antagonist Naltrexone (NTX). First, there is a variety of potential timing definitions concerning when a patient should be considered a NTX non-responder. Second, once a subject either responds to NTX (or does not respond), a variety of subsequent treatments are possible. The goal is to minimize the number of heavy drinking days over the 12 month study period.
EXAMPLE 2: Each subject is randomized twice, first to a definition of nonresponse/response (first decision point) and second to a subsequent treatment (second decision point). The two possible definitions of nonresponse are: nonresponse if 2 or more heavy drinking days within a two month period or nonresponse if 5 or more heavy drinking days within a two month period. As soon as a subject meets the definition of nonresponse, the subject is randomized to either NTX + CBI or to CBI alone. If the subject does not meet his/her assigned definition of nonresponse in the two month interval (a responder) then the subject is rerandomized to either a 6 month prescription of NTX or a 6 month prescription of NTX + TDM.
In a SMART design, subjects are randomized at selected critical decision points. In example 2, the critical decisions are first the timing of alterations in therapy and second the choice of the subsequent therapy for responders/nonresponders. Thus each subject is randomized twice, initially and then again once it is known if the subject is a responder or a nonresponder to initial therapy. Frequently and indeed in the example discussed here, the multiple randomizations can be performed prior to initial treatment; see Section 5 for discussion. Note that even though the SMART experimental design involves randomization, once an adaptive treatment strategy has been developed, the delivery of the treatment strategy (e.g. contrast the strategy in Example 1 with the SMART trial in Example 2) does not involve randomization.
Just as with any randomized trial, it is best to power SMART to address only a few primary strategy-building hypotheses so as to minimize sample size requirements. Potential primary hypotheses might address, “Is it useful to continue providing NTX to nonresponding patients in addition to CBI as compared to only providing CBI?” or “Do patients assigned a more stringent definition of nonresponse (2 or more heavy drinking days) do better overall than patients assigned a more lax definition of nonresponse (5 or more heavy drinking days)?” Both of these questions are addressed via two group comparisons (in the latter each group contains ½ of the total study sample; in the former each group contains ½ of the patients in the nonresponding group).
Secondary analyses may test for interactions of clinical and theoretical interest such as “Does the comparison between CBI and NTX+CBI for nonresponders change depending on the definition of nonresponse to initial NTX?” If there are significant interactions between patient variables and treatments then more complex adaptive treatment strategies are indicated. For example, patients who experience certain side effects while receiving NTX may respond differentially to NTX+CBI relative to CBI. A sufficiently strong interaction would indicate that these side effects should be used in deciding which secondary treatment is best for which nonresponder.
Following the analysis of the data from a SMART design, one may choose to proceed directly to a two group confirmatory trial in which the developed strategy is compared to an appropriate alternative or one may decide that additional randomized trials are needed. Consider example 2 once more. Suppose the following tests were planned: (1) test if NTX alone versus TDM+NTX produces differing outcomes among responders to the initial NTX, (2) test if among nonresponders to initial NTX, CBI alone produces different outcomes than CBI+NTX and (3) test if patients assigned a more stringent definition of nonresponse (2 or more heavy drinking days) do better overall than patients assigned a more lax definition of nonresponse (5 or more heavy drinking days) and (4) test for the following interaction: “Does overall level of side effects to NTX differentiate between nonresponders who do better on CBI alone and nonresponders who do better on CBI+NTX?” We conduct the study and find the following (suppose the primary outcome is the number of heavy drinking days).
EXAMPLE 2 CONTINUED: There is no difference between providing NTX or TDM + NTX for responders and, on average, better outcomes result if we provide CBI+ NTX rather than CBI alone to nonresponders. However we find that nonresponding individuals who are experiencing substantial side effects to NTX do better if switched to CBI alone as opposed to continuing with NTX and adding CBI. Also altering treatment earlier is associated with fewer heavy drinking days than altering treatment later.
Given these results, we can choose to preclude further refinement of the strategy and proceed directly to a randomized trial evaluation of the adaptive treatment strategy: “Patients begin on NTX. If a patient experiences 2 or more heavy drinking days within two months then the patient is provided CBI + NTX unless the patient experienced substantial side effects, in which case the patient is provided CBI. On the other hand, if the subject has at most 1 heavy drinking day within two months, then the subject is provided an NTX prescription.”
Alternatively suppose an additional post-hoc analysis yields a strong, unanticipated interaction: among responders to the initial NTX, subjects with poor social support do better on TDM + NTX prescription than these subjects do with NTX prescription alone. Thus a refining trial might seek to replicate this result and/or may add a component to improve social support so that more subjects could be managed effectively with the lower cost intervention (i.e., NTX only). This second trial might only study responders (those who experience one or fewer heavy drinking days in the first two months on NTX).