The level of missing data can be reduced by creative approaches in the formulation of protocols, informed consents, and data collection forms, as well as in the selection and education of both investigators and patients.
First, there should be proper distinction in study protocols between reasons for nonadherence (that is, for not receiving randomized therapy and hence for being “off study treatment”) versus nonretention (that is, for not obtaining outcome information and hence for being “off study”) (9
). There are only 2 valid reasons a patient can be off study: withdrawal of consent or the achievement of all required efficacy and safety end point information. If study end points are properly defined, the occurrence of death satisfies the latter condition rather than inducing missing data. Unfortunately, it is common for protocols to provide a long list of reasons that the patient will be off study, such as inability to tolerate the intervention, toxicity, physician choice, or need for other therapies. These may be valid reasons for nonadherence (for being off study treatment), but not for nonretention (for being off study). The protocol should separately list the 2 reasons a patient could go off study and the many reasons the patient could go off study treatment, with an indication that all reasonable efforts should be made to ensure patients who go off study treatment be consistently followed for outcomes unless they have withdrawn consent. The terminology inactive
rather than lost to follow-up
or off study
has been suggested for missing patients who have not withdrawn consent to reflect the possibility of achieving resumption of adherence or recovery of missing data (10
Second, the term withdrawal of consent
should not be used simply because the patient no longer wishes to receive randomized treatment or actively continue to return for follow-up assessments or simply to justify why efforts are not being made to continue to follow some patients who have discontinued their randomized intervention (9
). Rather, the term should be used only when the patient no longer wishes to participate in the trial and no longer authorizes the investigators to make efforts to continue to obtain their outcome data. Ideally, if patients withdraw their consent, it should be done in writing (11
). The rates of properly validated withdrawal of consent usually should be in the range of 1%, although higher rates might be expected in antipsychotic settings or where patients have impaired cognitive function. It is important that investigators be educated and evaluated about the proper use of the term withdrawal of consent
, and data monitoring committees should regularly assess whether the term was being used properly.
Third, patients should be adequately educated during the informed consent process about the continued scientific relevance of their data even if they discontinue treatment, as well as the deleterious effect that missing data has on trial integrity and credibility (8
). Patients join trials not only for their own personal gain but also for altruistic reasons. Although they should be informed that they can withdraw consent at any time, they also deserve to be informed that missing data diminish the scientific value of all patients’ altruistic contributions. Wording to this effect has been successfully added to informed consent forms to enable patients to make more informed decisions about their willingness to join a trial and to participate in continued follow-up without feeling inappropriately pressured to do so (10
Fourth, protocols should not give a misleading sense that biostatisticians have adequately corrected for the negative effect of substantial levels of missing data. Specifically, sections on statistical considerations frequently indicate that 10% to 50% increases in sample size have been made to address expected levels of missing data. Clarification is lacking that such adjustments in sample size address only the variability and not the bias induced by missing data so that these adjustments simply result in obtaining more precise biased estimates.
Fifth, protocols should specify the performance standards that should be met to achieve high quality of trial conduct, including specification of targeted levels of data capture (16
). A performance standards document should be developed before finalization of the study protocol that specifies targets about the enrollment and eligibility rates, event rate, adherence and retention rates, and currentness of data capture.
Finally, forms and procedures for data collection should include creative approaches to reduce missing data (12
). The burden on patients should be minimized by reducing the number of visits and assessments conducted, reducing the number of variables collected, formulating user-friendly case report forms, and enlarging the visit window. Investigators should be screened for their track record for retention and should be well trained in procedures to maximize data capture.