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Re: Dementia Related Psychosis Clinical Trial: Interim Analysis Completion Date?/gg "Is there any possibility for an early stop for efficacy? If the relapsers are relapsing within the first few weeks of the 26 week "relapse phase", does that mean the interim analysis could come as early as two quarters sooner? Anyone have any thoughts on this?" Since there is a planned interim analysis, yes, there is a possibility of an early stop for efficacy, "if the superiority of the treatment under study is clearly established ....If the emerging data suggest that those receiving the treatment are doing better, one might expect that a DMC would consider whether the study should be terminated earlier than planned. Estimates of treatment effect, however, will be unstable at early points in a study, and the chance is substantial of observing a nominally statistically significant benefit (e.g., p<0.05) at one of multiple interim analyses during a study of an ineffective product (see Section 4.4.2). A DMC, guided by a pre-specified statistical monitoring plan acceptable to both the DMC and the study leadership, will generally be charged with recommending early termination on the basis of a positive result only when the data are truly compelling and the risk of a false positive conclusion is acceptably low." (quotes from FDA, below). However, this is not always likely to occur. It is not supposed to happen routinely. The FDA prefers complete trials. It would be nice to find recent years studies/data indicating, as LongUSA quotes company reps, how many trials of similar design were stopped early for efficacy - "vast majority":? Of how many studies? I have not seen an answer to this question, but I have doubts that it has been most recent studies. Long estimates a 90% chance of success at interim; I think is may be closer to 50:50. But I do think eventual success is likely. Q: re interim on DRP, where is interim set / what is confidence? (36:00) A: Serge: 2 elements to inform us: historical and pima-specific. From previous withdrawal studies, vast majority have ended at interim. 2nd, in Devanon (sp?) study, positive outcome reached w/ small number of events/patients, so gives us indication of what might be expected. You may be aware of the concept of 'spending alpha' error on the interim. The FDA says that early unblinding of the trial to check efficacy is sort of like cheating, that it introduces statistical bias. So, they penalize you. If you want to look early, you will have to do a little more to reject the null hypothesis at trial conclusion than you would have had you not checked early. And, in LongUSA's quotes, we see an emphasis that the company was aware of this, and, therefore, only spent a little of their alpha on the planned early look, referring to this as 'setting the bar very high'. This is to have their cake and eat it too. They want to make sure they can achieve stat signficance in the final analysis (at trial conclusion), if it comes to that. So, this sounds like it might not be so easy (as implied in "vast majority) to prove efficacy is "clearly established", as viewed by the FDA, at the interim analysis. However, the rep also said their interim would likely be late in the study, so, even if trial was not stopped (and pps took a hit), it wouldn't be that much longer (relatively) until the trial conclusion analysis (a second and better bite at the apple of statistical significance). From an article getting into the statistics of the issue: "Every time we look at the data and consider stopping, we introduce the chance of falsely rejecting the null hypothesis. In other words, every time we look at the data, we have the chance of a type 1 error. If we look at the data multiple times, and we use alpha of 0.05 as our criterion for significance, we have a 5% chance of stopping each time. Under the true null hypothesis and just 2 looks at the data, we “approximate” the error rates as: Probability stop at the first look: 0.05, probability stop at the second look: 0.95 × 0.05 = 0.0475, and total probability of stopping is 0.0975." Interim analysis: A rational approach of decision making in clinical trialMore from the FDA about early stops Interim Analysis and Early Stopping (4.5) 25 An interim analysis is any analysis intended to compare treatment arms with respect to efficacy or safety at any time prior to formal completion of a trial. Because the number, methods, and consequences of these comparisons affect the interpretation of the trial, all interim analyses should be carefully planned in advance and described in the protocol. Special circumstances may dictate the need for an interim analysis that was not defined at the start of a trial. In these cases, a protocol amendment describing the interim analysis should be completed prior to unblinded access to treatment comparison data. When an interim analysis is planned with the intention of deciding whether or not to terminate a trial, this is usually accomplished by the use of a group sequential design that employs statistical monitoring schemes as guidelines (see section III.D). The goal of such an interim analysis is to stop the trial early if the superiority of the treatment under study is clearly established, if the demonstration of a relevant treatment difference has become unlikely, or if unacceptable adverse effects are apparent. Generally, boundaries for monitoring efficacy require more evidence to terminate a trial early (i.e., they are more conservative) than boundaries for monitoring safety. When the trial design and monitoring objective involve multiple endpoints, then this aspect of multiplicity may also need to be taken into account. The protocol should describe the schedule of interim analyses or, at least, the considerations that will govern its generation, for example, if flexible alpha spending function approaches are to be employed. Further details may be given in a protocol amendment before the time of the first interim analysis. The stopping guidelines and their properties should be clearly described in the protocol or amendments. The potential effects of early stopping on the analysis of other important variables should also be considered. This material should be written or approved by the data monitoring committee (see section IV.F), when the trial has one. Deviations from the planned procedure always bear the potential of invalidating the trial results. If it becomes necessary to make changes to the trial, any consequent changes to the statistical procedures should be specified in an amendment to the protocol at the earliest opportunity, especially discussing the impact on any analysis and inferences that such changes may cause. The procedures selected should always ensure that the overall probability of Type I error is controlled. The execution of an interim analysis should be a completely confidential process because unblinded data and results are potentially involved. All staff involved in the conduct of the trial should remain blind to the results of such analyses, because of the possibility that their attitudes to the trial will be modified and cause changes in the characteristics of patients to be recruited or biases in treatment comparisons. This principle may be applied to all investigator staff and to staff employed by the sponsor except for those who are directly involved in the execution of the interim analysis. Investigators should be informed only about the decision to continue or to discontinue the trial, or to implement modifications to trial procedures. Most clinical trials intended to support the efficacy and safety of an investigational product should proceed to full completion of planned sample size accrual; trials should be stopped early only for ethical reasons or if the power is no longer acceptable. However, it is recognized that drug development plans involve the need for sponsor access to comparative treatment data for a variety of reasons, such as planning other trials. It is also 26 recognized that only a subset of trials will involve the study of serious life-threatening outcomes or mortality which may need sequential monitoring of accruing comparative treatment effects for ethical reasons. In either of these situations, plans for interim statistical analysis should be in place in the protocol or in protocol amendments prior to the unblinded access to comparative treatment data in order to deal with the potential statistical and operational bias that may be introduced. For many clinical trials of investigational products, especially those that have major public health significance, the responsibility for monitoring comparisons of efficacy and/or safety outcomes should be assigned to an external independent group, often called an independent data monitoring committee (IDMC), a data and safety monitoring board, or a data monitoring committee, whose responsibilities should be clearly described. When a sponsor assumes the role of monitoring efficacy or safety comparisons and therefore has access to unblinded comparative information, particular care should be taken to protect the integrity of the trial and to manage and limit appropriately the sharing of information. The sponsor should ensure and document that the internal monitoring committee has complied with written standard operating procedures and that minutes of decisionmaking meetings, including records of interim results, are maintained. Any interim analysis that is not planned appropriately (with or without the consequences of stopping the trial early) may flaw the results of a trial and possibly weaken confidence in the conclusions drawn. Therefore, such analyses should be avoided. If unplanned interim analysis is conducted, the clinical study report should explain why it was necessary and the degree to which blindness had to be broken, and provide an assessment of the potential magnitude of bias introduced and the impact on the interpretation of the results. F. Role of Independent Data Monitoring Committee (IDMC) (4.6) (see sections 1.25 and 5.5.2 of ICH E6) An IDMC may be established by the sponsor to assess at intervals the progress of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor whether to continue, modify or terminate a trial. The IDMC should have written operating procedures and maintain records of all its meetings, including interim results; these should be available for review when the trial is complete. The independence of the IDMC is intended to control the sharing of important comparative information and to protect the integrity of the clinical trial from adverse impact resulting from access to trial information. The IDMC is a separate entity from an institutional review board (IRB) or an independent ethics committee (IEC), and its composition should include clinical trial scientists knowledgeable in the appropriate disciplines, including statistics. When there are sponsor representatives on the IDMC, their role should be clearly defined in the operating procedures of the committee (e.g., covering whether or not they can vote on key issues). Since these sponsor staff would have access to unblinded information, the 27 procedures should also address the control of dissemination of interim trial results within the sponsor organization." 1. [PDF] Guidance for Industry - FDA |
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Msg # | Subject | Author | Recs | Date Posted |
14145 | Re: Dementia Related Psychosis Clinical Trial: Interim Analysis Completion Date?/gg | longusa | 5 | 10/15/2018 4:16:24 AM |