Am J Med. May;(5)e Agreement of decision analyses and subsequent clinical studies in infectious diseases. Bress JN(1), Hulgan T, Lyon JA. subsequent clinical studies in the infectious disease literature to assess the validity of clinical studies in infectious diseases, supporting the validity of decision. FULL TEXT Abstract: Decision analysis techniques can compare management strategies when there are insufficient data from clinical studies to guide decision .
Clinical Studies: Subsequent
Just because one can assess and find between-treatment-arm differences in an endpoint does not mean it is an appropriate endpoint We consider two additional potential justifications for using PFS as a measure of therapeutic effect in the context of trials of maintenance therapies. This is particularly true for maintenance treatments, where the subsequent-line therapy in the control arm is frequently the maintenance agent making it a comparison of immediate vs a delayed administration strategy The fact that a PFS benefit of a particular maintenance therapy might be reflective of an OS benefit for this maintenance therapy if subsequent therapies did not exist is irrelevant in the real world, where such therapies do exist This suggests that in the absence of evidence that PFS predicts OS benefit in the presence of available second-line therapies, the only convincing way to assess OS benefit is to measure it directly.
An intermediate variable can be a good individual-level surrogate but a poor trial-level surrogate 31 ; this may be the case with PFS and OS in some settings A second possible justification for using PFS as a trial endpoint is that an improvement in PFS represents an improvement in patient QOL and therefore represents direct patient benefit.
However, progression in solid tumors is defined as an increase in radiographic measurement of tumor size above a predetermined threshold that was determined to represent biologic activity rather than clinical benefit 33 , 34 , and progression in hematologic malignancies is often determined by a change in laboratory values that would not be generally expected to cause symptoms 18 , Therefore, PFS differences could be driven by radiographic or laboratory changes that may be unnoticeable to the patient and thus do not translate into direct clinical benefit.
In view of that, the validity of PFS as a direct measure of QOL depends very much on the disease setting, magnitude of PFS improvement, and toxicity of the maintenance agent. For example, in a setting where progression usually leads to increased disease symptoms, delaying progression may have direct QOL benefits.
However, even in this setting, the QOL benefit due to a delayed progression and the magnitude of the delay would need to be considered in light of any QOL decrement due to the toxicity of the maintenance agent. For example, Ozols 36 questioned whether a seven-month improvement in median PFS from 21 to 28 months [ 37 ] because of maintenance therapy consisting of 12 cycles vs 3 cycles of intravenous paclitaxel given every 28 days was offering clinical benefit to ovarian cancer patients in complete remission.
Furthermore, in indolent disease settings with effective salvage treatments eg, first-line myeloma or follicular lymphoma , patients developing symptoms would be expected to quickly achieve a prolonged symptom-free remission when treated with salvage therapy. Another example of the potential role of PFS as the primary outcome in maintenance trials is given by the debate on the best strategy for use of rituximab in follicular lymphoma: After addition of rituximab to induction chemotherapy was shown to improve OS, rituximab maintenance was evaluated and approved for high-tumor-burden follicular lymphoma, in large part based on the PRIMA study 38— This study randomly assigned patients in complete or partial response after first-line immunochemotherapy to receive either two years of rituximab maintenance or observation.
After a six-year follow-up, the study demonstrated for the maintenance vs observation arm six-year PFS rates of Considering that the study also demonstrated no difference in QOL between the arms and a modest increase in toxic effects on the maintenance arm, it would appear that the PRIMA results represent evidence against the clinical benefit of rituximab maintenance 41 , 42 and, more broadly, evidence that PFS may not accurately measure QOL in indolent-disease maintenance settings.
Regardless of symptom prevention, it has been suggested that maintenance therapy that improves PFS without improvement in OS may provide patient QOL benefit by delaying subsequent more toxic lines of therapy To properly demonstrate a QOL benefit using this justification, however, maintenance trials should collect and compare the relevant QOL data toxicity, symptoms, treatment duration , not just over the maintenance treatment but also over the second-line treatment and, if possible, over the subsequent treatment lines.
This is needed to ensure that the delay in second-line therapy is not offset by QOL differences in the subsequent lines of therapy. There is often a concern that prolonged administration of an agent will lead to resistant relapse that may reduce ability of the patients to benefit from the same or similar agents in the future 44 , Because of this, several alternative endpoints to PFS have been introduced that are designed to assess the overall therapeutic effect of a maintenance early continuous treatment strategy vs a delayed treat at progression strategy.
Time from randomization to progression on the second-line therapy or death from any cause PFS2 Figure 3 has been used in myeloma, colorectal, and ovarian cancers and was suggested by the EMA as a possible endpoint 46 , Note that even though the baseline time is randomization, in establishing the RECIST documentation for the second progression the first scan that documented the first progression is used as the baseline scan.
By incorporating the treatment effect on both first and second lines of therapy, PFS2 provides a better reflection than PFS of the total effect of the maintenance treatment on the patient. The study results for the maintenance vs observation arms were as follows: Given the OS, QOL, and toxicity outcomes, the implication of these results for clinical practice depends on individual patient preference for treatment breaks vs a small improvement in survival.
In that context, the improvement in PFS2 adds confidence in the observed statistically insignificant 3. PFS2 results demonstrate that the initial PFS improvement is sustained in longer-term disease control. CAIRO3 trial design However, the study also demonstrated that results for the time to second progression on any second-line therapy endpoint were similar to the protocol-defined PFS2 results.
When it is not feasible to ensure consistent follow-up with regular tumor assessments until the time of second progression, time to second subsequent therapy or death TSST Figure 3 is sometimes used to approximate PFS2 When evaluating maintenance with an agent that is routinely used as a salvage therapy, a potential concern is that this maintenance strategy could reduce the number of therapeutic salvage options available for the patient.
For example, in a setting with three lines of effective therapy A, B, and C , using B in maintenance after A may leave the maintenance arm patients with only C as an effective salvage option at progression while the control arm patients would have B and C available. In this case, a clinically relevant comparison of the ability of the two strategies to control the disease could be based on comparing the time to first progression on the maintenance arm and the time to second progression on the control arm.
In clinical settings where the disease can be controlled with observation and strategic retreatment at each progression , a comparison of the maintenance and retreatment strategies could be based on comparing the time to first progression on the maintenance arm and the time to the failure to respond to retreatment on the retreatment arm similarly to the TAF endpoint.
For example, in low-burden follicular lymphoma patients responding to induction therapy, the RESORT trial 54 compared a maintenance strategy a single dose of rituximab every 13 weeks with a retreatment strategy observation with no treatment until progression, and then retreatment with four doses of rituximab at each progression. The primary endpoint in this study was time to treatment failure TTF , with treatment failure defined as no response to rituximab for the retreatment arm and progression for the maintenance arm.
In this setting, the TTF endpoint allowed one to quantify the lack of clinical benefit from the maintenance strategy; the study concluded that the retreatment strategy is preferable to maintenance For evaluating individual patient benefit from a maintenance strategy, the PFS endpoint, by itself, does not accurately capture the relevant therapeutic effect.
Endpoints that incorporate outcomes of subsequent lines of therapy eg, PFS2 allow one to address the concern about the effect of maintenance on the effectiveness of subsequent lines of therapy. Moreover, because these endpoints provide a better than PFS quantification of long-term disease control they are likely to provide a better reflection of maintenance effect on OS.
Use of these endpoints may require additional logistical considerations and resources associated with longer follow-up. Furthermore, defining these endpoints for patients who never receive subsequent therapy postprogression after randomization requires careful consideration. Two possible values in this case are: Therefore, if the number of these patients is nontrivial, then both approaches should be reported. Maintenance strategies are focused on a prolonged postinduction administration of agents s with established activity in more advanced settings.
When the therapeutic goal of a maintenance strategy is to prolong patient life, the RCT should be sized to detect a clinically meaningful improvement in OS, if such a study can be completed in a timely manner eg, in the mCRC or metastatic ovarian cancer settings. In indolent disease settings, where timely completion of an OS-targeted study is not feasible, endpoints incorporating outcomes of the subsequent lines of therapy could be considered to approximate the maintenance effect on OS.
When the main therapeutic goal of maintenance is to improve QOL, then the RCT should be designed to provide direct evidence of the net gain in overall QOL from the maintenance strategy. Finally, as the cost of cancer care has become one of the fastest growing components of US health care spending 55 , the implications of maintenance strategy for the sustainability of the public health system cannot be ignored.
Therefore, it is important for maintenance RCTs to provide society with an objective estimate of the clinical benefit of maintenance so its cost-effectiveness can be accurately quantified.
This approach can be used in the maintenance setting, where the phase II endpoint can be PFS looking for activity and the phase III endpoint can be OS looking for definitive clinical benefit. Unlike the regulatory setting, where the question is whether a new drug has enough activity to justify making it available to patients with a given disease, a maintenance question is typically focused on comparing an immediate treatment strategy with a delayed treat at progression strategy that often incorporates an active salvage agent.
In this context, the relevant therapeutic question, whether a patient presenting with a given disease would derive maximum benefit by using the agent early in maintenance vs later at the time of progression, is not fully captured by a PFS endpoint. Therefore, in order to provide definitive evidence to inform clinical practice, RCTs evaluating maintenance should, if possible, use either OS as the endpoint or endpoints directly measuring QOL.
In settings where this is not feasible, PFS2 or similar endpoints that accurately reflect the long-term therapeutic effect for the clinical situation at hand should be used.
Furthermore, to accurately isolate the clinical impact of maintenance, RCT designs should incorporate appropriate first-line and second-line therapies and minimize between-arm differences in follow-up schedules. Oxford University Press is a department of the University of Oxford.
It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Close mobile search navigation Article navigation. Choice of First-Line Therapy. Choice of Second-Line Therapy. Between-Arm Differences in Follow-up Schedules. Choice of Primary Endpoint. Abstract A potential therapeutic strategy for patients who respond or have stable disease on a fixed-duration induction therapy is to receive maintenance therapy, typically given for a prolonged period of time.
View large Download slide. Maintenance chemotherapy for advanced non-small-cell lung cancer: Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients withuntreated multiple myeloma: A randomized, controlled phase III study of cyclophosphamide, doxorubicin, and vincristine with etoposide CAV-E or teniposide CAV-T , followed by recombinant interferon-alpha maintenance therapy or observation, in small cell lung carcinoma patients with complete responses.
Estimation of survival distributions of treatment policies in two-stage random assignment designs in clinical trials. An experimental design for the development of adaptive treatment strategies. Adaptive therapy for androgen-independent prostate cancer: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: Considerations for the design of future clinical trials in metastatic renal cell carcinoma. Overall survival as the outcome for randomized clinical trials with effective subsequent therapies.
When you look matters: Proposal for the use of progression-free survival in unblinded randomized trials. Missing data and measurement variability in assessing progression-free survival endpoint in randomized clinical trials. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer.
Strategies for prolonged therapy in patients with advanced non-small-cell lung cancer. Maintenance treatment of advanced non-small-cell lung cancer: The value of progression-free survival to patients with advanced-stage cancer. The sponsor cannot initiate clinical trials until it receives approval for the CTA, even if the day period has elapsed.
The final assessment report will also be sent to any other MS joining the clinical trial. A sponsor must ensure that each clinical trial investigator obtains IRB approval for the protocol, informed consent form, etc.
The IRB meets, reviews the clinical trial documentation, and provides the investigator with a written decision. At the conclusion of their review, the IRB will provide a formal letter to the investigator. A copy of this letter is sent to the sponsor by the investigator s.
A sponsor can only send clinical trial investigational medication to an investigator who has received written IRB approval. In my experience, the timeline can be as little as two months or as much as a year or more. So, the interactions with the local IRB are through the investigator and not the sponsor.
Major differences between the U. For sponsors wishing to conduct multinational clinical trials, careful advanced planning is most important. Prior to consulting, Pierro worked for Barnett International as director of business development — consulting and clinical training, responsible for development and implementation of GCP-related SOPs, specialized compliance-related training programs, and related consulting services.
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Initiating Multinational Clinical Trials: Major Differences Between The U.S. And EU
We compared the outcomes of decision analyses and subsequent clinical studies in the infectious disease literature to assess the validity of the conclusions of. This is a multicenter, open-label, Phase II study in subjects with Human epidermal growth factor receptor (HER2)-positive metastatic breast. Official Title: The Prognostic Role of Subsequent Atrial Tachycardias Occurring After Atrial Fibrillation Termination: A Prospective Randomized Trial. Study Start.