{"id":883,"date":"2020-02-18T10:10:27","date_gmt":"2020-02-18T04:40:27","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=883"},"modified":"2020-02-18T10:10:27","modified_gmt":"2020-02-18T04:40:27","slug":"adaptive-study-designs","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/adaptive-study-designs\/","title":{"rendered":"Adaptive study designs"},"content":{"rendered":"\n
Adaptive study designs<\/strong><\/p>\n\n\n\n
Background<\/strong><\/p>\n\n\n\n
development of a new drug\u00e0 huge expenses are involved \u00e0 long time-consuming process.<\/li>
success rate of may not be reflected with respect to increased expenditure in the clinical trials\u00e0 the feasibility of investing in a clinical trial does not appear to be convincing.<\/li>
Thus the pharmaceutical companies do not appear enthusiastic in conducting a new clinical trial. This has hampered the process of development of new drugs by the pharmaceutical companies.<\/li>
Noting the stagnation in the development of innovative products \u00e0 US FDA issued a statement in 2004 known as Critical Path Initiative (CPI)<\/strong> raising an alarm in the reduced number of innovative medical products submitted for FDA approval<\/li>
The pharmaceutical industries have realised that the conventional study design (those with a fixed sample size that do not use adaptive elements) of the trial does not allow the flexibility to incorporate these changes in the trial.<\/li>
To keep in pace with the progress in the scientific research and development of a new drug, a need for improved and innovative testing methods was felt and accordingly measures were developed.<\/li><\/ul>\n\n\n\n
FDA in 2004 in its CPI recommended the use of Adaptive Study Designs and use of Bayesian approach in the clinical research and development. Similarly, in 2006, the European Medicines Agency (EMEA) issued a paper regarding the flexible or adaptive study designs in the new drug development.<\/p>\n\n\n\n
Defining adaptive study design<\/strong><\/p>\n\n\n\n
\u201cstudy that includes a prospectively<\/strong> planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study<\/em>.\u201d<\/p>\n\n\n\n
Without undermining the validity and integrity of the trial<\/strong>.<\/p>\n\n\n\n
term \u2018prospective\u2019 \u00e0 means that the adaptation was pre-planned after the study has been started and depends on the data of the study.<\/li>
This means that the adaptation can be introduced after the study has started if the blinded state of the personnel involved in the analysis of the data is maintained when the modification plan is proposed. These revisions raise major concerns about the study integrity <\/strong>(i.e. the potential to introduce bias). In contrast the revisions introduced after the interim analysis of the blinded data even by the same personnel do not introduce statistical bias.<\/li>
It is of importance that the integrity and the validity of the trial is not undermined. The main purpose of the ASD is to make the trial more flexible, efficient and fast. Therefore, these trials are also known as \u2018flexible designs\u2019.<\/li><\/ul>\n\n\n\n
They are also known as Bayesian adaptive designs<\/strong> owing to the use of Bayesian approach for the trial design. (Bayesian analysis<\/em> is a statistical procedure which endeavours to estimate parameters of an underlying distribution based on the observed distribution<\/strong>.)<\/p>\n\n\n\n
What is not ASD<\/strong><\/p>\n\n\n\n
The revisions based on the information obtained entirely from sources outside the specific study are not considered as ASD.<\/p>\n\n\n\n
It is to be noted that the changes done in the study design that occur after an interim analysis of the unblinded study data and which were not prospectively planned are not a part of the ASD.<\/p>\n\n\n\n
Types of adaptations<\/strong><\/p>\n\n\n\n
Prospective (design) \u2013 adaptations are envisioned and approved in the beginning of the trial.<\/li>
Concurrent (ad hoc) \u2013 changes could not be envisioned in the beginning but their need becomes apparent as the trial continues.<\/li>
Retrospective \u2013 changes in the statistical analysis plan made prior to the data unblinding.<\/li><\/ol>\n\n\n\n
Modifications that can be prospectively planned include examples like<\/strong><\/p>\n\n\n\n
Trial procedures<\/strong><\/td>
Statistical procedure<\/strong><\/td><\/tr>
Eligibility criteria<\/td>
Randomization<\/td><\/tr>
Study dose \u2013 therapy regimen<\/td>
Study design<\/td><\/tr>
Duration of treatment<\/td>
Study hypothesis<\/td><\/tr>
Study endpoints<\/td>
Sample size<\/td><\/tr>
Lab testing procedures<\/td>
Data monitoring<\/td><\/tr>
Diagnostic procedures<\/td>
Interim analysis<\/td><\/tr>
Concomitant treatments used<\/td>
Statistical analysis plan\/Methods for data analysis<\/td><\/tr>
Planned schedule of the patient evaluations for the data collection (eg. number of the intermediate time points, timing of the last patient observation and duration of the patient study participation)<\/td>
<\/td><\/tr>
Criteria for evaluation and assessment of clinical responses<\/td>
<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n
Well understood ASD with valid approaches to implementation<\/strong><\/p>\n\n\n\n
Adaptation of Study Eligibility Criteria Based on Analyses of Pre-treatment (Baseline) Data<\/strong><\/li><\/ol>\n\n\n\n
While conducting a trial it may be noticed that the patients enrolled in the study might not be the expected population<\/strong> which was supposed to be enrolled. Thus, examining the baseline characteristics<\/strong> at any time during the study does not introduce statistical bias as long as the treatment assignment of the patients remains unblinded. However, there is a possible risk of impairment of the study result when the study population changes in the middle of the result.<\/p>\n\n\n\n
Adaptations to Maintain Study Power Based on Blinded Interim Analyses<\/strong> of Aggregate Data<\/li><\/ul>\n\n\n\n
A blinded analysis of the overall event rate can be compared to the assumptions planned in the study design. This does not introduce statistical bias. If the event rate is found to be lower<\/strong> than the initial assumption, the study will be underpowered<\/strong>. To increase the study power the study sample size can be increased, or the duration of the study<\/strong> can be increased.<\/p>\n\n\n\n
Adaptations based on the interim results of an outcome unrelated to efficacy<\/strong><\/li><\/ul>\n\n\n\n
In a study the incidence of SAE effect may be found to be high in a particular group<\/strong> in the interim analysis. Accordingly, the group in which the toxicity is observed is appropriate the group can be dropped<\/strong> which can be done in a ASD. For eg. a ADR is observed with a particular dose in a dose response study.<\/strong><\/p>\n\n\n\n
Adaptations Using Group Sequential Methods and Unblinded Analyses for Early Study Termination Because of Either Lack of Benefit or Demonstrated Efficacy<\/strong><\/li><\/ul>\n\n\n\n
Adaptations based on the Data Analysis Plan<\/strong> not dependent on within study, between group outcome differences.<\/li><\/ul>\n\n\n\n
The prospective statistical analysis plan should be prospectively written carefully and completely<\/strong>. After blinded inspection of data the SAP can be updated regarding the appropriate data transformations.<\/p>\n\n\n\n
Adaptation for the primary endpoint\u2019<\/strong><\/li><\/ul>\n\n\n\n
When the outcome assessment that is preferred as the primary endpoint proves difficult to obtain, a substantial amount of missing data may occur for this assessment.<\/strong><\/p>\n\n\n\n
Multiple adaptations in a single study increase complexity and difficult in planning the study, with increased difficulty in interpreting the study result.<\/p>\n\n\n\n
Allocation rule<\/strong> How subjects will be allocated to the different arms Comprises \u2013 response adaptive randomization and covariate adaptive allocation<\/td><\/tr>
Sampling rule<\/strong> How many subjects will be sampled at next stage Comprises \u2013 sample re-estimation and drop the loser design<\/td><\/tr>
Stopping rule<\/strong> When to stop the trial Comprises \u2013 Group sequential design and adaptive treatment switch design<\/td><\/tr>
Decision rule<\/strong> Changes not considered in above the three categories Comprises hypothesis adaptive design, change the primary endpoint or statistical method or patient population design.<\/td><\/tr>
Fifth rule<\/strong> Comprises multiple adaptions and seamless phase II\/III designs<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n
Adaptive randomization<\/strong><\/p>\n\n\n\n
Adaptive randomization is a form of treatment allocation in which the probability of patient assignment to any particular treatment group of the study is adjusted based on repeated comparative analyses of the accumulated outcome responses of patients previously enrolled (often called outcome dependent randomization<\/em>, for example, the play the winner <\/em>approach<\/strong>).<\/p>\n\n\n\n