ADAPTIVE DESIGNS IN CLINICAL TRAILS

 

                      ADAPTIVE DESIGNS IN CLINICAL TRAILS

INTRODUCTION:

              Development of a new medicine is more expensive and time consuming process. In the past few decades, it is identified and recognized that increasing in biomedical research on pharmaceutical product do not reflect on increase in the success rate of product. Stagnation in the development of innovative pharmaceutical products  gave an alarming call to the United States Food and Drug Administration (FDA). In 2004 the  FOOD AND DRUG ADMINISTRATION gave attention to an alarming call,  that decline in innovative pharmaceutical medicinal products being submitted to FDA  approval.  One of the innovations strongly recommended by the Food And Drug Administration is the use of this adaptive design methods and the appropriate use of the Bayesian method approach in the clinical research and its development.  The purpose of this designs in clinical study trials is to give the investigator ,the flexibility for identifying and recognizing the optimal clinical benefit of the test treatment under the study without undermining the validity and integrity of the intended clinical study.

WHAT IS AN ADAPTIVE CLINICAL TRIAL

                  An adaptive design is defined as the design that allows modifications to the trial design or statistical procedures of the clinical trials. The purpose of these designs is to make trials more fast, efficient and flexibility. The modifications and the adaptations has to be pre-planned and they should be based on data collected from the clinical study. Adaptive clinical trial designs have been used extensively in medical devices development and applied to drug development. Adaptive design is extensively useful for adequately controlled clinical safety and efficacy trials and also beneficial in early phase studies. This approach of adaptive designs has the ethical benefit of exposing fewer subjects to the suboptimal treatments.

Type of adaptive designs
Based on adaptations employed, commonly considered adaptive
design methods in clinical trials include :
(i) an adaptive randomization design,
(ii) a group sequential design,
(iii) a sample size re-estimation design,
(iv) a drop-the-loser design,
(v) an adaptive dose-finding design,
(vi) a biomarker-adaptive design,
(vii) an adaptive treatment-switching design,
(viii) a hypothesis-adaptive design,
(ix) an adaptive seamless phase II or III trial design and
(x) multiple adaptive designs

· Adaptive randomization design
An adaptive randomization design may be a design that permits modification
of randomization, schedules supported varied or unequal probabilities
of treatment assignment to extend the probability of
success. Commonly applied adaptive randomization procedures
include treatment-adaptive randomization, covariate-adaptive
randomization and response-adaptive randomization.

· Group sequential design
A group sequential design may be a design that permits prematurely
stopping a trial due to safety/efficacy or both with options of
additional adaptations based on results of the interim analysis. A group
sequential, responsive-adaptive design for randomized clinical trials
there has been considerable methodological research on response- adaptive designs for clinical trials but have seldom been used in practice.

· Sample size re-estimation design
A sample size re-estimation design is mentioned as an adaptive design
that allows for sample size adjustment or re-estimation. Sample size
adjustment or re-estimation might be wiped out either a blinding or
unblinding fashion supported the standards of treatment effect-size,
conditional power, and/or reproducibility probability. Sample size re-
estimation suffers from an equivalent disadvantage because the original power
analysis for sample size calculation before the conduct of the study
because it is done by treating estimates of the study parameters,
which are obtained from supported data observed at interim, as true values.

· Drop-the-losers design
A drop-the-losers design may be a design that permits dropping the inferior
treatment groups. A drop-the-losers design also allows adding
additional arms. A drop-the-losers design is beneficial in phase II clinical trial clinical
development especially when there are uncertainties regarding the
dose levels. The selection criteria and decision rules play important
roles in drop-the-loser designs. Dose groups that are dropped may
contain valuable information regarding dose-response of the treatment
understudy

· Adaptive dose-finding design
An adaptive dose-finding design is usually utilized in early phase clinical
development to spot the minimum effective dose (MED) and/or
the maximum tolerable dose (MTD), which is employed to work out the dose level for the next phase of clinical trials. For adaptive dose-finding
design, the tactic of continual reassessment method (CRM) in
conjunction with Bayesian approach is usually considered. Mugno et
al. in 2004 introduced a nonparametric adaptive urn design approach
for estimating a dose-response curve.

· Biomarker-adaptive design
A biomarker-adaptive design may be a design that permits adaptations
based on the response of biomarkers like genomic markers. An-
adaptive biomarker design involves biomarker qualification and
standard, optimal screening design, and model selection and
validation. It should be noted that there's a niche between identifying
biomarkers that are related to clinical outcomes and establishing the predictive model between relevant biomarkers and clinical outcomes in clinical development.

· Adaptive treatment-switching design
An adaptive treatment-switching design may be a design that permits the
investigator to modify a patient's treatment from an initial assignment
to an alternate treatment if there's evidence of lack of efficacy or
safety of the initial treatment. In oncology, clinical trials, estimation of
survival may be a challenge when treatment-switching has occurred in
some patients.

· Adaptive-hypotheses design
An adaptive-hypotheses design refers to a design that allows
modifications or changes in hypotheses supported by the interim analysis
results. Adaptive-hypotheses designs are often considered before the database
lock and/or before data unblinding.

· Adaptive seamless phase II/III design
An adaptive seamless phase II/III design is referred to as a program
that addresses within single-trial objectives that are normally achieved
through separate trials in phase IIb and phase III clinical trials of clinical
development. An adaptive seamless phase II/III design is an adaptive
seamless phase II/III trial design that might use data from patients
enrolled before and after the difference within the end. An
adaptive seamless phase II/III design may be a two-stage design consisting
of a learning stage i.e., phase IIb and a confirmatory stage i.e., phase III.

· Multiple adaptive designs
Finally, a multiple-adaptive design is any combination of the above
adaptive designs. Commonly considered multiple-adaptation designs
include a combination of
(i) adaptive group sequential design, drop-the-losers design and
adaptive seamless trial design and
(ii) adaptive dose-escalation design with adaptive randomization
.In practice, since statistical inference for a multiple-
adaptation design is usually difficult, it's suggested that a
clinical trial simulation be conducted to evaluate the
performance of the resultant multiple adaptive designs at the
planning stage.

CHALLENGES ,OBSTACLES AND CONTROVERSIES IN THE PATH OF ADAPTIVE TRIALS

             There are some operational difficulties in the adaptive designs. These trials  use the Bayesian statistical approach, but this is logistically complex and might not be practical in all situations. The sheer logistics of a high-level adaptive design also require careful consideration. Quick and reliable electronic data collection would seem to be mandatory for a trial that is dependent on constant updating and to implement these adaptations, the data monitoring committee needs to meet regularly and quickly. Adaptive designs require computer-based simulations of clinical trials to develop the design , protocol that requires more work force.

There is also lack of uniformity in the adaptive clinical trials. These adaptations are more encouraged in the phase I and phase II A studies but criticized in phase III studies.

ADVANTAGES OF ADAPTIVE DESIGNS

              One of the most important advantage of adaptive design is that potential modifications are approved before by regulatory authorities and ethical committees so that there is no need to file protocol amendments. There is a complete flexibility to react to unanticipated events and options to introduce new doses, change end points. Credibility of results is also maintained. Many compounds in drug development may fail, but these designs allow to earlier detection and earlier stoppage of clinical trial.

CURRENT SCENARIO

              Current signals from pharmaceutical companies are much positive. Regulatory agencies in the major markets have developed positive decisions on adaptive designs in clinical trials. Many software and information technology companies are developing software and clinical trial management system solutions to give support to adaptive designs in clinical trials. Two step adaptive proof-of-concept and dose finding adaptive designed clinical trial have been used already for migraine studies. A 3+3 adaptive designs are already used in oncology studies.

Conclusion:

The role of Adaptive designs   in clinical trials paves a way to investigate ,  flexibility for identifying the satisfactory clinical benefit of the test treatment under study without compromising the validity and integrity of the purposive study. It’s capacious usage in medical device development and also in drug development hypes it’s significance. Involving the different designs or models made the usage of Adaptive designs prominent in the clinical study or trail. These not only have a positive impact value, in the perception that efficacy of a drug is established earlier by using consistent designs, but also have a negative- impact value, in the perception that ineffective treatments can be terminated at an earlier stage.  Even though facing the obstacles and challenges, the Adaptive designs favours the earlier detection and earlier stoppage of clinical trial , yet  many compounds in drug development may fail. Currently multiple software and information technology companies are progressing the  software and clinical trial management system solutions to assist  adaptive designs in clinical trials and making their developing process cheaper and easier.

                   -By

Haritha Yadav Nanneboina (B.pharm)

Jennifer Mangala (B.pharm)

Bindu K.          ( B.pharm)

Students at Clinosol Research Pvt. LTD.