In the ever-evolving landscape of pharmaceuticals, the need for innovative approaches to clinical trials has become paramount. Today, let’s delve into the game-changing realm of adaptive trial designs and how they are catalyzing the acceleration of drug development, especially for small and medium-sized pharma companies.
Traditional clinical trials follow a linear three-phase process—initial design, conduct, and analysis. However, this rigid structure lacks flexibility for adjustments that may prove necessary or beneficial during the trial. Adaptive designs, often described as ‘planning to be flexible’ or ‘taking out insurance’ against assumptions, introduce a review–adapt loop into the conventional sequence (Fundamentals of Clinical Trials, Lawrence M. Friedman , Curt D. Furberg , David L. DeMets).
These designs introduce a review–adapt loop into the conventional linear design–conduct–analysis sequence. They permit scheduled interim examinations of the data during the ongoing trial, allowing for pre-specified adjustments to the trial based on accumulating data analyses.
Multiple adaptations may be used in a single trial, e.g. a group-sequential design may also feature mid-course sample size re-estimation and/or adaptive randomisation, and many multi-arm multi-stage (MAMS) designs are inherently seamless. Adaptive designs can improve trials across all phases of clinical development, and seamless designs allow for a more rapid transition between phases I and II or phases II and III. Some well-recognized adaptations and examples of their use can be founded in the following list (Adaptive designs in clinical trials: why use them, and how to run and report them, Philip Pallmann, et al.):
- Sample size re-estimation: Adjust sample size to ensure the desired power (DEVELOP-UK , COVID-19). Clinical trials typically set a predetermined sample size, often based on estimates for generating meaningful results. However, these estimations may not be entirely accurate. With sample size re-estimation, sponsors can evaluate patient data at a specific milestone and adjust the trial size if necessary. For instance, if a trial plans to recruit 160 patients, a reassessment after the first 40 patients can determine if more are needed.Benefits:- Cost and Time Efficiency: Adjusting the patient number based on actual data can reduce overall costs and expedite time to market.- Avoiding Negative Studies: If data suggests efficacy but requires a larger sample size, this approach helps avoid negative outcomes.- Financial Appeal: This model is attractive to financial decision-makers, presenting an opportunity to potentially lower costs and mitigate risks.
- Group-sequential: Include options to stop the trial early for safety, futility or efficacy (DEVELOP-UK , FETO, PROTECTED TAVR). In this adaptive model, sponsors conduct a mid-point analysis to evaluate trial progress. Positive results may prompt an early conclusion, while negative findings could lead to trial cessation to prevent further patient exposure to an ineffective treatment.Benefits:- Accelerated Decision-Making: Valuable conclusions are reached sooner, aiding current and future investment decisions.- Ethical Trial Management: If endpoints seem unachievable, data justifies trial termination to avoid exposing more patients to ineffective treatments.- Time-to-Market Acceleration: Overwhelmingly positive results enable sponsors to expedite the time to market.
- Adjusting the study population: Narrow down recruitment to patients more likely to benefit (most) from the treatment (Rizatriptan study [2, 3]). In an adaptive design, sponsors can validate treatment effects on specific subpopulations by adjusting the population mid-trial (e.g., population enrichment). Analyzing data at an interim milestone enables assessment of treatment effects in certain populations, allowing adjustments to inclusion/exclusion criteria for remaining recruits.Subpopulations and data-driven decisions must be predefined in the study plan to maintain scientific integrity.Benefits:- Rapid Recruitment: Adjustment permits quicker recruitment from a broader population, with a contingency plan for a smaller, more responsive population if needed.- Reduced Trial Risk: Enhances the population with the highest treatment response, reducing the likelihood of a negative trial.- Lowered Patient Risks: Fewer populations are recruited that aren’t likely to respond or have a higher likelihood of adverse events.
- Continual reassessment method: Model-based dose escalation to estimate the maximum tolerated dose (TRAFIC , Viola , RomiCar , CASPALLO).
- Multi-arm multi-stage: Explore multiple treatments, doses, durations or combinations with options to ‘drop losers’ or ‘select winners’ early (TAILoR , STAMPEDE [8, 9], COMPARE , 18-F PET study ).
- Biomarker-adaptive: Incorporate information from or adapt on biomarkers (FOCUS4 , DILfrequency ; examples in [14, 15]).
- Adaptive randomization: Shift allocation ratio towards more promising or informative treatment(s) (DexFEM ; case studies in [17, 18]).
- Adaptive dose-ranging: Shift allocation ratio towards more promising or informative dose(s) (DILfrequency ).
- Seamless phase I/II: Combine safety and activity assessment into one trial (MK-0572 , Matchpoint [20, 21]).
- Seamless phase II/III: Combine selection and confirmatory stages into one trial (Case studies in ).
Each of these models can bring benefits, but only if sponsors give their clinical trial designers the additional time and support to do the design research and analysis up-front. This can be a challenge, particularly when teams face pressure to complete planning as quickly as possible so recruiting can begin.
The Adaptive Advantage for Small and Medium Pharma 🌱
Adaptive trial designs represent a paradigm shift, providing an unparalleled level of flexibility compared to traditional trial approaches. For smaller players in the pharma arena, this adaptability is a game-changer. Here’s why:
- Resource Optimization: Adaptive designs allow for real-time adjustments, optimizing resources as the trial progresses. This is particularly crucial for companies with limited budgets, ensuring efficient resource allocation.
- Faster Decision-Making: The ability to modify the trial based on interim results means quicker decision-making. For small and medium pharma, where agility is a competitive edge, this accelerates the entire drug development process.
- Risk Mitigation: Adaptive designs enable early identification of unsuccessful paths, minimizing the risk of investing resources in ineffective strategies. This risk mitigation is a lifeline for companies navigating the complexities of drug development.
Case Studies: Illuminating Success Stories 💡
Let’s shine a spotlight on some noteworthy case studies where adaptive trial designs have transformed the landscape:
- Swift Identification of Efficacy: Company X, a mid-sized pharma, leveraged adaptive designs to swiftly identify the most effective dosage, reducing trial duration by 30%. The result? Faster progression to the next development phase.
- Patient-Centric Approaches: In Trial Y, a small pharma company incorporated adaptive elements to adjust patient enrollment criteria based on early outcomes. This patient-centric approach not only enhanced participant experience but also ensured more accurate results.
- Optimizing Treatment Arms: Company Z, faced with uncertainties in treatment efficacy, utilized adaptive designs to dynamically adjust treatment arms. The result was a streamlined trial, minimizing unnecessary exposure to ineffective treatments.
Flexibility Redefined: Meeting Changing Needs 🔄
One of the hallmarks of adaptive trial designs is their responsiveness to changing dynamics. For small and medium pharma navigating the unpredictable nature of drug development, this flexibility is transformative:
- Protocol Amendments in Real-Time: Adaptive designs allow seamless protocol amendments during the trial, accommodating unforeseen challenges or emerging insights without halting the entire process.
- Enhanced Statistical Efficiency: Statistical methods within adaptive designs enable efficient use of accrued data, maximizing the value extracted from every stage of the trial. This not only accelerates timelines but also ensures robust results.
- Tailoring to Patient Diversity: Small and medium pharma often grapple with diverse patient populations. Adaptive designs permit adjustments based on emerging demographic insights, ensuring inclusivity and relevance.
The era of adaptive trial designs heralds a new dawn for small and medium pharma companies. Embracing adaptability isn’t just a strategy; it’s a necessity for those determined to lead the charge in the pharmaceutical frontier.
Let’s continue the conversation. How do you envision adaptive trial designs shaping the future of drug development? Share your thoughts! 🚀🔬
- Fisher AJ, Yonan N, Mascaro J, Marczin N, Tsui S, Simon A, et al. A study of donor ex-vivo lung perfusion in UK lung transplantation (DEVELOP-UK). J Heart Lung Transplant. 2016
- Ho TW, Pearlman E, Lewis D, Hämäläinen M, Connor K, Michelson D, et al. Efficacy and tolerability of rizatriptan in pediatric migraineurs: results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design. Cephalalgia. 2012
- Wang SJ, Hung HMJ. Adaptive enrichment with subpopulation selection at interim: methodologies, applications and design considerations. Contemp Clin Trials. 2013
- Cole M, Stocken D, Yap C. A pragmatic approach to the design and calibration of a Bayesian CRM dose finding trial. Trials. 2015
- Yap C, Billingham LJ, Cheung YK, Craddock C, O’Quigley J. Dose transition pathways: the missing link between complex dose-finding designs and simple decision making. Clin Cancer Res. 2017
- Yap C, Craddock C, Collins G, Khan J, Siddique S, Billingham L. Implementation of adaptive dose-finding designs in two early phase haematological trials: clinical, operational, and methodological challenges. Trials. 2013
- Pushpakom SP, Taylor C, Kolamunnage-Dona R, Spowart C, Vora J, García-Fiñana M, et al. Telmisartan and insulin resistance in HIV (TAILoR): protocol for a dose-ranging phase II randomised open-labelled trial of telmisartan as a strategy for the reduction of insulin resistance in HIV-positive individuals on combination antiretroviral therapy. BMJ Open. 2015
- Sydes MR, Parmar MKB, James ND, Clarke NW, Dearnaley DP, Mason MD, et al. Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials. 2009
- Sydes MR, Parmar MKB, Mason MD, Clarke NW, Amos C, Anderson J, et al. Flexible trial design in practice—stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials. 2012
- Gaunt P, Mehanna H, Yap C. The design of a multi-arm multi-stage (MAMS) phase III randomised controlled trial comparing alternative regimens for escalating (COMPARE) treatment of intermediate and high-risk oropharyngeal cancer with reflections on the complications of introducing a new experimental arm. Trials. 2015
- Gerety EL, Lawrence EM, Wason J, Yan H, Hilborne S, Buscombe J, et al. Prospective study evaluating the relative sensitivity of 18F-NaF PET/CT for detecting skeletal metastases from renal cell carcinoma in comparison to multidetector CT and 99mTc-MDP bone scintigraphy, using an adaptive trial design. Ann Oncol. 2015
- Kaplan R, Maughan T, Crook A, Fisher D, Wilson R, Brown L, et al. Evaluating many treatments and biomarkers in oncology: a new design. J Clin Oncol. 2013
- Waldron-Lynch F, Kareclas P, Irons K, Walker NM, Mander A, Wicker LS, et al. Rationale and study design of the adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): a non-randomised, open label, adaptive dose finding trial. BMJ Open. 2014
- Biankin AV, Piantadosi S, Hollingsworth SJ. Patient-centric trials for therapeutic development in precision oncology. Nature. 2015
- Antoniou M, Jorgensen AL, Kolamunnage-Dona R. Biomarker-guided adaptive trial designs in phase II and phase III: a methodological review. PLoS One. 2016
- Warner P, Weir CJ, Hansen CH, Douglas A, Madhra M, Hillier SG, et al. Low-dose dexamethasone as a treatment for women with heavy menstrual bleeding: protocol for response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM). BMJ Open. 2015
- Fardipour P, Littman G, Burns DD, Dragalin V, Padmanabhan SK, Parke T, et al. Planning and executing response-adaptive learn-phase clinical trials: 2. case studies. Drug Inf J. 2009
- Grieve AP. Response-adaptive clinical trials: case studies in the medical literature. Pharm Stat. 2017
- Whitehead J, Thygesen H, Jaki T, Davies S, Halford S, Turner H, et al. A novel phase I/IIa design for early phase oncology studies and its application in the evaluation of MK-0752 in pancreatic cancer. Stat Med. 2012
- Khan J, Yap C, Clark R, Fenwick N, Marin D. Practical implementation of an adaptive phase I/II design in chronic myeloid leukaemia: evaluating both efficacy and toxicity using the EffTox design. Trials. 2013
- Brock K, Billingham L, Copland M, Siddique S, Sirovica M, Yap C. Implementing the EffTox dose-finding design in the Matchpoint trial. BMC Med Res Methodol. 2017
- Cuffe RL, Lawrence D, Stone A, Vandemeulebroecke M. When is a seamless study desirable? Case studies from different pharmaceutical sponsors. Pharm Stat. 2014