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Adaptive trial designs have the potential to transform success rates, but require new operating strategies and practices.
Risk-based monitoring, patient centricity, and investigative site management reform (e.g., selection, training, and accreditation) are widely cited today as critical areas that will transform drug development performance, cost, and inefficiency. Adaptive trial designs are one area that has received scant attention but that holds the near-term potential to have a far more transformational impact.
Adaptive trial designs are preplanned, typically through the use of trial simulations and scenario planning where one or more specified clinical trial design elements are modified and adjusted—while the trial is underway—based on an analysis of interim data. Most transformational approaches receiving attention today aspire to reduce cost and development duration. Adaptive trial designs could potentially improve success rate. With less than 20% of drugs that enter clinical testing ultimately receiving regulatory approval, modest increases in success rates have been a coveted yet elusive goal.
In late 2012, the Tufts Center for the Study of Drug Development (Tufts CSDD) conducted a study among 12 major pharmaceutical companies. Based on in-depth interviews, Tufts CSDD probed current adoption rates and their impact on drug development study economics and durations. As a follow-up to the in-depth interviews, in February 2013, Tufts CSDD hosted and facilitated a roundtable in Boston to gather a more comprehensive assessment of industry-wide adaptive trial design practices and perspectives. Forty senior executives representing 31 companies participated in the roundtable. Executives represented cross-functional viewpoints from clinical research and development, biostatistics, project management, and clinical operations. Perspectives from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were also represented in the roundtable meeting. This study was funded by an unrestricted grant from Aptiv Solutions.
The results of this study suggest that overall, simple adaptive designs are being used on approximately one out of five (20%) later stage Phase III clinical trials. Sponsor companies report, however, that they expect the adoption of adaptive trial designs in earlier exploratory phase clinical trials to increase significantly over the next several years.
"Study terminations due to futility" is the most common simple adaptive design used and it is becoming widely adopted throughout the industry. Sponsor companies unanimously agreed that early terminations due to futility are relatively easy to implement and should become standard practice in Phase II and Phase III studies, across all therapy areas. Although companies view sample size re-estimation as a relatively simple adaptive design, the adoption of this approach appears to be well below that of futility stopping.
The adoption rate of more sophisticated adaptive design approaches—dose-finding and seamless Phase II/III studies—appears low at less than 10% of clinical trials. Despite the fact that sophisticated adaptive designs during exploratory phase clinical trials could have the greatest impact on improving later phase success rates, Tufts CSDD found low use of adaptive dose finding and extremely low use of seamless Phase II/IIII studies.
Although the concept of adaptive trial designs has been discussed and explored by pharmaceutical and biotechnology companies for decades, adoption has been slow for a variety of reasons. Tufts CSDD interviews revealed that internal organizational resistance appears to be the primary factor limiting more widespread adoption. Regulatory agency receptivity to the use of adaptive trial designs does not appear to be a barrier to adoption. Agency clarity to sponsor companies on its position regarding the use of adaptive designs appears to be lacking.
Clinical teams and operating functions perceive enrollment and logistical factors—specifically delays and disruptions in trial execution, patient participation, and distribution of clinical supplies—as major barriers to adoption.
Sponsor companies express concerns around how to monitor data without introducing bias; the lack of adaptive trial design experience among both internal development teams and external contract research organizations; gaps in infrastructure and technology to implement more sophisticated adaptive designs; and the limited capacity of independent data monitoring committees.
Senior pharmaceutical company executives perceive that regulatory affairs functions are risk averse to adopting sophisticated adaptive design approaches due to their belief that more clarity from regulatory agencies is needed.
Regulatory agencies, in contrast, appear highly receptive to exploratory phase adaptive trial designs to challenge and inform clinical teams prior to committing to pivotal late-phase studies. The agencies are concerned that early development approaches are not efficiently detecting failures prior to Phase III or that decisions taken in exploratory development are sub-optimal leading to unnecessary Phase III failure. Using adaptive trial designs to perform Phase II dose response assessments, for example, could dramatically improve dose selection in Phase III clinical trials.
In theory, adaptive trial designs may help to reduce the number of protocol amendments. In a 2012 study conducted by Tufts CSDD, we found that sponsor organizations spend approximately half-a-million dollars in direct costs and an additional 60 days to implement each protocol amendment. In our interviews on adaptive trial design adoption, however, several sponsors have indicated that not all amendments will go away since certain country-specific health authorities will still require protocol modifications after pre-planned adaptations have been approved.
Early study terminations due to futility and sample size re-estimation could save up to a hundred million dollars in direct and indirect costs annually for a sponsor company depending on clinical trial scope, when the trial is actually terminated, and on the sponsor's overall implementation of this adaptive approach across the development portfolio.
A global top 20 drug development company that has been applying simple adaptive trial designs to Phase II and Phase III studies across its portfolio for five years reported saving more than $70 million each year through the adoption of simple adaptive dose-finding studies in Phase II and sample size adjustments and futility stopping in Phase III.
Sponsor companies recognize that the greatest potential value created by adaptive trial designs will come from improvements in late-stage success rates. Even modest improvements in success rates for new molecular entities (NME) and new biologic entities (BME) represent billions of dollars in increased revenue potential for research sponsors.
In the immediate term, adaptive trial designs are already offering cross-functional teams direct insights into study design through scenario planning and trial simulation prior to finalizing the protocol. Rigorous upfront planning is forcing organizations to challenge protocol feasibility prior to placing the protocol in the clinic.
In most sponsor organizations, awareness and knowledge about the usage and the potential impact of adaptive trial designs has been limited to statistical functions. Cross-functional education and support, aided by senior management encouragement, will go far in increasing general awareness and stimulating usage. Sponsor organizations that have established strong proponents among therapy area heads, medical experts, and clinical operations professionals in addition to their statistical functions—have been far more effective in promoting successful adoption.
Sponsor organizations higher up the adoption curve did so by starting with simple and straightforward adaptations (e.g., sample size re-estimation and futility analyses). Simple designs applied across the portfolio appear to ease the company into implementing adaptive designs and to facilitate a smoother transition to sophisticated approaches. Companies that have applied sophisticated and complicated adaptive designs to a few select studies early in the organization's adoption process have had a lot of difficulty promoting more widespread usage.
The adoption of more sophisticated adaptive designs in exploratory development may necessitate the use of new technology solutions and operating practices and will require organizations to re-evaluate their existing clinical operating processes.
Clinical operations teams will need to focus particular attention on obtaining expertise in planning and forecasting logistics and resource requirements under more flexible study designs. At this time, most sponsors have set very rigid performance and cost variance thresholds making it challenging for operating staff to entertain more variable capacity and resource planning practices. Clinical teams will also need to work more closely with investigative site personnel to ensure that patient safety and expectations are maintained under more adaptive clinical trial conditions.
Active and careful measurement of cost savings from the use of adaptive designs (e.g., futility analysis) is an essential ingredient in convincing organizations—particularly senior management—to continue to support and extend adoption. Companies that have led successful implementations have been particularly adept at publicizing quantitative measures of the impact of adaptive trial design use.
Adaptive trial designs represent a critical opportunity for pharmaceutical and biotechnology companies to transform drug development performance, efficiency and—most importantly—success rates. Beyond building awareness, as always, the challenge will be implementing successful adoption of simple adaptive designs leading to more sophisticated approaches.
Kenneth A. Getz MBA, is the Director of Sponsored Research at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, e-mail: [email protected]