The roundtable will bring together a select group of senior level biopharmaceutical company executives from multiple functions and therapeutic areas to discuss — in a closed room setting — the adoption, impact and integration of adaptive trial design approaches. Tufts CSDD will present the results of research characterizing the impact of adaptive design approaches on reducing clinical trial cost and time. Senior executives from several major pharmaceutical companies discuss their strategies and experiences with adaptive trial design approaches. And representatives from regulatory agencies will participate on a panel to discuss their role in assisting in the adoption of adaptive designs.

This is a very timely topic. The executive roundtable format offers a unique opportunity for senior level decision makers to share experiences, ideas and insights in an open forum with their peers. The roundtable will begin at 9:30am and run through 3:30pm. For more information visit http://csdd.tufts.edu/courses. Also follow @AptivSolutions for Twitter updates throughout tomorrow’s event.

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Although adaptive design concepts have been available for some time, only recently has implementation (especially for complex design trials) been achievable. This breakthrough has been possible because of the development of integrated technologies specifically designed to support the execution of ACTs. The utilization of adaptive execution technologies alongside specific adaptive processes governing biostatistics, data management, project management and monitoring is opening up the potential for wider use of adaptive designs in clinical development.

In our view, the following are the top five reasons for implementing adaptive trial technology:

1. Ability to Change Course During a Study

In a traditional clinical trial, very few changes can be implemented after a recruited subject was assigned to a treatment protocol. In contrast, in clinical study that uses adaptive trial design, a specific Data Monitoring Committee (DMC) can have multiple access points to information about drug efficacy and safety during the study. The DMC can then use that information to make pre-planned adaptations to the trial to optimize treatment protocols at later stages of the trial, and in such way increase the value of information generated by the trial (http://contractpharma.com/issues/2011-05/view_features/the-growth-of-adaptive-designs/).

2. Increased Flexibility in Dosing

Enhanced flexibility of drug testing is the major advantage of an adaptive trial design. In conventional trials, the only option to deal with drug toxicity is to stop the study. In adaptive clinical trials, drug doses with potentially toxic effects are initially tested in a small group of subjects. The doses with toxic effects are abandoned early and patients are re-assigned to a different treatment group. Vice versa, the doses without any effects are also stopped. This is also important because it limits the futile usage of resources. These patients can also be re-assigned to a different treatment protocol.

3. Improved Sample Size Estimation

For success of a clinical trial it is critical to obtain conclusive data. The failure to achieve this may occur when patient sample size was underestimated. In adaptive trials, it is possible to assess the statistical power of observed effects and adjust the sample size during the course of the study. Thus, adaptive trials enable the ability to “play the winner” by focusing the efforts on the most relevant experimental setting. Estimation of statistical power may also make it obvious, that the effect of tested compound is profound and that the originally planned sample size is too large. Continuation with such sample would lead to unnecessary use of resources. Thus, the possibility of relevant adjustments to sample size brings forward another key benefit of adaptive designs – cost reduction.

4. Shortened Development Time

The return on investment for a new product is driven by the time it takes to get the product to the market – and hence the length of the clinical development process. Adaptive clinical trials make it possible to implement streamlined strategies, and in turn, shorten the time to market. Where traditionally two conventional trials would be required, adaptive designs offer the possibility of combining the trials into one.  For example, at early stages, proof of concept and dose ranging can be combined; while at later stages, phases II and III phase can be merged into a seamless design.

5. Data Quality and Objectivity

Finally, adaptive clinical trials assure obtaining high quality data with enhanced objectivity due to the advanced planning and transparency of interventions. This in turn minimizes the possibility of failure of the clinical trial, which represents the most significant futile cost to sponsors.

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Benjamin Hunting
Aptiv Solutions Blogging Team

The ‘Best Practices for Adaptive Clinical Trials’ guidance covers topics such as when the implementation of adaptive trials is appropriate, and describes the major advantages of this type of design from a cost, data quality, and patient safety perspective.  More importantly, it outlines the expectations of FDA reviewers when evaluating a given study and creates a roadmap that CROs and sponsors can follow to create the most effective adaptive trials possible.

According to FDANews, the FDA identifies five adaptive clinical trials design models within the guidance:

1. Using baseline data to alter study eligibility criteria
2. Using blinded aggregate data to maintain study power
3. Adapting a study based on interim data indicating an outcome unrelated to efficacy
4. Early study termination based on group sequential methods and unblinded analyses
5. Changing the analysis plan to accommodate nonconforming data

Six additional ‘alternate’ adaptive trial design models are also listed, providing a total of eleven options for investigators looking to implement best practices. These models are all expected by the FDA to be supported and strengthened by prospective planning that anticipates potential modifications to a trial in the design phase, controls for bias and error (especially when discussing alternate models), as well as a cohesive set of protocols and analysis plans for statistics throughout all trial phases.

‘Best Practices for Adaptive Clinical Trials’ is a must-read for any organization currently in the planning or pre-planning phase of their first adaptive trial, as well as vital guidance for sponsors and researchers looking to fine tune their adaptive trial execution.  Moving beyond the nuts and bolts of what the FDA requires when evaluating an adaptive design, the guidance document also offers valuable insight concerning the obstacles that these types of studies typically encounter, discusses what modifications are viewed as suitable for a given situation, and also offers an overview of the Administration’s current attitude towards adaptive clinical trials.  An extensive series of appendices attached to the guidance also offers a thorough reference for investigators at any stage of the design process.

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• Download a new report from the Tufts Center for the Study of Drug Development.

Benjamin Hunting
Aptiv Solutions Blogging Team

Current FDA regulations do not explicitly describe how rigorous source data verification (SDV) must be in a given clinical trial, which has led investigators to lean towards 100% SDV in order to ensure both quality and regulatory compliance. The issue with this costly approach is that it ignores the fact that the FDA is primarily interested in sound monitoring methodologies that are capable of ensuring patient protection and data quality. The definition of ‘adequate monitoring’ is left in the hands of trial sponsors, which provides ample leeway for innovative and cost effective strategies.

Moving away from regularly-scheduled on-site monitoring can introduce both economic efficiencies as well as improvements in data quality. Reducing the travel required to visit each and every trial site, as well as the number of monitors needed to effectively cover an entire investigation, can lower the cost of a study by a considerable amount. Choosing a central monitoring strategy also allows for real-time analysis of study data that can reveal anomalies and trends in a study design that can be corrected and reacted to more effectively during the course of the investigation.

Investigating non-traditional approaches to trial monitoring further reveals a long list of intriguing possibilities for drug companies seeking to streamline their clinical investigations without jeopardizing safety or quality of data.

• Risk-based monitoring targets data points which are most likely to make a significant impact on the quality of the study and which have been determined to be more error-prone in terms of interpretation. This methodology has been highlighted by the FDA as a more effective tool than 100% SDV and on-site monitoring.
• Adaptive monitoring takes this one step further by using the approach developed for adaptive clinical trials in order to customize the level of SDV and the number of required site visits based on actual study results.
• Remote monitoring takes the central monitoring concept further by moving many traditional on-site activities off-site, improving the flow of data from each trial location and reducing the monitoring burden by a considerable margin.

With the weight of the FDA now behind adaptive, risk-based, remote, and central monitoring methodologies, a greater number of sponsors have become interested in discovering how they can best leverage these techniques to improve their own study data as well as cut costs. Aptiv Solutions has developed a specific technology platform that supports these new monitoring techniques for adaptive clinical trials. However, this technology platform can also be used for traditional trials,  enabling sponsors to realize the efficiency benefits of these new approaches across a wide range of studies.

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Benjamin Hunting
Aptiv Solutions Blogging Team

It is this desire to reduce drug development time and lower the overall investment in each product that has caused a greater number of pharmaceutical companies to shift from traditional clinical trials to adaptive trial design. The real benefit of an adaptive design trial is the increased value of the information that arises from the trial which enables drug developers to make better decisions, leading to cost efficiency, reduced rework, and the selection of the right treatment to carry forward into future studies. Thus, the total value of an adaptive approach has to be measured across the entire development program and not just at a single step.

The Tufts CSDD noted in its report that many executives in the pharmaceutical industry are seriously considering the incorporation of adaptive trials in their R&D strategies. These same companies have begun to look into the advantages offered through partnerships with contract research organizations that offer expertise and experience in adaptive trial execution. The ability for CROs to eliminate many of the costs associated with traditional clinical trial designs has become a key aspect of the relationships between these entities and Pharma. CROs now employ the majority of the world’s clinical development experts – many of whom see the advantages of an adaptive approach – and the depth of institutional knowledge represented by these groups is providing additional weight to support the promulgation of adaptive trials.

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Benjamin Hunting
Aptiv Solutions Blogging Team

In the face of increasing demands for better, safer and cheaper drugs, however, decreased R&D productivity is creating a fundamental problem for the industry. The authors call for a more radical mindset and for the implementation of changes that correspond to recent developments in science, technology, and society over all.

To show that the change is inevitable, the authors analyzed the period between 1996 and 2010. During that time, 450 new therapeutic drugs were approved by the FDA and placed on the market. The earlier part of this period – from 1996 to 2004 – was characterized by the robust approval of new drugs and the high return on capital, hence the name “Era of Abundance.” This era ended in September 2004 when Merck voluntarily withdrew its major money-maker, Vioxx, from the market. The FDA responded to this situation by imposing stricter regulations. Consequently, the rate of drug approvals has decreased by 40% since 2004. The world economic crisis also contributed to weaker sales and low return on capital. Hence, the years from 2004 to 2010 earned the label “Era of Scarcity.”

After shedding light on multiple intrinsic problems arising from the earlier mindset of pharmaceutical companies, the authors speculate about how the industry should change to create more products, while spending less. They suggest four primary shifts: raising the bar on innovation; considering the payers’ problems; treating drugs as rare; and playing to win (e.g. creating a better balance between competition and collaboration among companies). Finally, the authors discuss in detail how the industry should implement these changes.

Aptiv Solutions has already addressed many of these suggestions in its efforts toward replacing conventional clinical trials with adaptive trials.  Adaptive clinical trials rely on the timely collection of data in defined interim analysis steps providing the opportunity for the trial to adapt to emerging data. For example, following an interim analysis, a decision may be made to re-estimate the size of the trial, stop the overall trial for futility, drop ineffective treatments, or change the randomization allocation in favor of more effective treatments in defined sub-populations of patients. Importantly, these are not ad-hoc changes but are design changes that are pre-specified and planned in advance, which is essential from a regulatory perspective. There are also ethical advantages with fewer patients on unsafe or ineffective doses.

While adaptive design concepts have been available for some time – only recently has implementation (especially for complex design trials) been achievable. This breakthrough has been possible because of the development of integrated technologies specifically designed to support the execution of adaptive trials. Adaptive implementation technology is also opening up the potential for wider use of innovative adaptive designs which will dramatically increase the efficiency of the whole clinical development process.

Thus with an adaptive approach the risk for patients significantly decreases,  the likelihood of meeting FDA regulatory standards and the yield of conclusive data increase,  and, in turn, pharmaceutical firms should realize greater returns on their investment.

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Amid this change, one response that has been rapidly gaining ground is the acceptance and use of adaptive design trials as a key component of the clinical development process. An adaptive trial is conducted in stages where interim data is used to plan the next stage of the trial. Drug and medical device developers can use this approach through all phases of clinical development to modify aspects of the study without undermining the validity and integrity of the trial. Regulators in the US and Europe support the use of adaptive design trials, and both the FDA and EMA have published Guidance Documents on the implementation of adaptive design trials.

As the only pharmaceutical and medical device development company to offer design, implementation, and execution of adaptive clinical trials, our goal is to use this blog to educate, inform, and engage readers on the use and value of adaptive design trials in modern day clinical development. To support this important initiative, we have created an in-house Innovation Centre comprising world-leading adaptive trial experts who are available to provide insight into the design and conduct of adaptive trials in which the ultimate objective is to generate high-value clinical data that enables smarter product development decision making.

We look forward to sharing news and information about the rapidly evolving field of adaptive design trials. We will provide education on tools and technologies that are essential for adopting an adaptive approach, and we hope to engage and connect with the growing community of adaptive trial innovators who are integrating this exciting approach into their product development programmes, and who will ultimately benefit from its success.

Next Steps

• Subscribe to our blog to stay informed on industry news and insight.
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Aptiv Solutions Blogging Team