Adaptive Clinical Trials Likely to Increase RAPS Program to Cover Regulatory Requirements

Posted 30 May 2013 | By

It's no secret that developing a new drug or medical device is an expensive and time-consuming endeavor. Often, despite the best efforts of those involved, traditional clinical trials end up wasting money, time and patients' goodwill on studies resulting in dead ends. Adaptive design clinical trials can give sponsor companies the flexibility to make changes to a trial in progress without compromising the validity of its findings. This flexibility can help make trials more efficient, increase their chances of success, reduce costs and time to market, and help increase opportunities for patients participating to benefit from the treatments being studied, which could also help boost trial recruitment efforts in the long run.

Clearly, there is a lot for companies involved in conducting clinical trials to like about using adaptive designs, and the adoption rate has increased in recent years. A new report from the Tufts Center for the Study of Drug Development (CSDD) found that adaptive designs are being used in about 20% of clinical trials, and suggests that usage is likely to "increase significantly" over the next few years, particularly for exploratory phase trials. There have been other indications that adaptive trials are poised to become a key topic in regulatory circles, as well. Last year, RAPS members created an Adaptive Clinical Trials Special Interest Group on RAPS' online member community, Regulatory Exchange, to facilitate discussion and education on the subject.

While more companies are warming to the use of adaptive designs, some hesitation from industry remains in implementing adaptive trials. The Tufts report points to internal resistance within life sciences companies as one of the primary limiting factors. In another study of professionals involved with clinical trials, from pharmaceutical market research firm ISR Reports, 94% of respondents said adaptive trials were at least somewhat risky.

Despite industry hesitance, regulators seem ready to work with sponsors designing and conducting adaptive trials and have shared their current thinking on them in several documents. The US Food and Drug Administration (FDA) issued its draft guidance on the topic in February 2010, and last year published a draft guidance on enrichment strategies for clinical trials that also touches on adaptive elements. For its part, the European Medicines Agency (EMA) published a reflection paper in 2007, and conducted workshops in 2007 and again in 2009.

The documentation helps explain how FDA and EMA view adaptive design trials and what sponsors should keep in mind when planning trials, but still there are challenges and pitfalls. Regulatory professionals working with companies using adaptive designs need to understand how they work and how to work with internal stakeholders and with regulators to ensure that adaptive trials are planned appropriately to both protect the trial's integrity and to satisfy agency requirements.

To help regulatory professionals better understand how adaptive design trials work as well as their unique regulatory demands, review case studies and get FDA's perspective, RAPS will host a half-day virtual program, Understanding the Regulatory Landscape for Adaptive Design Trials, 18 June, 12-5 pm EDT.

The program will examine the impact of adaptive design on the development process in both simple and more complex designs. Stella Stergiopoulos, project manager, Tufts CSDD, will speak, discussing the Tufts study and its findings. Sue-Jane Wang, PhD, associate director for adaptive design and pharmacogenomics, Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research, FDA, will discuss the agency's support for adaptive trials.

Other presenters for the workshop will be Vlad Dragalin, PhD, senior vice president, Innovation Center, Aptiv Solutions; and Phil Lavin, PhD, FASA, FRAPS, executive vice president, Innovation Center, Aptiv Solutions.

Aptiv specializes in adaptive trials and helps clients implement them. Lavin underscores the importance of ensuring trials are conducted to minimize any risk of compromising results. "The main risk is to ensure trial validity and integrity are not undermined, but technology, systems and processes are available to effectively manage this," says Lavin. On the other side of the equation, Lavin says, the benefits of adaptive trials include "more information per dollar invested, better product development decision making, reduced costs particularly at the portfolio level, faster product development and increased probability of success in pivotal trials. There are also considerable ethical benefits to patients."

Cost savings can come from stopping futile trials early or from reducing the number of unplanned changes. "Sponsor organizations could save hundreds of millions of dollars if they choose to stop a trial early," says Stergiopoulos. "Adaptive trials may reduce the total number of protocol amendments, thereby decreasing the cost of the trial. Tufts CSDD estimates that one protocol amendment costs around $500,000 and requires 60 days to implement," she observes.

This is one of the key differentiators of an adaptive design vs. a traditional clinical trial. "Pre-planned adaptations to the trial can be made at an interim analysis step without the need to submit a protocol amendment," says Lavin. But the pre-planning is critical and requires more up-front work than in traditional trials. They require a lot of advance planning and coordination, and this part is also important to FDA. "The very first definition in FDA's draft guidance on adaptive design is a 'prospectively planned opportunity to adapt,'" Wang pointed out during her presentation at last year's 2012 RAPS: The Regulatory Convergence in Seattle.

While FDA is invested in supporting adaptive trials and has answered some important questions in the guidance documents it has released, some in industry feel the need for additional direction from regulators. Stergiopoulos says that the Tufts study indicates many regulatory professionals believe the FDA adaptive trials guidance "does not provide enough clarity for the use of complex adaptive trial designs."

"The key to success is to approach the regulatory agencies with the right expertise and data package to support the adaptations you wish to consider in your protocol," says Lavin. "The simulation plan is a key document as is the use of validated software to run the simulations and select the adaptive design. The regulatory agencies will also want to know how you will execute the trial to maintain trial integrity. This will include what systems, processes and working procedures will be followed. The availability of comprehensive and prospectively written SOPs that define who will implement interim analysis and the adaptation plan are key."

Challenges remain in implementing a successful adaptive design trial, but the RAPS workshop presenters agree that adaptive trials are on track to quickly gain traction. The consensus at Tufts CSDD is that "drug companies will use adaptive trial designs more regularly, especially in exploratory phases," says Stergiopoulos. According to Lavin, "For drug trials, there is no doubt that adaptive design will be used more routinely particularly in exploratory development where learning more about the drug at Phase 2 is critical. The regulatory agencies are strongly supporting this. For device trials, the use of simple designs in pivotal studies will continue to rise."

For more information or to register for the RAPS virtual workshop, visit Understanding the Regulatory Landscape for Adaptive Design Trials.


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