Adaptive Design Can Reduce Time to Market, Lower Development Costs

With statistics showing that roughly 50 percent of Phase 3 study drugs never reach the market and financial and economic pressures limiting product development funding, clinical trial sponsors are giving new consideration to an approach that would allow them to evaluate interim data and either make mid-trial adjustments to move the study toward market approval or cut their losses and put their resources elsewhere.

This approach – adaptive design – could reduce both the cost and duration of clinical trials while improving their quality, according to Olga Marchenko, Global Head of Data Services Therapeutic Consulting, i3 Statprobe.

“Pre-planned analysis of accumulating data, conducted in a way that doesn’t undermine the validity of the trial, can create more efficient trials that produce more positive results,” she said. “However, adaptive designs require additional upfront work to ensure that all options are considered and that simulations, sophisticated technology and departmental coordination are utilized throughout the process.”

To be successful, adaptive design must include careful advance planning, be utilized only when clearly warranted according to established protocols, and include high-quality data and documentation. “Sponsors need to consider several factors when deciding whether adaptive design is appropriate for specific trials,” Marchenko advised. “For example, sponsors need to ask: What are the endpoints? How long will enrollment take? How large or small will the study be? Will there be sufficient time for thorough advance planning? Does the company’s infrastructure support the cross-functional coordination and implementation that is necessary for this approach?”

All studies should go through adaptive design review, she indicated. “Determining which statistical methods are right for a particular study design depends on the data and technology that you have and the study questions you need to answer.”

Adaptive design offers flexibility for certain trials

Adaptive design was defined by the European Medicines Agency (EMEA) in 2006 as studies in which statistical methodologies allow the modification of a design element (e.g., sample size, randomization ratio and number of treatment arms) at an interim analysis, with full control of the Type I error. That same year, the Pharmaceutical Research and Manufacturers of America (PhRMA) defined adaptive designs as multi-stage study designs that use accumulating data to decide how to modify aspects of the trial without undermining the validity and integrity of the trial.

“In general, when adaptive design is employed for an entire development program, sponsors can maximize allocation of patients, choose the best doses for patients and run fewer trials,” Marchenko said. “When an interim analysis of the data is done, the study may be stopped for overwhelming efficacy, at which point the sponsor can file for approval right away or, if the data show futility, discontinue the study,” she explained.

Adaptive design’s benefits also include improving patient care and truncating time to market. According to a recent article in the Drug Information Journal, adaptive design has “the potential to translate into more ethical treatment of patients within a trial (e.g., responsive-adaptive), increased likelihood of taking the right doses into phase 3 (e.g., model-based adaptive dose finding) and also faster product registration (e.g., seamless phase 2/3).”¹ Adaptive design’s potential advantages could transform the way certain trials are done, but, the article’s authors caution, “adaptive designs are not a substitute for poor planning” and investigators and sponsors should not “use them just to use them.” ²

Overcoming adaptive design barriers

Drug and biologics companies seeking to enjoy the benefits of adaptive design need to develop a road map that avoids some adaptive design pitfalls, such as introducing bias, undermining the study’s validity or simply failing to devote study planning and monitoring resources to adaptive design projects, according to Marchenko.

“Although there are distinct advantages of using an adaptive design process, there are barriers to doing it properly,” she said. “When you do adaptive design right, using developed protocols in advance to evaluate all of the studies on the radar, you can optimize efforts for a company’s whole development program,” she said.

One barrier is getting buy-in from the regulatory agency to which the sponsor will submit its premarket application. The Food and Drug Administration (FDA) issued draft guidance on adaptive design clinical trials for drugs and biologics in February 2010. In the draft guidance, the FDA concedes that adaptive design approaches may lead to studies that (1) are more efficient; (2) increase the likelihood of success on the study objective; or (3) yield better understanding of the treatment’s effect. ³

The agency adds, however, that although it “shares the interest of drug developers in these advantages … it also is concerned with several aspects of such approaches, notably the introduction of bias and the increased possibility of an incorrect conclusion.”⁴ In the FDA’s view, the two principal issues raised by adaptive study designs are as follows:

• Whether the adaptation process has led to design, analysis or conduct flaws that have introduced bias that increases the chance of a false conclusion that a treatment is effective (a Type I error); and
• Whether the adaptation process has led to positive study results that are difficult to interpret irrespective of having control of Type I error. ⁵

Additionally, the FDA notes that “protecting study blinding is particularly important to avoid the introduction of bias in the study conduct and to maintain confidence in the validity of the study’s results.” Marchenko suggested that sponsors can offset concerns about bias and validity of results by having an independent statistical center (ISC) and a data monitoring committee (DMC) analyze the interim data. “Expertise in interpreting this type of data and in the specific therapeutic area for which the drug is being studied also is an important factor,” she added.

Adaptive design requires a team approach

Understanding that an adaptive design approach calls for a paradigm shift in the product development arena is a significant step toward achieving the goals of this innovative clinical trial approach. For example, making sure that all product development functions are part of the planning process is key, Marchenko remarked, because so many departments – e.g., clinical, regulatory, drug supply – and staff members must be involved in the process to accommodate the adaptive design aberrations, such as a greater quantity of different doses for dose-selection studies, control of an enrollment rate, additional and timely meetings with regulators, etc.

To help sponsors navigate adaptive design barriers and to accommodate the growing popularity and the complexity of adaptive design trials, i3 Statprobe established the Adaptive Design Consulting Group in 2006. i3’s Adaptive Design Consulting Group works with sponsors early in the study design and planning stages to evaluate trials for adaptive design appropriateness.

The Group remains current with industry and academic research regarding adaptive design, provides consultation on the design, conducts trial simulation, supports statisticians working on adaptive design methodology, and provides training in the area of sequential trials, adaptive designs and Bayesian methods. Significantly, i3 Statprobe has extensive experience serving as ISCs and DMCs, which contributes greatly to the acceptance and credibility of adaptive design trial results.

Further, i3 Statprobe’s Adaptive Design Consulting Group has access to advanced simulation technologies – EAST, EastAdapt and AddPlan – which allows its consultants to design and run adaptive trials efficiently. Adaptive Design teams also have access to SAS, R and WinBugs, and EDC is used for all adaptive studies to collect and clean data in an efficient manner. “It is vital there be a balance between clean, high-quality data and the study timeline,” Marchenko explained. “i3 Statprobe understands that data extraction and analysis must be time-sensitive.”

When done correctly, adaptive design can be very beneficial, Marchenko noted. “i3 Statprobe can offer new ways of providing the quality, speed and efficiency that this type of trial mandates,” she said. “Adaptive design does introduce new statistical and operational challenges, but i3 can help sponsors overcome some of those challenges and focus on the rewards.”

¹ Gaydos, Brenda; Anderson, Keaven M.; Berry, Donald; Burnham, Nancy; Chuang, Christy; et al., “Good Practices for Adaptive Clinical Trials in Pharmaceutical Product Development,” Drug Information Journal (September 2009).
² Id.
³ “Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics – Draft,” FDA (February 2010).
⁴ Id.
⁵ Id.

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