By Maxine Bookbinder 

 

January 28, 2014 | In an industry not known for change, more pharmaceutical companies are embracing adaptive clinical trial designs to boost success rates, decrease costs, and hasten timelines.  “This may be the Renaissance period for adaptive trial designs,” notes Kenneth Kaitin, PhD, Director of the Tufts Center for the Study of Drug Development. 

 

Adaptive trial designs began around 2000, but have been slow to emerge due to a lack of independent statistical confirmation, initial FDA concerns, application refusals, long clinical timelines, and general fear of the unknown.  “You never know what will happen when you submit a new drug or biologic application to the FDA,” says Dr. Kaitin. There is always the risk that additional studies will be required or the application will be rejected, which can negatively impact a company’s growth prospects as well as an individual’s career.    

 

Adaptive trial designs are identified as clinical trials with built-in interim analysis of accumulated data. Approximately 20 percent of current trials use adaptive designs. 

 

The interest in adaptive design is growing. “The drug development model has not fundamentally changed in 50 years, when the Kefauver-Harris Amendment established the current standard for clinical testing of investigational drugs,” says Dr. Kaitin. “A new model is needed.” 

 

Despite their slow emergence, adaptive designs are a positive addition to trials. They provide information more efficiently, increase the likelihood of success, and yield improved understanding of a drug’s effect, which can then lead to more efficient, subsequent studies. Simple adaptive designs, such as those that allow the sponsor to reach a go/no go decision point sooner, are growing. A 2013 Tufts report, The Adoption and Impact of Trial Design, notes that Phase II and III futility analyses should become trial standards.   

 

Adaptive designs provide increasing awareness of individual differences in patients and can home in on personalized, or target, populations more effectively.  In traditional studies, says Dr. Kaitin, researchers must typically first complete a clinical study, mine the data for evidence of efficacy in specific populations, and then redo the study with just this group. An adaptive design allows researchers to analyze data at an interim point, resulting in a shorter trial, fewer patients, and quicker demonstration of drug efficacy.  It could also speed the time to a company’s decision to terminate a likely unsuccessful drug candidate, saving time and money and avoiding unnecessary exposure of test subjects to investigational drugs. Critics argue, however, that this might cost extra money, since someone needs to un-blind the study and review the data. 

 

However, this additional cost can become cost-effective; adaptive designs can reduce the number of required protocol amendments. One protocol can cost up to $500,000 and take 60 days to implement. In addition, interim futility and sample-size data analysis that result in termination can save companies millions of dollars yearly.   

 

In the last few years, the incentive to use adaptive designs has increased, due to rising costs of trials and a decrease in drug developmental success. Some corporations have devoted resources to incorporating adaptive design into their trials, even encouraging other companies to adopt it. “This is not altruistic on their part," notes Dr. Kaitin. “No one wants to be the only company doing it.” As more companies submit applications with adaptive design, the FDA’s comfort level with and acceptance of these trials will grow.”   

 

Adaptive designs aren’t for short trials or those with poor Phase III success rates.   When incorporated, they must be planned, not just inserted as an impromptu afterthought. Occasionally, says Dr. Kaitin, an intuitive sense to stop a trial early, analyze data, and tweak dosage can save time and money. 

 

“It’s important to get buy-in up front,” advises Dr. Kaitin. “Discuss it with and get feedback from the FDA before beginning the trial. The FDA does not like surprises at the time of application submission.” 

 

With advantages come weaknesses. Adaptations must be kept to a minimum to avoid complicating a specific trial. Ad hoc changes based on unblinded data can endanger study integrity. This risk, however, can be eliminated by justifying interim analyses and avoiding routine interruptions or when it is suspected that insufficient data will be drawn.   

 

Adaptive designs may offer an additional advantage: the creation of truly integrated cross-functional teams within a company. Team members, for example, from R&D, clinical, statistics, discovery, regulatory affairs, and marketing groups often work and plan trials together from the onset, foresee potential difficulties, and insert adaptive designs together. 

 

Traditionally, “functions within companies are siloed,” says Dr. Kaitin. “They don’t talk to each other. Cross-functional teams allow for better communication and knowledge-sharing, and can dramatically increase R&D efficiency.” 

 

Dr. Kaitin adds that pharma “for a long time has been enamored with small companies and biotech that appear to embrace cross-functional teams naturally—and often out of necessity.”  However, he states the idea that small companies develop products faster and cheaper may be more “a perception than a reality.”