Three years ago a research team sponsored by Pfizer set out to establish whether neutrophil inhibitory factor (NIF) (UK-279,276) improved recovery in acute ischemic stroke patients; in a rat model, it had reduced brain infarct volume.
In a traditional phase II clinical trial, researchers would have compared a placebo to three doses of the drug. But even if the drug proved effective, the most precise dose response curve for the drug would have been unclear. And even if preliminary data showed an overwhelming benefit or futility in patients, researchers would not have been able to terminate the trial until results were in for all the study participants.
Instead, the team randomized 966 acute stroke patients to a group scheduled to receive either a placebo or one of 15 possible doses of NIF (10 to 120 mg). Using data obtained in this early part of the study, they could determine which dose range would provide the best information about the efficacy of the drug. The ASTIN (Acute Stroke Therapy by Inhibition of Neutrophils) trial design also enabled the team to end the trial when day 90 data from 500 patients showed that NIF was ineffective (Stroke 2003;34:2543).
Adapting trials to find an earlier proof of concept is not a new idea – but as it becomes more expensive to conduct clinical trials, the idea has become more popular. In July, the Food and Drug Administration announced that it would consider developing guidelines for adaptive trials as part of its Critical Path initiative, which aims to modernize and streamline the clinical trials process. Experts told Neurology Today that this would help advance research, but they emphasized that the guidelines must resolve several ethical and scientific issues.
WHAT IS AN ADAPTIVE TRIAL?
What defines an adaptive trial? It might take several forms, but in essence, the trial design may allow for modifications based on early results and while the study is still in progress. Scott Gottlieb, MD, FDA Deputy Commissioner for Medical and Scientific Affairs, said in a July speech that one well-known form of adaptive design enables a scientifically predetermined outcome to be measured and a treatment to be randomized to patients most likely to benefit from it. For example, a tumor drug could be targeted to patients with a specific tumor marker.
Another approach allows investigators to assess the patient sample size continuously, to avoid under- or over-allotment of patients. If the trend seems to move toward effectiveness of the treatment, more patients would be added to that study arm to accelerate reaching the conclusion.
Ira Shoulson, MD, Chair of the Huntington Study Group Executive Committee, said adaptive trial design has been evolving as a concept over the past ten years. “I think it's inevitable that we're going to be seeing more adaptive designs in clinical trials and this initiative is very welcome to those of us doing experimental therapeutics in neurological disorders, particularly those that are chronic disorders that take a lot of time to complete.”
Dr. Shoulson, Professor of Neurology, Medicine, and Pharmacology and Louis C. Lasagna Professor of Experimental Therapeutics at the University of Rochester, recently used an adaptive design to determine the safety and efficacy of the drug CEP-1347 in early Parkinson disease. After randomizing patients to receive either the placebo or drug twice a day – at 10 mg, 25 mg, 50 mg – the team concluded the study at 21.4 months of follow up, when the treatment was deemed to be futile. The study abstract was published in the July 11 issue of Neurology (67:185).
Marc Walton, MD, PhD, FDA Deputy Director of the Division of Neurology Products, told Neurology Today that this approach could help drug companies better determine which drugs are worth developing. With a traditional design, “you might pick a candidate drug that is ultimately unsuccessful but you have to carry it all the way through an extensive development program before finding that out. Then not only had there been resources wasted on an unsuccessful drug, but there's also been a delay in moving on to the next drug candidate, which might be a successful therapy.”
Dr. Shoulson said that about 80 percent of clinical trials end up with negative results, despite huge investments of time and money. “So the question is how can we improve on that to make the whole process more efficient, less costly, and more productive in terms of finding compounds that might be helpful to smaller populations of patients?”
FINDING PATIENTS WHO WOULD BENEFIT
Weeding out the patients who would most benefit from a particular therapy is key, said Darryl C. De Vivo, MD, Sidney Carter Professor of Neurology and Pediatrics, and Co-Director of the Center for Motor Neuron Biology and Disease at Columbia University Medical Center.
He said the concept driving adaptive trials is the well-known variability with which people respond to diseases and to treatments. “When you take a large patient population and enter them into a clinical trial, usually expecting the group response to be modest anyway, you may miss the beneficial response of a subgroup because that subgroup is mixed in with a subgroup [of people] who are not responding or who are suffering an adverse side effect.
“If we can improve on the study design as we go along, and say, ‘we found a certain number of people who have not responded to the drug or are responding poorly,’ and we cull them out of the study and examine the remaining population who are tolerating the drug and may be showing some benefit – we may amplify the drug benefit in this patient subgroup.”
An adaptive design could also prevent patients from being included in a control group for a therapy that is already suspected to be ineffective. “If… you can make that decision earlier on, then it would cut down the risk of continuously exposing people to something that's not helpful or even potentially harmful,” Dr. Shoulson said. This would also give patients more of an incentive to participate in clinical trials since there is less chance of being given a potentially ineffective or hazardous treatment, he said.
SOME LIMITATIONS WITH ADAPTIVE DESIGN
A major concern, however, is that design changes could be made too soon based on preliminary data. Dr. Walton noted, for example, that that the data might not be as accurate as that obtained if the trial had been allowed to run its entire course without revising the design. With studies that begin with dose-testing, for example, researchers analyze preliminary data and then choose several doses to continue testing. If the data are limited, this might lead them to choose a sub-optimal dose, which would distort the drug's safety and efficacy, he said.
Nestor Galvez-Jimenez, MD, Chief of the Cleveland Clinic Movement Disorders Program in Florida, said adaptive trials might be better suited to test a drug's effectiveness rather than studies aimed at changing the biology of a slowly progressive degenerative condition, such as Alzheimer disease or Parkinson disease. “If you want to change the progression of one of these diseases, you won't be able to bypass time,” he said.
Dr. De Vivo pointed out that there is also the potential for operational bias. “There may be unintended consequences when you modify a traditional labor-intensive, time-consuming, expensive clinical study design to make it more efficient and less costly. You may realize a result that is not reflective of the ultimate experience when the drug is given to the general public.”
Said Dr. Galvez: “Obviously, pharmaceutical companies are interested because it would make it easier and faster for them to get the benefit that they want, the response that they want, and they don't have to put in a lot of money to obtain the results.”
To avoid this, Dr. Shoulson said, adjustments should be decided only by independent researchers experienced in analyzing data; anyone with a conflict of interest should be excluded from the process.
FDA GUIDANCE IMPORTANT
Dr. Shoulson added that FDA guidelines would encourage researchers to explore alternative approaches. The guidelines, he said, should clarify which designs are considered adaptive trials, what kind of information is needed before adjustments are made, and what rules are in place for timing the analysis. The agency also needs to state who should recommend adjustments to the trial and how and when the recommendation is disclosed.
Dr. Walton said adaptive design is an attractive idea within the FDA and the general drug development community. “Any way that can improve the efficiency of developing good therapies is something everybody is interested in.”
ARTICLE IN BRIEF
✓ The FDA announced in July that it will develop guidelines for adaptive trials, but experts say that the approach raises several ethical and scientific issues.