Adaptive trial designs are nothing new to Scott Gottlieb. In 2006, when he was a deputy commissioner at FDA, he spoke about the benefits. The adaptive approach allows researchers to build in options that would allow them to adjust along the way, based on data collected, rather than locking in a study design from the start. This approach could make the trials larger or smaller, add or remove arms, or change how incoming patients are assigned.
Now Gottleib, President Trump’s choice to head FDA, is meeting with lawmakers who want to shorten the timeframe for drug and med device trials. He is again repeating his zeal for adaptive trial designs. If approved, he will encourage wider use of this approach. ScienceInsider has spoken to experts who expect there will be obstacles to wider use.
Gottlieb’s 5 April confirmation hearing before the Senate’s health committee was relatively smooth. And at times, the physician and health policy veteran offered adaptive trials as a possible solution to a number of problems raised by senators. When Senator Mike Enzi (R–WY) remarked that companies often have to “fight it out with FDA” in a lengthy process to get a drug approved, Gottlieb said new tools like flexible trial designs could make the agency’s review more efficient. He cited adaptive trials in explaining to Senator Tim Scott (R–SC) how the agency could incentivize new treatments for pediatric cancer. And when Senator Richard Burr (R–NC) wondered whether investigators should bother with double-blind studies at all, Gottlieb deflected with an assurance that FDA could at least accept adaptive trials, with their looser rules for randomizing patients.
“‘Adaptive clinical trials’ is one of those buzzwords that get brought up all the time,” says Rachel Sachs, an innovation and health law professor at Washington University in St. Louis in Missouri, and “there is definitely real momentum to actually do more trials this way.” She notes that in the 21st Century Cures Act, signed into law this past December, Congress required that FDA issue guidance and hold a public meeting to clarify how drug sponsors can use adaptive trials in their submissions for drug and device approvals. Legislation that must pass this year to reauthorize FDA’s user fee program commits the agency to create a pilot program to review such innovative trial proposals and the computer simulations that often guide them.
There is not a lot of hard data on how many such trials are proposed to FDA, but a recent study of applications for premarket approval to the agency’s Center for Devices and Radiological health found that of 225 submissions between 2007 and 2013, only about 10% contained adaptive designs.
Improve Speed And Effectiveness Of Epidemic Trials
When an infectious disease epidemic hits, there needs to be a rapid and robust mobilization of a clinical research program exploring whether investigational therapeutics and vaccines are safe and effective. This effort will, in part, depend on our ability to strengthen response and research capacities in low-income countries and engaging people living in affected communities. The mobilization effort will also necessitate conducting safety trials before an epidemic hits. Those are the findings of a new report from the National Academies of Sciences, Engineering, and Medicine.
Using key lessons learned from the Ebola epidemic in West Africa, the report outlines how to improve the speed and effectiveness of clinical trial research while an epidemic is occurring, especially in settings where there is limited health care and research infrastructure.
The research and development of therapeutics and vaccines is a long, complex, and expensive process and cannot be compressed into the course of a rapidly progressing outbreak. The development of a drug "from bench to bedside" is estimated, on average, to take at least 10 years and cost $2.6 billion, with less than 12 percent likelihood of eventual licensing.
Therefore, making progress on the research and development of products - such as therapeutics and vaccines - before an epidemic breaks is the only way to ensure that promising candidates are ready for trials once an outbreak occurs, said the committee that carried out the study and wrote the report. In addition, clinical trials could be more rapidly planned, approved, and implemented during an outbreak if promising products are studied through Phase 1 or Phase 2 safety trials in advance of an outbreak and if emergency response planning includes clinical research considerations and clinical researchers in the discussions from the beginning.
The 2014-2015 Ebola epidemic was the longest and most deadly Ebola outbreak since the virus was first discovered in 1976, resulting in 28,616 cases and 11,310 deaths in Guinea, Liberia, and Sierra Leone. In August 2014, the World Health Organization declared the epidemic a public health emergency of international concern. Researchers discussed how to conduct clinical trials on potential Ebola therapeutics and vaccines in West Africa, and ultimately, several teams conducted formal clinical trials in the Ebola-affected countries during the outbreak.
The clinical trial teams overcame immense logistical obstacles encountered while trying to design and implement trials in West Africa in the midst of a rapidly spreading epidemic of a highly dangerous contagious disease. However, none of the therapeutic trials ended with conclusive results on product efficacy, although limited evidence from the trial for the ZMapp treatment did trend toward a possible benefit. Given the resources, time, and effort put into these trials, they were not as successful as they could have been. The results of the vaccine trials were more fruitful. Two Ebola vaccine candidates have data that suggest they may be safe and produce an immune response, and one is most likely protective, but further data are needed.
Proposed Tax Change Will Benefit CROs
Pharma companies that conduct clinical research in-house essentially get a 100 percent tax break on the expenses incurred from that research (about 70 percent of which are typically wages). If that same company instead outsources that research to a CRO, it may claim only 65 percent of eligible expenses. The CRO gets no tax break. So, that 35 percent difference simply disappears. If a group of congressmen get their way, that situation might soon change.
“In many other countries, including Canada, France, U.K., Australia, and Austria, CROs may claim a portion of the tax credit as the entity employing the individuals conducting the research,” says John Lewis, SVP of policy and affairs for the Association of Clinical Research Organizations (ACRO). “In some cases, that can actually be 100 percent of the total tax credit. In the U.S., our model rewards the intellectual property holder (the sponsor) which is not necessarily the entity employing the researchers or conducting the research.”
According to Lewis, this leaves CROs with a perverse incentive to conduct clinical trials outside the U.S. This is certainly not the only factor CROs consider when deciding where to conduct research. Other considerations include disease prevalence, patient population, the regulatory environment, and availability of investigators, to name a few. But tax policy is definitely a consideration, and may be encouraging some companies to take their research overseas.
“Here is one example,” states Lewis. “I have seen a few situations where a CRO will purchase a facility, such as a lab, from a pharma company. When the pharma company owned the lab, the research conducted there qualified for the R&D tax credit. But the next day, with the CRO owning the facility and conducting the same research on behalf of several sponsors, the tax credit disappears and the CRO gets none of it. This happens, despite the fact that the CRO is conducting the same work in the same facility with the same employees.”
The bipartisan bill (H.R. 1234), also referred to as the Domestic Research Enhancement Act of 2017, would amend the Internal Revenue Code of 1986 by making CROs eligible for a 35 percent tax credit on research expenses incurred while working under contract. H.R. 1234 was introduced by Rep. Patrick Meehan (R-PA) and cosponsored by two North Carolina congressmen (Republican Rep. George Holding and Democratic Rep. G. K. Butterfield).
Can Selfies Improve Clinical Trial Medication Adherence?
It may seem a little invasive for patients to prove they have taken their medication with a selfie, but a study of AiCure‘s medication adherence tool by the National Institutes of Health (NIH) suggests that it can be effective. The findings were published in the journal, Stroke, in a paper authored by people associated with AiCure.
AiCure’s tool uses a form of artificial intelligence for facial recognition to confirm that patients have taken the correct medication. The 12-week randomized controlled trial evaluated the impact of the tool on adherence rates for diabigatran, rivaroxaban, and apixaban and warfarin compared with a control group. Plasma sampling from the 28 participants, who have each had an ischemic stroke, was intended to quantify effectiveness, according to a description of the study. The average age of the participants was 57 years old.
The findings showed that all of the patients using AiCure took their medication but only 50 percent (six out of 12 patients) in the control group took the anticoagulants. Given that learning new technology can be a stumbling block in digital health, the company said in a statement that it was encouraged that AiCure’s tool didn’t pose this problem.
Medications that have to be taken over a long-term period, such as anticoagulants, tend to be associated with poor adherence. A JAMA study noted that the need to improve adherence is less appreciated in anticoagulation therapy, because in the past, low prescription rate was responsible for a large percentage of underuse. Increasing physician adherence to prescribing guidelines has led to an improvement in prescription rates in past decades.