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RCT alternatives useful, but require careful consideration
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Randomized controlled trials are the gold standard for testing novel interventions. Through careful evaluation in defined populations, they allow researchers to determine the safety and efficacy of experimental treatments in a way that leaves as little as possible to chance.
While such designs are often ideal, the sudden emergence of highly infectious diseases can render the time-consuming, resource-intensive trials impractical. It is an issue that surrounded the rise of HIV and West Nile virus, and it has resurfaced with the ongoing outbreak of Ebola virus.
“We accept that [randomized controlled trials (RCTs)] can generate strong evidence in ordinary circumstances; not, however, in the midst of the worst Ebola epidemic in history,” a group of senior health professionals and ethicists wrote in an open letter to The Lancet in October 2014. “The priority must be to generate data about effectiveness and safety as swiftly as possible, so that the most useful new treatments can be identified for rapid deployment. Alternative trial designs have the potential to do this more quickly, and with greatest social and ethical acceptability.”
Among these alternatives is what is known as an adaptive design. This can encompass a wide variety of approaches, with the most effective often involving steady increases in the dosage of an experimental treatment in infected patients. If the intervention appears to be safe and effective, and as production of the treatment expands, the cohort can be gradually increased.
Steven Joffe
Although such a design is faster, flexible and makes efficient use of limited resources, the lack of a reliable reference group can greatly hamper validity.
“You really have no placebo control population, so you may not get as clean a read on safety and adverse effects as you would like,” Richard Whitley, MD, distinguished professor of pediatrics, microbiology, medicine and neurosurgery at the University of Alabama at Birmingham School of Medicine, told Infectious Disease News. “That’s always a potential problem — you’d like to get as clean a read as possible, and the only way to do that is with a true placebo population.”
Certain situations, on the other hand, may diminish this concern, such as when the effect of an experimental treatment can clearly be observed.
“If you have a really good handle on the baseline, or what happens in the absence of the drug, then you might not need a randomized simultaneous control group,” Steven Joffe, MD, MPH, associate professor of medical ethics and health policy at the University of Pennsylvania Perelman School of Medicine, told Infectious Disease News. “For example, if you knew for sure that everybody died without the treatment, you wouldn’t need a comparison group because if you saw anything less than a 100% mortality rate, you would be confident that it is effective.”
Richard Whitley
There also are channels within the FDA that allow for the rapid evaluation of novel treatments. Upon receiving investigational new drug exemption, drug sponsors can also petition the agency to distribute the treatment under emergency conditions if early data appears promising, while physicians can request access to the drug through the Individual Patient Expanded Access Applications program currently under revision. In addition, experimental treatments may receive approval from the agency through the “Animal Rule” if, according to FDA documentation, the drug has proven efficacious in more than one animal species, does not appear to be hazardous to humans, and human studies are unfeasible and unethical.
These are guidelines that the FDA takes very seriously, Whitley said in reference to his own experiences working with treatments for West Nile virus. Although such allowances are rare, he is able to understand their scrutiny.
“I think the FDA — at least the people I know in the antiviral branch — are terrific, and they want to make decisions in the best interest of patients,” Whitley said. “They don’t want to impede drug development, but they don’t want it done incorrectly. Unfortunately, with these emerging infections, it becomes increasingly more difficult.”
The arguments for exemptions, adaptive designs and other alternatives to RCTs each come from a desire to reduce mortality during severe outbreaks. However, both Whitley and Joffe warned that situations of compassionate use have the possibility to do more harm than good, and that any means of accelerating treatment should have a minimal negative effect on the collection of clinical data.
“There is a very understandable public pressure to get treatments out as quickly as possible,” Joffe said. “You see people in need, so it’s very natural when there’s some kind of treatment out there for a life-threatening disease to want to use that.
“But at the same time, when putting in place public health programs, we want those programs to be evidence-based, which means doing careful evaluation. That’s a tension that we’re going to have to live with forever.” – by David Muoio
References:
Adebamowo C. Lancet. 2014;384:1423-1424.
FDA. Guidance for Industry: Product Development under the Animal Rule. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm399217.pdf. Accessed Jan. 25, 2015.
FDA. Investigational New Drug (IND) Application. www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investi-gationalnewdrugindapplication/default.htm. Accessed Jan. 26, 2015.
Disclosure: Joffe and Whitley report no relevant financial disclosures.