Toward a Consensus
Several groups have voiced concerns over the efficacy of preclinical research in recent years. Indeed, in its investigation, the McGill team identified more than 2,029 citations denoting preclinical guideline documents. Around half of those covered neurological and cerebrovascular diseases. This was not entirely surprising, Dr. Kimmelman says, because some of the earliest initiatives aimed at improving preclinical research began with stroke drug development, and were swiftly endorsed by researchers studying conditions like Alzheimer’s disease and amyotrophic lateral sclerosis.
Interestingly, though, the researchers found none that explicitly addressed the development of cancer drugs.
“We regard it as encouraging that distinct guidelines are available for different disease areas,” the researchers write in PLOS, noting that validity threats can be disease-specific. For example, they said, the confounding effects of anesthetics present a greater threat to the validity of cardiovascular preclinical studies than to those for cancer because anesthesia can affect heart function, but rarely impacts tumors.
Still, an apparent lack of cancer-specific preclinical research guidelines is a cause for concern. Shy of proposing a potential reason for this, Dr. Kimmelman points to the competitive nature of oncology drug development. “Adopting recommendations contained in the guidelines will require a change in culture of preclinical research,” he says. “That culture shift has just not yet penetrated cancer drug development.”
But the need for significant change extends beyond culture. Incentives must also be addressed. “Researchers and research sponsors—like all of us—respond to incentives and disincentives, and they calibrate their behavior against what others are doing,” Dr. Kimmelman says. “The task here is to change both the culture and incentive structure in preclinical research.”
To do so, he notes, will require the involvement of multiple stakeholders. Researchers should work to produce more robust and reproducible results, yes, but sponsors must also act. For their part, funding agencies should stipulate explicit criteria for the conduct of preclinical research and ethics committees ought to implement more rigorous reviews of proposed studies. Meantime, journal publishers ought to establish reporting requirements, and professional societies should promote better practices.
Overall, Dr. Kimmelman suggests it is high time preclinical research be interpreted in context. Achieving promising results in animal models is a critical step in the march toward the clinic, he says, but “the perception that a clinical trial launch is itself a milestone of clinical advance” is misleading. “It is [such a milestone] if the evidence supporting the launch is extensive and sound given the objectives of the trial,” he says. “If it isn’t, trial launch is less a marker of advance than foolish optimism.”
“Threats to validity in the design and conduct of preclinical efficacy studies: A systematic review of guidelines for in vivo animal experiments” was published July 23 in PLOS Medicine.