This post is a part of our Bioethics in the News series
By Hannah Giunta, MPH, PhD
The problem of balancing access to new drugs with the conduct of rigorous clinical trials is not new. Indeed, readers might be interested in checking out a previous Bioethics in the News column that dealt with the right to try novel therapies. But, despite all the coverage, answers are hard to find. The public want access to new therapies that are safe and effective; but, both patients and professionals remain relatively uninformed of how and why the current process operates as it does. While we may rebalance the benefits and burdens of drug development, we can never provide early and widespread access without risk.
During his campaign, President Trump repeatedly promised to eliminate red tape at the Federal Food and Drug Administration (FDA) and speed the approval process for potentially life-saving medications; although, just how he will attempt to accomplish these objectives remains unclear. But, many ethicists are alarmed that current regulations and requirements do not go far enough. Early phase trials are by their design risky propositions. A recent CNN article by Jen Christensen brings these concerns to the forefront. In the article, Christensen highlights the trepidations of several leading ethicists about the current clinical trial process, emphasizing the fact that clinical trial sponsors do not need to provide proof of efficacy in order to begin early phase trials even though the trials can have significant risks for participants. Christensen focuses on a 2016 French clinical trial where six healthy volunteers were gravely injured, and in one case even killed, during a phase 1 trial of a novel painkiller. Previous trials of similar compounds had shown the agents to be clinically ineffective, but the company was not required to show proof of possible clinical efficacy before launching the trial. Ethicists in Christensen’s article suggest that the solution is creating an independent advisory body within the FDA charged with evaluating preclinical evidence of efficacy. Is this a good idea? Possibly, if indeed there is sufficient scientific literature to review and that literature correlates to some degree with efficacy in humans. But, it will not change the necessary step of administering a drug to humans for the first time. No amount of animal testing can establish precisely what will happen in vivo. The very nature of experimentation necessitates a certain level of risk, and early access without risk is impossible.
In the current system, the FDA focuses on the safety and toxicity of compounds in phase 1 trials before moving on to efficacy assessments in phase 2 and 3 trials. The thought seems to be that toxicity is the first bar to overcome, since efficacy matters little if subjects are harmed by the drug itself. The classic model for phase 1 trials is the dose escalation study where participants are randomly assigned to receive an ever increasing dose of an experimental agent until unacceptable toxicities develop. In the current case, 90 healthy volunteers were recruited for just such a trial. News of a problem was first publicized in January 2016 after one participant was declared brain dead and five others were hospitalized (Bichell, 2016). Medical findings at the time indicated that the previously healthy man who died suffered a massive stroke in his brainstem. Five other men who received an equally high dose of the experimental agent after the first man became symptomatic were also hospitalized. Four suffered headaches, altered consciousness, and short-term memory difficulties (Bichell, 2016).
The question of how the trial went wrong is an indictment and profound misunderstanding of the current system. The investigators gave extremely high levels of the drug in order to determine what dose would be toxic and at what dose the pain receptor in question would be 100% blocked by the agent (Bichell, 2016). In other words, they did it for rigorous scientific reasons in accordance with their approved protocol. The scientific purpose of a phase 1 trial is to establish the dosage level that is toxic. Agents in a phase 1 trial are not dosed as they would be in clinical practice. A second complaint leveled at investigators concerns the fact that similar agents tested in previous trials had failed to markedly reduce pain (Bichell, 2016). Again, these complaints belie a poor understanding of the drug development process. Small differences in chemical structure can make a large difference in pharmaceutical outcomes, and scientists never know when a compound will radically change medical practice. The nature of research means that many drugs will not be successful, but a few will be. A final complaint lodged against the trial investigators suggested that some neurotoxicity in animal studies should have forced scientists to re-evaluate their plan for a phase 1 trial. But, even the scientist lodging this complaint admits that these injuries have happened with other experimental agents (not this particular class of drugs), and those agents caused no problems in human subjects (Bichell, 2016). Of note, the sponsor has made changes regarding how they are notified of subject hospitalization due to concern that additional volunteers received a high dose after the first man was hospitalized.
So, how does what happened last year in France factor into current promises to speed access to new drugs? By scientific standards, the phase 1 trial in question did not fail. It established the outer limits of toxicity. The outcry over what happened in France highlights the differences between how scientists think and how most patients and health care professionals think. Most drugs in the development pipeline will never gain FDA approval. Scientists are concerned with insuring safety and efficacy through a rigorous scientific process that takes time. What is a promising drug today may be a complete flop tomorrow. Expanding access requires that we accept a different standard of evidence (i.e. retrospective clinical data, clinical dosing guidelines without scientifically established maximum doses, etc.). Accepting different standards may make a lot of sense, but it will not mean access without risk. Perhaps the most important step we should take is to test drugs in people who suffer from the disease in question and not healthy volunteers. At least then, the burdens will be borne by those who stand to benefit. Yet, any of these solutions will not change the fact that medical progress is not a straight line, and we are putting people at risk today for the sake of tomorrow.
Hannah Giunta is an eighth year DO-PhD student at Michigan State University. She received her MPH in May 2015 and her philosophy PhD in May 2016. She is currently completing her medical school clerkships and plans to graduate in May 2017.
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- Bichell, R.E. (2016, May 3). Botched French Drug Trial Followed Rules But Lacked ‘Common Sense’. NPR. Retrieved from http://www.npr.org/sections/health-shots/2016/05/03/475867184/botched-french-drug-trial-followed-rules-but-lacked-common-sense.
- Brennan, Z. (2016, Nov. 10). What the Incoming Trump Administration may Mean for FDA, Biopharma and Device Companies. Regulatory Affairs Professionals Society. Retrieved from http://www.raps.org/Regulatory-Focus/News/2016/11/10/26163/What-the-Incoming-Trump-Administration-may-Mean-for-FDA-Biopharma-and-Device-Companies/.
- Christensen, J. (2017, Jan 30). After trial death and before Trump change, a call for drug approval reform. CNN. Retrieved from http://www.cnn.com/2017/01/30/health/fix-drug-approval-process/.