February 9, 2023
I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Our nonprofit research center scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products. So, I have no conflicts of interest.
My perspective is based on post-doc training in epidemiology and public health, my previous policy positions at Congressional Committees with oversight over FDA, my previous position at the US Department of Health and Human Services, and as a faculty member and researcher at Harvard and Yale. I am also a founding Board member of the Alliance for a Stronger FDA, a nonprofit coalition that urges Congress to provide sufficient appropriations so that FDA can do its very important job.
On a personal note, a family member recently died of rectal cancer and I am well aware that this is a terrible disease and the standard treatment is toxic. A less toxic, equally effective treatment is needed. I find the research promising but there are too many unanswered questions that two small single arm trials can’t answer.
Designing a randomized controlled trial is our best chance to answer these important questions. These questions will be impossible to answer if the drug is approved for this indication a few years from now based on the proposed studies – because patients are much less willing to participate in a randomized controlled trial for a drug approved for the same indication.
#1: The sponsor proposes 2 open label single arm trials. You have heard that it may not be feasible to do a randomized trial. I am sure it would be difficult, but this specific disease is not so rare that it is impossible. It would be a mistake to give up on a well-designed study without even trying. There are patients who can only afford good treatment in the context of a clinical trial, or who are afraid to deviate from a well-established standard of care when there are no long-term OS data for the experimental treatment. The people recruiting patients for the trial need to clearly explain to patients why both arms of the randomized trial are good options – a proven treatment vs. a promising but unproven treatment. The standard of care arm can be smaller than the experimental arm but it should be randomized.
#2. As previous speakers have specified, rectal cancer patients who are treated at the best, high volume medical centers have much better outcomes than other patients. Memorial Sloan Kettering is not an average cancer center –it’s one of the best in the country, so we can’t assume their results are typical. 2 This is another reason why a randomized trial of a representative sample is so important.
#3. Patients deserve to be able to make treatment decisions based on meaningful clinical outcomes. That’s why a solid study design is so important. Overall survival is the key outcome, and quality of life is as well. The new treatment doesn’t need to be superior to standard of care but it does need to be proven to be at least as good.
And beyond the specifics of this FDA decision, let’s think of the big picture. When FDA allows single arm trials, it sets a dangerous precedent. Future sponsors will try to follow that precedent by also demanding single arm trials, and FDA will be pressured into making randomized trials optional instead of required. And as we all know: Without an appropriate control group, it is not possible to provide the type of evidence that patients and doctors need to make informed decisions. Even relatively small studies with a somewhat smaller randomized control group is better than a single arm trial.