February 10, 2022
I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Our center is a nonprofit think tank that scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products. My expertise is based on post-doc training in epidemiology and public health, and as a faculty member and researcher at Vassar, Yale, and Harvard. I’ve also worked at HHS and the White House, and I’m on the Board of the nonprofit Alliance for a Stronger FDA, which educates Congress about the need to support the work of the FDA.
On a personal note, I am a cancer survivor, and so I understand the pressure to find new treatments. My goal today is to be as objective as I can in evaluating the evidence regarding Sintilimab.
There are many problems with the data supporting this application, but let’s start with the first mistake:
#1: The sponsor did not consult with the FDA regarding the trial’s design or conduct. That is almost always a big mistake, and it definitely is in this case. The result is a very inadequate trial design, including a non-representative group of patients.
#2: Most important to me, the study relied on progression-free survival as the primary endpoint. We agree with FDA scientists that other drugs in the same class have shown highly significant improvement in overall survival. What matters most to cancer patients is how long they will live and the quality of their remaining lives, not whether or not they die of the cancer they are being treated for. So what could possibly be the justification for approving a cancer drug that is not as good as those already available for the same indication?
#3: FDA is sometimes flexible about its usual requirements, especially when there is an unmet need. We agree with the FDA scientists that this drug does not address an unmet need, since several treatments proven to improve overall survival are already available. This drug review therefore “does not warrant regulatory flexibility.”
#4: As you know, the data are all based on patients in China. For the FDA to consider foreign data as the sole basis for marketing approval, the data are supposed to be applicable to the U.S. population and to U.S. medical practice. We agree with the FDA that the data presented today are neither. The population studied is not at all representative of the U.S.’s diverse population. Equally problematic, the study’s comparative control arm was based on chemotherapy alone, and that is not consistent with the U.S. standard of care. Therefore a different control group would be needed to determine the benefits and risks of Sintilimab.
FDA notes that the studies have NOT been performed by clinical investigators of recognized competence. And that FDA has not had enough contact with the investigators to be confident of their competence.
#5: The sponsor has proposed an additional study, but their proposed study does not address the serious design issues that have been criticized today. We agree with the FDA reviewers that this additional study does “not address the concerns regarding endpoint selection.”
In conclusion, you’ve been asked to vote on whether additional clinical trials with data applicable to U.S. patients and U.S. standard of care are necessary before a final regulatory decision is made. I am very concerned about the inadequate informed consent for patients in the study that was conducted. I hope you will agree that yes, additional trials are needed and they need to address all the major shortcomings of the data submitted so far before the FDA decides whether to approve it. Overall survival is the essential endpoint, at a level that is meaningful to patients. The patients studied must be representative of U.S. patients in terms of race, age, and other key variables, and the comparison group needs to have the kind of medical care that is the standard of care in the U.S.
FDA notes that they have more than 25 applications whose studies are at least predominantly based on clinical trial data from China. Each should be evaluated on its own merits, but the FDA’s decision regarding Sintilimab should not set a precedent for FDA approval decisions of medical products that are not appropriately studied to determine the risks and benefits of patients in the U.S.