Varuna Srinivasan MBBS MPH, National Center for Health Research, October 18th 2018
Thank you for the opportunity to speak today. My name is Dr. Varuna Srinivasan. I am a physician and currently work as a senior fellow for the National Center for Health Research. Our Center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest.
We have concerns about the drug in question today: Prucalopride
One of our primary concerns is that the clinical trials are not representative of the patients in the US that have CIC. The patients in the clinical trial are younger, white, and non-obese, with a low risk for cardiovascular events. That is not a representative group of patients. In addition, there is no information about other patient characteristics that may affect the safety and efficacy of the drug, such as smoking history, family history of heart disease, or other medical conditions and treatments related to constipation.
The only studies done in American populations were 2 studies completed in 1999. In addition to most patients being white and relatively young, they were probably less likely to be obese. I say that because the prevalence of obesity in the U.S. has increased dramatically in the last 2 decades, and is now 25-40% in almost all states today, according to the CDC. The American diet has also changed, as well as more sedentary habits and an increase in the use of prescription medications. We can’t assume that a trial done in 1999 that pertains to constipation is applicable today.
When we consider those shortcomings of the old studies and the new ones, there is not enough information for FDA to evaluate whether the benefits of this drug outweigh the risks for the U.S. population that is likely to be prescribed this drug if it is approved. There are too many differences between the patients studied in all those trials and the patients likely to be prescribed the drug in the U.S. In addition to obesity, diabetes, diet, and exercise, think also of the number of prescription drugs that older people in the U.S. take compared to younger patients from Australia, Asia and Europe. All of these health concerns could affect the safety of the drug.
Even in terms of something as important as drug interactions, we are unclear about the effect of prucalopride on other medications. For example, research trials done in Australia shows that this drug can reduce the efficacy of oral contraceptives taken by some women. This information is included in the Janssen label for resotran, but was not mentioned in the FDA review that you received. It seems likely that the drug would have a similar result in US women who are taking hormones for contraception, and could also have an unfortunate interaction for women taking hormones for menopause symptoms or to prevent estrogen-receptor positive breast cancer.
Biological and cultural factors affect the occurrence and severity of constipation episodes. The lack of diversity and lack of U.S. data mean that we cannot predict how effective or safe the drug will be in most of the patients that would be expected to be treated with the drug.
Lastly, the short duration of the clinical trials raises other safety concerns. The longest clinical trial was only 24 weeks long. This disease is a chronic condition, so patients would be expected to take this drug on and off for years. Many of the heart-related adverse events may take years to manifest. This is why FDA typically requires longer clinical trials for such drugs, so as to better identify additional safety concerns such as heart failure.
In summary, this drug was tested on a population with limited demographic variability and we should really focus on whether this drug will be effective and safe for the American population. The FDA must require further verification of the efficacy and safety of this drug in relevant populations in order to make an informed decision.
The advisory committee voted to approve Prucalopride 10-0 on 18th October 2018