February 12, 2014
Good afternoon. My name is Laurén Doamekpor, and I am a senior fellow at the National Research Center for Women & Families. Our non-profit research center assesses scientific and medical data and provides objective health information to patients, providers and policy makers. Our organization does not accept funding from pharmaceutical companies, and therefore I have no conflicts of interest.
We’ve examined the data provided to the FDA by the sponsor, and want to share our perspective.
We are concerned about the methodology used in the CHAMPION PHOENIX trial. It is worth noting that the two previous clinical trials, CHAMPION PLATFORM and CHAMPION PCI, were terminated because they failed to show that Cangrelor was more efficacious than the controls. It is essential for all of us to consider why the data from this 3rd trial shows a different result.
The sponsor’s data from the CHAMPION PHOENIX trial showed a statistically significant reduction in the risk of the primary composite end-point measure (death, myocardial infarction/ischemia-driven revascularization or stent thrombosis) at 48 hours with cangrelor compared to clopidogrel.
Unfortunately, the loading doses of the comparison drug were inconsistent, and that is the likely reason for the difference in efficacy. Ninety-eight percent of the cangrelor patients received the higher 600 mg dose. In comparison, only 74% of the clopidogrel patients received 600 mg. If only the patients taking 600 mg of each drug are compared, it seems that the outcome would no longer be statistically significant.
Manipulation of dosage is an unfortunate tradition in sponsor-funded comparative effectiveness research, as documented in research by Dr. Drummond Rennie, an editor at JAMA. He found that when researchers want to show how effective their drug is, they increase the dosage compared to the other drug. If researchers want to show their drug has fewer side effects, they increase the dosage of the comparison drug. Whether intentional or unintentional, the differences in dosages in the study you are considering today apparently influenced the results and those differences must be statistically controlled before the FDA makes an approval decision. And, even though there may be no universal guidelines for the timing of administration of the drug, the differences in timing also should have been controlled for statistically. Please urge the FDA to require a re-analysis or to revise the clinical trial to address these inconsistencies between the dosage and timing of the administration of the two drugs. That is needed in order to clearly establish the efficacy of this new drug.
Another major concern is the lack of representation of racial and ethnic minorities, women and the elderly in the sample. The PHOENIX trial included less than 30% women, only 18% above age 75, and 3% were Black/African American. We are concerned about the generalizability of the results and the use of this drug in non-White, female, and elderly populations when the drug has not been analyzed separately for these groups. The sponsor’s report states that cangrelor’s efficacy was demonstrated for subgroups based on gender, age and race. But this finding seems unlikely because these subgroups are too small for a meaningful subgroup analysis. In addition, no subgroup analysis is provided.
This is especially important since heart disease is the #1 killer of women and the elderly, and is a even greater problem in Blacks than Whites.
Studies show that cardiovascular risk may be higher for women and ethnic minorities following PCI. Without subgroup analysis, it is impossible to determine what, if any, dose is safe and effective for women, and for anyone other than whites.
Our final concern is about the safety of this drug for all patients. The data showed that certain subgroups of patients experienced more bleeding with canglelor compared to clopidogrel. Such risks might be worth taking if efficacy was firmly established, but that is not the case here. Such risks cannot be warranted.
We understand the pressure to approve a new drug and try to answer these questions in post-market studies. That is not acceptable when alternatives already exist. We know that physicians want new options for their patients, but those options should be adequately tested before the FDA approves them, not after.
Research has shown that the track record for starting and completing post-market studies tends to be slow, and patient enrollment is often slower and lower than required. Typically, it can take 10 years for a post-market study to be completed, and even then the promised subgroup analyses are often not done because of limited diversity in the trials. The companies no longer have the incentive to do the studies in a timely and complete manner once their product is on the market.
We urge you to ensure that the FDA require the sponsor to complete a trial that includes a more diverse sample and addresses the methodological concerns BEFORE approving this drug.