Testimony at FDA on Romosozumab to Help Manage Postmenopausal Osteoporosis

Varuna Srinivasan MBBS MPH, National Center for Health Research, January 16, 2019

Thank you for the opportunity to speak today. My name is Dr.Varuna Srinivasan. I am a physician with a Masters of Public Health from Johns Hopkins University, and a Senior Fellow at the National Center for Health Research.We 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.

I would like to commend Amgen for conducting several long-term studies with adequate racial representation. Unfortunately, they had several shortcomings that make it difficult to know who is most likely to benefit from Romosozumab and who is most likely to be harmed.

The study results indicate that the drug reduces the risk for vertebral fractures for postmenopausal women with osteoporosis – but the absolute risk goes down only 1% during the first year and less than 2% the second year.  That is a very tiny risk that does not benefit 98% of patients.  What are the clinical implications of these hairline fractures based on radiographic evidence rather than clinical symptoms?  Vertebral fractures are common in postmenopausal women over the age of 65 and many of them are asymptomatic and many never cause pain or health problems. In the manufacturer’s efficacy studies, the fractures were evaluated only via morphometric and radiological assessments.  As such, they do not measure meaningful outcomes for the patient, such as pain and other quality of life indicators.

Most important, while the reduction in vertebral fractures and some other measures were statistically significant, the absolute risk remained small.  Very few patients had any type of fracture in either the drug group or the placebo group.

Meanwhile, the results also indicate an increase in major adverse cardiovascular events.  In fact, the relative risk of major cardiovascular events is similar to the reduction in relative risk for fractures. Neither is a good outcome, but cardiovascular events are more likely to be fatal.

The meta-analysis showed an increased risk of MACE. We don’t yet know if that is an increase on average for all patients, or if some patients are at an even higher risk while others are not.  Additional clinical trials are necessary to determine whether some  types of patients are likely to benefit from this drug without an increased risk of a severe cardiovascular event.  Such research should examine potentially influential characteristics such as age, previous history of cardiovascular disease, and drug interactions.

This is important information that should be evaluated before the drug goes on the market for two reasons:  1)  Patients can’t make informed decisions without it and 2) Trying to obtain this information from post approval real world evidence would be very difficult. Once a drug is on the market and advertised, far more people are exposed to its potential side effects and interactions than would be the case in a pre-market clinical trial.

Relying on post-market databases and registries to tell us which groups of people are at-risk is a reasonable strategy for some treatments, but doesn’t make sense in this situation because the benefits are relatively modest compared to the life-threatening cardiovascular risks.  To protect patients from serious harm, the sponsor needs to re-analyze the data or collect new randomized double blind study data to enable them to identify the patients for whom the benefits are most likely to outweigh the risks.

In the interest of patient safety, we respectfully urge the committee today to require the manufacturer to re-analyze the data they have to focus on which patients are most likely to show meaningful benefit (reduced hip fracture) and which are most likely to have cardiovascular harm.  If such analysis is inconclusive, the sponsor should be required to conduct additional pre-market safety outcome trials for Romosozumab before approval to determine which patient groups would best benefit from this drug, and which should avoid it.

The panel voted 18 (yes) -1 (no) on the question: “Is the overall benefit/risk profile of Romosozumab acceptable to support approval.”