FDA's revised osteoporosis drug guidance should use fracture reduction as a primary endpoint, while increases in bone mineral density should remain a surrogate endpoint, FDA's Endocrinologic & Metabolic Drugs Advisory Committee said Sept. 25.

"I actually ultimately want to see fracture data on any drug that comes out that's going to be used for preventing or treating osteoporosis," Committee Chair Glenn Braunstein, MD, Cedars-Sinai Medical Center, said.

FDA convened the advisory committee to hear suggestions for clinical trial design for new osteoporosis treatments. The agency is revising its 1994 osteoporosis guidance, which recommended a BMD endpoint for a prevention claim for non-estrogens and a fracture endpoint for treatment.

FDA asked the committee when an increase in BMD could serve as the primary endpoint for a clinical trial of an osteoporosis treatment. Many in the committee stated that BMD increases do not adequately predict prevention or reduction in bone fracture risk. [View a ¹ webcast/video of this meeting at FDAAdvisory Committee.com.]

"As a prescriber, I would find it very difficult to prescribe a drug that I could not say to a patient caused a decrease in fracture rate," committee member Lynne Levitsky, MD, Harvard University, said.

Some committee members argued that in normal bone, low BMD leads to a high risk of fracture but that increasing BMD does not necessarily prevent bone fractures.

"There's actually no data to show that the population that's treated for prevention of bone loss is actually protected from fracture later on," committee guest Nelson Watts, MD, University of Cincinnati, said.

FDA also asked the committee whether there was any class of osteoporosis agent in which BMD would be a satisfactory endpoint.

Some committee members felt that BMD would be a satisfactory endpoint for bisphosphonates, a class with which clinicians already have experience. Merck's Fosamax (alendronate) and Proctor & Gamble's Actonel (risedronate) fall into the class for osteoporosis.

"In classes of drugs where we're confident about the relationship already between BMD and fracture risk...then accepting a bone density endpoint for registration of the drug with the presumption that it would translate into fracture reduction, I think, is adequate," committee guest Michael McClung, MD, Oregon Osteoporosis Center, said.

Classes with one or no approved drugs, such as selective estrogen receptor modulators, would require a fracture endpoint, the committee agreed.

Agents in which a link between BMD and fracture reduction has already been established could use BMD for new indications or dosing regimens.

"If we have a drug in class that has been shown to reduce fractures, and we can show that a different regimen of the same drug, or perhaps another drug in class, has the same effect on density and turnover markers, I would be much more comfortable and I would be willing to extrapolate, then, anti-fracture efficacy," Watts said.

However, some members argued that no class has yet demonstrated an adequate relationship between BMD and low fracture risk. "We're talking about class effects. How many amino bisphosphonates do we have on the market where this relationship is proven? Two. How many have been studied where this relationship wasn't proved? One, maybe two," Watts said.

During the open public hearing, representatives from Lilly and NPS Pharmaceuticals suggested that the revised guidance should correlate with international guidances so that international trials would be easier to conduct under uniform regulations.

The EU's Committee on Proprietary Medicinal Products guidance, issued in January 2001, does not consider BMD an appropriate surrogate endpoint for treatment of osteoperosis and recommends that a treatment trial last a minimum of two years.

Many committee members supported fracture studies of two to three years in duration. Some members said that efficacy in vertebral fracture and bone mineral density could be shown in 12 to 18 months, but that non-vertebral fractures would take longer.

"For BMD endpoints, I would want a minimum of a year, probably about 18 months, to show an increase. For fracture endpoints, a minimum of three years," Braunstein said.

"For safety endpoints, a minimum of five years, especially considering the wide distribution of these agents to a large number of the population who are also taking other medications," Braunstein added.

Committee members acknowledged that FDA might approve an agent following confirmation of efficacy, but in those situations, safety data should continue to be collected post-approval.

"For safety circumstances...both skeletal and extra-skeletal safety effects may not show up in nearly that time, and there needs to be, even if approval is granted, a plan to have long-term surveillance about safety type issues," McClung said.

Some members suggested creating incentives for companies to perform long-term safety trials by approving the drug for length of time the agent was studied.

"Link the approval to the duration of the evidence that's in front of you, in other words...it's approved for two, three, five, 10 years, or indefinite use, and that depends on the nature of the evidence you've been provided," committee guest Steven Cummings, MD, University of California-San Francisco, recommended.

Some members suggested creating a registry "where these patients, as long as they're on the drug, will continue to be monitored and information gets put into a database that is accessible to people about efficacy as well as safety issues and adverse events," committee member Marie Gelato, MD/PhD, State University of New York-Stonybrook, said.

Other committee members suggested using time to fracture instead of a three-year trial. Such a trial "would diminish the risk for any individual person," Levitsky said. "It does reduce the burden of the people who aren't treated. They at least don't get multiple fractures, or stay on it a very long time and accumulate the risk," FDA Office of Medical Policy Director Robert Temple, MD, said.

Industry recommendations made by Lilly, Roche, and GlaxoSmithKline agreed with the committee that fracture reduction should be the primary endpoint.

NPS, which is conducting Phase III trials for Preos (parathyroid hormone) in osteoporosis, recommended that FDA's revised guidance simplify and shorten trial requirements.

"It is clear that it is possible to demonstrate statistically significant increases in BMD in short periods of time with many agents, and statistically significant decreases in vertebral fracture incidence, for example, in less than three years," Thomas Marriott, PhD, VP development research NPS, said.

Members of the committee generally agreed that placebo trials in which all patients took a background of calcium and vitamin D could be conducted ethically for osteoporosis agents for lower risk patients, patients with low BMD but no recent or multiple fractures.

"For very low risk patients, there is no ethical concern about the safety of a placebo control trial, but there is, in my view, real questions about why one would do it, because it's less clear to me, as time goes on, about the need for pharmacologic intervention in very low risk patients," McClung said.

GSK cautioned that low-risk patients (i.e. patients with low BMD and absence of prevalent fractures) may not yield the best benefit-to-risk ratio. "Most of these patients would have little benefit to expect in terms of fracture risk reduction during the trial, but would still be exposed to the potential risk related to treatment-related adverse events," GSK said.

McClung ultimately recommended "a modest risk category. I am perfectly comfortable with patients such as those being involved in placebo-controlled trials, think that's the right group in which to do the studies."

Members of the committee debated the ethics of conducting a placebo trial in the presence of current efficacious treatment. "If the consensus among experts, like you guys, is that people with a certain condition ought to be treated to prevent those things, I think it's very difficult to say that leaving them untreated is easy," Temple said.

Committee members agreed that a high-risk patient, or a patient in a trial, who suffers multiple fractures, should be treated with active control.

Osteoporosis Primary Endpoint Should Remain Fracture Reduction

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