2004D-0035 - Draft Guidance for Industry on the Preclinical and Clinical Evaluation of Agents Used in the Prevention or Treatment of Postmenopausal Osteoporosis; Availability
FDA Comment Number : EC2
Submitter : Ms. Susan Mayer Date & Time: 04/13/2004 12:04:03
Organization : Organon Pharmaceuticals Inc.
Drug Industry
Category :
Issue Areas/Comments
Is it appropriate to continue to use placebo controls in fracture end-point trials?

Placebo-controlled trials with fracture end-points are quite important for new drugs which are intended to prevent fractures. It is not possible to test the fracture prevention effects of a new drug in either a non-inferiority or a equivalency trial since the sample size in such a trial with fracture rate as the primary end-point would need to extremely large (15,000 - > 30, 000 subjects per group). A trial of this magnitude creates not only an obvious burden on Sponsors but potentially on a very large group of subjects as well, in the event safety issues emerge during a trial with a new drug. In addition, it has been shown that placebo controlled trials in osteoporosis, which are conducted on relatively healthy populations, pose no significant risk of increased death in the placebo group. The following ethical questions/issues should be considered when evaluating the need for placebo-controlled trials in osteoporosis:
Do approved osteoporosis products decrease mortality or irreversible morbidity?
The addition of calcium and vitamin D to the placebo treatment to reduce the risk for the subjects
Exclusion of subjects with a high risk of fracture
The addition of a mechanism within the protocol to detect subjects with rapid bone loss or fracture

Placebo controlled trials are still the most efficient way and the best feasible option to show efficacy in treatment of osteoporosis, yet, individual risk should be minimized.

Do fracture end-point trials need to be 3 years in duration, or could shorter studies provide adequate evidence of new osteoporosis drug's effectiveness and safety?

It may be possible to shorten the duration of fracture endpoint trials by 1 year in order to get approval after 2-years, if:
1. an increase in BMD is seen in trials of 1-2 years duration,
2. good bone quality data is generated in the pre-clinical and clinical arena,
3. the trial continues as an open study for at least 1 year in order to collect more long term safety data
4. appropriate postmarketing surveillance is put in place