CTSI Blogs

The Research Ethics Blog by Bernard Lo, MD

What Would You Recommend? - Case 2: Placebo Controlled Trials for Osteoporosis in Women

Two recent well-designed randomized controlled trials (RCTs) showed that two new agents, 1) lasofoxifene, a selective estrogen-receptor modulator, and 2) denosumab, a monoclonal antibody that inhibits osteoclasts, prevented fractures in women with osteoporosis.  The RCTs compared the new agent vs. placebo added to calcium + vitamin D.  However, other therapies are known reduce the incidence of fractures by 30%-50% compared to calcium + vitamin D. 

Placebo controlled trials for osteoporosis have been controversial when effective therapies exist.  Such trials are clearly unethical if participants are at risk for serious harm or if they do not give informed consent.  However, how do we determine whether harm is serious or whether consent is informed?  In one of the trials, incidence of hip fractures in the placebo was 1.2% vs. 0.7% in the active group, and the incidence of vertebral fracture was 7.2% vs. 2.3% respectively.  All hip fractures are serious; many vertebral fractures are clinically silent.  In these studies, all women were informed of the availability of drugs that prevent osteoporotic fractures.  If a participant developed a new fracture or her bone mineral density dropped below predetermined thresholds, she was referred to her treating physician to consider off-study treatments for osteoporosis.  

What would you recommend? Suppose you are a member of an Institutional Review Board (IRB) reviewing a clinical trial of a new drug for osteoporosis, comparing the new drug vs. placebo added to calcium + vitamin D. First, to ensure that the benefit/risk ratio in the trial is acceptable, what protocol requirements and IRB procedures would you recommend?  And second, what measures would you require to ensure that consent is informed and voluntary? 

Comments

For protocol requirements I would: -Make sure there is a formal protocol in place for patients with outcomes of fractures to seek additional therapies. -Make sure there is a DSMB in place to assess the progress of the study -Have clear pre-specified stopping criteria and time points, in case an effect is seen -Have a post-study plan to determine if a benefit is found, if patients randomized to placebo will be given active therapy, and who would pay for it. To make sure consent is informed and voluntary: -I would ask for a script to be included in the application, to assure that the wording used to describe other alternatives to the studied therapy is appropriately stated.

There will need to be monitoring for drug safety during the f/u period of this study. Since the new drug is being compared to placebo, you should include only patients at low-moderate risk for fracture (since there are proven efficacious therapies to help people at high risk, and it might be considered unethical to give placebo to this group). It should also be explicitly stated in the protocol that patients (and physicians caring for them) should have access to other osteoporosis therapies during the study period. Consent should be very thorough and all patients should understand that there are already proven therapies for the prevention of osteoporosis related fractures, and that those therapies are not part of the treatment protocol. The IRB will play a role in making sure the consent is honest and comprehensive. To ensure the "voluntary" nature of consent, it may be useful to have consent performed by someone other than the pt's PMD (with whom the pt may have a relationship and feel compelled to enroll).

Scientifically and ethically, the trial would have been better designed to compare new therapies to existing, efficacious therapies as opposed to 'placebo' (though in this case, even the placebo is, in fact a therapy, just not the most effective). However, given the current parameters of the trial, every effort should be made to minimize the risk of adverse events in the control population - this might mean enrolling only a low(er) risk population that wouldn't otherwise be on highly efficacious therapy (a costly choice); establishing frequent data safety monitoring with careful and unbiased adjudication of outcomes; and ensure that the consent form clearly identifies the alternatives to participation in the present study. Additionally, the IRB will need to ensure that incentives for participation in this study are not coercive since education relative to the options available for prophylaxis and SES may be co-linear.

I agree with this comment overall. In particular, McCabe makes a good point that it will be particularly important to monitor adverse events. In addition to his cautions that regarding incentives, I would add that any study offering medications to older patients should have a thoughtful consenting process due to other potential factors (i.e. cognitive decline) that make this population vulnerable.

I agree with J. McCabe's comment. He clearly hits all the points necessary to proceed before going forward in a trial that is not giving patients the best alternative to a test treatment. The participant pool will shrink since only lower-risk participants will be chosen but that comes with the territory of such a trial. I wonder whether the existing therapies could be used as a third option.

Firstly, I would ensure that the trial is restricted to those not already at a great risk of fracture. Second, I would make sure that the protocol calls for intensive monitoring for hip fractures, partly through careful education of the study's participants about the signs, and has provisions for termination in case it is no longer possible for the new drug to be as good as calcium+vitamin D. (Incidentally, I would be curious why the study authors did not consider a third group with both calcium and the new drug) In terms of informed consent, I would educate all participants about the consequences of a hip fracture, including the connection with decreased lifespan, and the high probability of receiving a placebo. I would also be sure to mention the results of previous studies measuring the efficacy of calcium+vitamin D in reducing fractures and compare that to previous trials with the new drug. Finally, I would make sure any payments and free medical care to the patients do not amount to enough to be coercive.

I would feel pretty strongly that any new drug for the treatment of osteoporosis should be compared to the existing therapy in an equivalence or non-inferiority trial. As the author of this post describes in the first paragraph, here are therapies that can reduce the incidence of fractures by up to 50% over the placebo. In the equivalence trial, the primary endpoint can be differences in the rates of hip/vertebral fractures between the new drug and the existing therapy, with secondary endpoints of side effects/adverse drug events, drug tolerance and participant adherence. Another strategy in which it may be ethical to test the new therapy is to use osteoporosis as an outcome, and look at women with reduced T scores or osteopenia. In these women, its a clinical decision to start an additional therapy with calcium and vitamin D, so it may be more ethical to offer them enrollment into a placebo-controlled trial. The outcome in this case would be osteoporosis (which may not be as clinically relevant to the manufacturers of the drug). In either case, women would have to be healthy volunteers, who understand that they may benefit from standard therapy, may receive placebo through this trial and may not benefit in any ways. I would want to have measures in place to prevent the development of severe osteoporosis in either group--so frequent DEXA scans and x-rays to assess for bone mineral density and silent fractures. I would also want to have a DSMB to assess for differences in event rates at interim times periods throughout the trial.

While I agree that an equivalence trial could be appropriate for this study, my concern is the conclusions investigators may draw if there is an unexpected result in the existing therapy arm compared to previous studies that evaluated the existing therapy. For example, if the existing therapy is able to reduce fractures by 60% in this study, but 50% in previous studies, and the new therapy reduces fractures by 50%, how would the investigators justify that the new therapy is just as effective (assuming the 10% is a significant difference)?

To ensure that the benefit/risk ratio is acceptable, the protocol must include safety features such as monitoring of BMD and referral for off-study treatments of osteoporosis as this trial did. Additional procedures including an external physician (or treating physician) performing additional visits to ensure that all participants including women on placebo fully understand that they should continue weight-bearing activity for exercise and if they experience a fall that they be monitored extremely closely with imaging and exams. To ensure that consent is informed and voluntary, detailed discussions about the pros and cons of the current treatments and the proposed alternative treatments must be conducted. Also, the fact that a placebo may be prescribed WITHOUT THEIR KNOWLEDGE must be explained and that the placebo may be WORSE than the known therapy that they may have actually been prescribed before by a PMD should be fully understood. Family members should be involved to help with this. The benefits of participating (e.g. increased monitoring, future benefits to others) must be explained as well. Risks of BMD falling and fractures while off known therapies should be detailed and procedures to avert these risks (as built in to the study, see above) should be described. At the same time, mortality risk from hip fracture should also be mentioned.

Given that there are other effective therapies for osteoporosis that have already been proven it is difficult to rationalize to possible study participants the benefit of testing a new drug. So to initially ensure that the risk/benefit ratio is acceptable in the trial, stict monitoring of the outcomes and appropriate referral to post-fracture treatment would need to be ensured by the investigators likely through the DSMB. Beyond monitoring, the investigators should also consider giving information and education about other therapies to both placebo and treatment subjects as part of the informed consent. Although this might make it more difficult to recruit subjects, it seems necessary to make sure participants are fully aware of all other proven therapies.