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.

I agree with Nicholas. While I believe it is unethical to proceed with the placebo treatment in this trial, if the trial is irrevocably designed this way, patients should be given clear and explicit information about the possible consequences of both the placebo and drug. Also, the utility of this study would be increased if the new drug were compared to existing therapies.

I would recommend the following protocol changes: Subjects: Exclude women with a prior hip or vertebral fracture. Monitoring: have the DSMB monitor for adverse events closely and do interim analyses in case the placebo group is having statistically significantly more events earlier than the end of the study period. Intervention: could consider a non-inferiority trial with one of the other more effective interventions already available. Informed consent: Make sure that patients know that there are other drugs available that are proven to be better than the placebo arm, and that they may end up getting only the placebo, Vit D and Ca intervention.

If it is reported that there are other therapies which have better efficacy compared to a placebo treatment, study investigators and board members should look into those options thoroughly. First of all, we have to check if the reported efficacy is convincing enough. The results should be derived from well-designed and appropriately approved clinical trials. Next, the safety issues and the reimbursement strategies for the other options need to be reviewed as well as the efficacy results. If the other therapies have great efficacies but also have serious safety issues or unaffordable reimbursement strategies, those should be excluded from the treatment options in the prospective study here. From the review process, if superiority of the existing other therapies are confirmed, the placebo treatment (here, placebo added calcium + vitamin D) needs to be replaced. Study participants should be informed all the information about every treatment used in this study including incidence of reduction rate of the control group and all possible adverse effects. Before getting efficacy data to ensure benefit of the new drug, a Phase I clinical trial with dose-escalating should be performed first to observe its side effects and secure its safety. Posted by Sungwon Lim.

If it is reported that there are other therapies which have better efficacy compared to a placebo treatment, study investigators and board members should look into those options thoroughly. First of all, we have to check if the reported efficacy is convincing enough. The results should be derived from well-designed and appropriately approved clinical trials. Next, the safety issues and the reimbursement strategies for the other options need to be reviewed as well as the efficacy results. If the other therapies have great efficacies but also have serious safety issues or unaffordable reimbursement strategies, those should be excluded from the treatment options in the prospective study here. From the review process, if superiority of the existing other therapies are confirmed, the placebo treatment (here, placebo added calcium + vitamin D) needs to be replaced. Study participants should be informed all the information about every treatment used in this study including incidence of reduction rate of the control group and all possible adverse effects. Before getting efficacy data to ensure benefit of the new drug, a Phase I clinical trial with dose-escalating should be performed first to observe its side effects and secure its safety. Posted by Sungwon Lim.

If it is reported that there are other therapies which have better efficacy compared to a placebo treatment, study investigators and board members should look into those options thoroughly. First of all, we have to check if the reported efficacy is convincing enough. The results should be derived from well-designed and appropriately approved clinical trials. Next, the safety issues and the reimbursement strategies for the other options need to be reviewed as well as the efficacy results. If the other therapies have great efficacies but also have serious safety issues or unaffordable reimbursement strategies, those should be excluded from the treatment options in the prospective study here. From the review process, if superiority of the existing other therapies are confirmed, the placebo treatment (here, placebo added calcium + vitamin D) needs to be replaced. Study participants should be informed all the information about every treatment used in this study including incidence of reduction rate of the control group and all possible adverse effects. Before getting efficacy data to ensure benefit of the new drug, a Phase I clinical trial with dose-escalating should be performed first to observe its side effects and secure its safety.

The decision about acceptability of risk of hip fractures should be made by the participant made as part of the informed consent process. That being said, investigators need to make it well known that there are other effective therapies out there, the chances of being randomized to the placebo group (1:1, 2:1, etc), and the adverse events associated. To ensure that the consent is informed and voluntary, someone other than the primary physician/study investigator should be present to inform the pros/cons of participating. To make the study more enticing for participants, it may be worth randomizing 2:1 so that more individuals may enroll in hopes of being randomized to the experimental group. In addition, the sample size calculations should account for possibility of higher drop out in the placebo group.

If it is reported that there are other therapies which have better efficacy compared to a placebo treatment, study investigators and board members should look into those options thoroughly. First of all, we have to check if the reported efficacy is convincing enough. The results should be derived from well-designed and appropriately approved clinical trials. Next, the safety issues and the reimbursement strategies for the other options need to be reviewed as well as the efficacy results. If the other therapies have great efficacies but also have serious safety issues or unaffordable reimbursement strategies, those should be excluded from the treatment options in the prospective study here. From the review process, if superiority of the existing other therapies are confirmed, the placebo treatment (here, placebo added calcium + vitamin D) needs to be replaced. Study participants should be informed all the information about every treatment used in this study including incidence of reduction rate of the control group and all possible adverse effects. Before getting efficacy data to ensure benefit of the new drug, a Phase I clinical trial with dose-escalating should be performed first to observe its side effects and secure its safety.

There is general agreement that placebo-controlled trials are unethical when an effective therapy is available. Perhaps it will be less important to withhold the treatment if this alternative has minor or rare adverse outcomes. Unfortunately, this is not the case in osteoporosis: e.g the hip fracture has been shown to be associated with 30% risk of death at 1 year after the event. Secondly, it is very hard to find true placebo group: all of the osteoporotic patients received vitamin D and calcium and are getting advice on physical activity.

In this clinical trial of a new drug that may be effective in fracture prevention versus placebo, all patients are denied access to other therapeutic interventions known to have a benefit on the prevention of fractures. Measures to ensure patients are not harmed by their involvement in this study could include, teaching on lifestyle and dietary factors that can be helpful in fracture prevention, serial monitoring of bmd and imaging for suspicion of fractures, prompt referral for any concerns with low bmd or fractures and a letter or discussion with the patients primary care physician about the nature of the study and the benefits/risks to the patient. There should also be a study member available to the patients for any concerns they may have with their involvement in this study. As a part of the informed consent, I think all patients need to be aware of the medications that are known to help reduce fracture risk and be told of the benefits/risks to themselves of being invovled in the trial and thereby not being on these medications. Perhaps a referral to a outside specialist with no interest in the trial may be helpful to allow them to make a informed decision.

If I were on the IRB reviewing such a protocol, I would absolutely advocate that patients who meet the criteria set forth by the National Osteoporosis Foundation for intervention with a bisphosphonate should receive receive the standard of care or a potentially equivalent/superior therapy (e.g., anyone with a history vertebral or hip fracture, or any post-menopausal female with a T-score

I agree that it is difficult to justify using a placebo when there are known approved effective treatments available, especially if they are already being used as part of standard care. Though they are somewhat more difficult to do and to interpret, a non-inferiority trial may be helpful in comparing a new treatment to one that is already existing. It would be important to inform potential subjects of the existing medications so that they know their options if they are not enrolled in the trial. In addition, there needs to be a rigorous follow up schedule with appropriate studies to identify patients early who are at risk for fracture. A DSMB should follow the outcome events in the trial continuously. Sharon Poisson

Since there are evidences of medications that have better efficacy in preventing fracture than palcebo plus vitamin D and Calcium. This study involve issue of "Withholding participants benefit from effective treatment " Therefore it need proving by this following; patient fails or cannot tolerate the medications, Self-limiting condition, sufficient time to follow up side effect from treatment (eg. 5 years or more).In addition to participant consents. To ensure voluntariness of inform conset, it also need a assess the comprehension of participants about risk and benefit from trial.

There are two possible approaches: 1) you could study osteopenic women who would not meet criterial for tx and see if the new treatment reduces fracture risk 2) you could compare the new study drug to current standard of care The downside to this is that this would require a greater N andbe more expensive but at least more ethical. The second option is likely the most clinically useful because currently there are several treatments on the market, each with their own benefits and risks. It would be great to have a trial that compares efficacy in choosing what may be the best option for patients In order to get proper consent, it would be important to educate patients on all the treatment options as well as what the current guidelines are.

I agree that women who meet criteria for treatment of osteoporosis should definitely be encouraged to take a bisphosphonate (or other approved therapy) because the risk of fracture is serious and since very effective treatments already exist they should be used by patients at risk. I understand that it would be very difficult to power a study with fracture as an endpoint (as required by the FDA) if participants were randomized to new drug vs. existing therapy (bisphosphonate for example) as event rates would be very low. I think it is reasonable for the FDA to consider using surrogate endpoints for drug approval - and once a new drug has been shown to improve a surrogate endpoint, it could be approved. then over time we could see if fracture rates decrease as well.