Osteoporosis panel summary.
THIS CONFERENCE BROUGHT TOGETHER clinical investigators; epidemiologists; representatives of government regulatory agencies, industry, and Institutional Review Boards; government scientists; ethicists; and concerned laypersons to address critical issues in the development of new therapies for osteoporosis to prevent bone fractures. The meeting was not intended to achieve consensus. Rather, the American Society for Bone and Mineral Research wished to highlight emerging concerns. Doing so now is timely because additional potentially effective approaches to the problems of diagnosis of osteoporosis and prevention and treatment of fragility fractures are being developed. The problem of osteoporosis is likely to become even greater as the world population ages. This panel report will summarize some of the key issues developed at the conference. Detailed analyses of these issues are presented in the accompanying manuscripts. Currently we can predict that at least one-half of women and up to one-quarter of men over the age of 50 years in industrialized countries will experience a fragility fracture. Although the relative risk of fragility fractures may be lower in other parts of the world today, this will change because their populations are aging rapidly. The majority of fractures will occur in the most highly populated areas. For example, it has been predicted that one-half of all hip fractures in the world in 2050 will occur in China. If the October 2000 revision of the Helsinki Declaration is taken literally, placebo-controlled trials can not be conducted with subjects who have osteoporosis as defined by the World Health Organization (WHO), because there is a “current therapeutic method” for this disorder. In response to the problems that the 2000 revision raises for all controlled trials, the World Medical Association (WMA) issued a written clarification in 2001. The clarification states that placebos may be used when necessary for “compelling scientific and sound methodological reasons,” but leaves such reasons undefined. Therefore, the investigators and sponsors of research in the field are left in limbo with regard to the ethical issues involved. Investigators and research sponsors have complained that Institutional Review Boards (IRBs), in exercising their responsibility to protect human subjects at their institutions, are becoming increasingly conservative in the standards they apply to research where some effective treatments exist. This stems from a perceived need to protect their institutions from audit and potential suspension of research by the Office of Human Research Protection (OHRP). This might result in refusal to approve some clinical research studies that were scientifically and ethically acceptable. The registration of a new drug for treatment of osteoporosis currently requires demonstration of fracture efficacy. However, increases in bone mass and strength are predictive of such efficacy. Registration of new drugs for osteoporosis prevention might thus be based on their efficacy in increasing bone mineral density (BMD) and reducing bone turnover, together with demonstration of high bone quality and strength in animal as well as human studies. Evaluation would include histological analysis of bone in treated subjects. Use of this approach for initial osteoporosis clinical trials was the major recommendation from the pharmaceutical industry. The use of placebos in such studies still involves some risk, but this would be less than for clinical trials involving high-risk subjects. However, this might not apply to new agents with different mechanisms of action. The optimal populations for such studies were not defined. Whatever the population, there must ultimately be demonstration of antifracture efficacy in humans before the drug will be widely accepted. The methods for showing such fracture efficacy in postmarketing studies have not been defined and would need to be developed and presented at the time of drug registration. The high-risk group needs to be studied because this group, by virtue of its imminent and high risk of bone fracture, is in greatest need of discovery of the most effective therapeutic agents. Extrapolation of findings from studies of low-risk groups to high-risk groups may not be valid. It is better to test efficacy of a new therapeutic agent in a population where the effect size is likely to be large and the time to show a drug effect is short. The most controversial aspect of the discussion of high-risk trials was whether placebo controls should be allowed. Despite the arguments in favor of placebo controls in the high-risk, short-term trial, there were serious concerns regarding protection of human subjects. Several speakers did not view placebo-controlled high-risk trials as ethical because of the severe consequences for the individual subject who would be denied standard therapy. They felt that the high-risk subject is in need of some form of therapy by usual care standards and cannot be ethically assigned to a placebo group. Some conference participants advanced the utilitarian argument that the population good would outweigh the individual risk. However, others argued that this approach was not ethical because individual subjects would still be put at risk and that the Helsinki guidelines refer to the individual as distinct from society. In addition, it was argued that because of the vulnerability of the high-risk person, there is an added responsibility for the investigator to ensure that each subject understands the worst-case scenario that applies specifically to him or her as a result of participation in the trial. It is not enough that the risks have been explained carefully and completely to patient/subjects; rather, special care must be exercised to ascertain what each subject understands and to respond appropriately with further information. A placebo-controlled trial in a relatively low-risk population has both ethical and scientific advantages as well as disadvantages. There is no universal agreement as to the use of current pharmacologic agents in the low-risk group; therefore, the problem of withholding “standard therapy” either does not arise or is attenuated. If an inexpensive drug with minimal side effects could be shown to reduce fractures in this population, it might make it possible to provide the large populations at risk with an effective therapy. The greatest disadvantage of such trials is that the fracture incidence would be so low that large numbers of subjects would have to be studied to provide the total number of fractures required to show significant antifracture efficacy, especially if the end-points were hip and/or vertebral fractures. Use of all fragility fractures as end-points, the “hip-fracture equivalence” concept, might be helpful in that the total number of fractures required to show efficacy might be achieved with fewer subjects and fewer hip and vertebral fractures. The addition of a second drug, for example, an anabolic agent in subjects receiving an antiresorptive agent, is an appropriate and ethically justifiable approach to show efficacy in high-risk groups and can be placebo controlled, some argued. Such add-on trials will require demonstration of compatibility and safety in phase II studies. Superiority trials comparing different agents of the same or different classes could also be considered. However, this would require compelling evidence of a potential for sufficient superiority of the new agent to make such a trial feasible with a reasonable number of subjects. The major scientific concern as to superiority trials was that in the absence of a placebo control, the actual efficacy of either the comparator agent or the new agent in that population would not be known. Many participants did not consider non-inferiority trials to be appropriate to new drug development for both societal and scientific reasons. Large comparative and combination therapy trials will be of increasing importance as more agents became available, speakers noted. It was suggested that these studies might be best conducted under combined support from government or nonprofit agencies and the pharmaceutical industry and developed by appropriate panels of scientific experts. Surveillance for usage, efficacy, and adverse effects should be carried out both by the pharmaceutical sponsor and independent researchers using available databases, speakers noted. For example, future Medicare data on fractures and drug use might be matched. It was also suggested that future large government surveys of population health status, such as the National Health and Nutrition Evaluation Survey (NHANES), should incorporate questions that shed light on use of diagnostic tests as well as prevention and therapy for osteoporosis. Observational epidemiologic studies (e.g., case control, cohort designs) will become more important in assessing the benefits and risks of specific therapeutic regimens if placebo-controlled trials become more restricted. These designs are necessary in any event for assessing the effectiveness (as opposed to efficacy) of treatments as they are actually used in the community. Such study designs are ethical under the provisions of the revised Helsinki guidelines. Several participants pointed out that patients for whom costs of obtaining a medical intervention are prohibitive are vulnerable because their need may lead them to agree to enroll in a study they would not otherwise agree to participate in. Therefore, investigators and IRBs need to take seriously the requirement of justice in selection of subjects and ensure that subjects are not disproportionately recruited from vulnerable populations. Some investigators argued in favor of using a placebo control on scientific grounds and contended that subjects should be permitted to accept the risk of forgoing an established effective treatment voluntarily. It was generally agreed that such a study would be ethically acceptable if the risks of not receiving the established treatment are minor and transitory. When the risks are more serious or irreversible, many IRBs are reluctant to approve a study. If an IRB does approve a study based on a favorable risk-benefit ratio, the consent form should explicitly inform the subjects of the risks they face by forgoing established therapies. In particular, they should know that they can obtain the standard treatment as an alternative to enrolling in the study and that enrolling in the study amounts to choosing to do something to benefit science and future patients rather than for any personal benefit. This should be differentiated from the situation in which a subject might enroll because other treatments have been tried and found inadequate or unacceptable. One of two women over the age of 60 years can anticipate a fracture. As many as one of four men over the age of 60 can anticipate a fracture. Because the incidence of fractures for women is greater than for men, the occurrence of fractures in men—although substantial—has not been adequately studied. Racial and ethnic groups in which there is relatively lower incidence of fractures still have a substantial health burden from osteoporosis, and this also needs to be addressed. Likewise, the effects of hip and vertebral fractures are so debilitating that fractures of other bones, such as the wrist, have not received adequate attention, although they account for a larger total number of fragility fractures. Investigators must ensure that studies are designed based on “thorough knowledge of the scientific literature” (Helsinki Declaration, Article 11). When new information becomes available during an ongoing research project that alters the risk-benefit ratio, the grounds on which selection or exclusion criteria were based, or other aspects of the study, investigators should submit appropriate revisions in the protocol to the IRB. This conference provided a useful starting point for the further analysis of the problem of developing ethically acceptable and scientifically sound trials in osteoporosis. The speakers helped to define the problem and presented many potential approaches. None of these were identified as clearly superior at the present, but the presentations and extensive discussions did succeed in “Framing the Issues for Future Dialogue.” New information is emerging on the genetics and pathogenesis of osteoporosis along with new therapeutic approaches that may lead to entirely new ways of testing efficacy and cost benefit. The many constituencies that are deeply concerned with reducing the burden of osteoporosis need to continue this effort and maintain an open and effective dialogue.
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