MP: Why do we have placebo-controlled trials?
Joseph Romano: Placebo controlled trials are essential for the evaluation of the safety and efficacy of new products. The placebo control group in a clinical trial provides the means of establishing any specific safety issues with a product, as well as the effectiveness of the product at preventing HIV transmission. In terms of determining efficacy in microbicide studies, or in studies of other HIV prevention products, the trials are set up so that one group receives the treatment product and the other group uses the placebo product. The number of participants in each group that is necessary to establish the effectiveness of a product with a high degree of certainty can be calculated, and this establishes the size of the trial population. At the end of the study, the number of seroconversions in each group is established and a mathematical comparison between the two groups is conducted. If the number of new infections in the treatment group is lower than the number in the placebo group such that a predetermined statistical threshold is met, the drug can be defined as effective with a certain level of certainty. This type of calculation would not be possible without the placebo group in the trial.
MP: What do we learn by including placebos?
Joseph Romano: The placebo group is necessary to establish the safety of a product. Even if a product is shown to be highly effective relative to a placebo, the product cannot be used if it also produces a significant number of side effects or adverse events relative to the placebo group. In the case of HIV prevention products like microbicides, the importance of the placebo group to establishing safety goes beyond adverse events. The people who will use these products are HIV negative. Thus, it is crucial to show that the use of these products in no way enhances the potential for acquiring an HIV infection during the course of the trial. One of the very early clinical trials of an N-9 based microbicide product demonstrated that use of this product led to an enhanced risk of HIV infection relative to people who used the placebo. This was particularly important since the product used in this study was present in many over the counter products. Thus, the placebo control not only served to show that this product could not protect against HIV infection, it was also the means by which this product was shown to have an increased risk of enhancing HIV infection. The placebo control also allows for comparisons to be made during the course of the trial, prior to its completion. Most trials are designed to have blinded review of the data from the treatment and placebo groups during the course of the study. Again, by using certain calculations, it can be determined whether or not a product will likely be shown to be effective in a trial based on the analysis of data obtained partially through a study. If these types of interim evaluations of a product relative to placebo show that it is highly unlikely for a product to be effective against HIV transmission by the end of the study, a trial can be stopped. This early termination of a trail will obviously save significant amounts of money and resources, but more importantly, it will prevent continued experimentation in subjects with a product that is not likely to be of any benefit. This use of the placebo group has been used to stop a number of HIV prevention trials, including specific microbicide trials.
MP: What is meant by the term “placebo window?”
Joseph Romano: The “placebo window” refers to the time period during which it will be feasible to conduct placebo controlled efficacy studies. This period typically exists during the time when approved products for the intended indication are not yet available. Currently, there are no approved microbicide products available for HIV prevention. Consequently, there is no established “standard of care” for this indication. Without an established way of providing people with a product that is known to work for the indication, it is ethical to use placebo controlled trials since the placebo should provide no additional risk relative to people who are not part of the trials. However, once a microbicide product has been adequately shown to prevent HIV infection, there will then be a standard of care available that provides more protection to people using that product, as opposed to people who would use a placebo. With the availability of a product with well-established efficacy, it would then be unethical to enroll people into studies that involve a placebo product since people receiving the placebo product would essentially be denied access to something that affords some level of protection. So, once a microbicide product has been adequately shown to prevent HIV transmission, it will no longer be possible to run placebo controlled trials, and the “window” will be closed. It may even be the case that once any HIV prevention strategy is shown to prevent HIV transmission, it will be necessary to use that effective strategy in a trial designed to evaluate an alternative prevention strategy. For example, if an oral PrEP strategy is shown to be effective at preventing HIV transmission before an effective microbicide product is available, it may be necessary to run future microbicide studies in comparison to the oral PrEP product.
MP: Is the field adequately prepared for the day when the placebo window closes? What needs to be done to prepare? And how will it be decided when that day comes? Who gets to decide?
Joseph Romano: The key issue here is the definition of an available, effective product. This is conventionally established by regulatory agencies, which are responsible for examining all data from a product and determining if those data are adequate to establish effectiveness with an appropriate level of certainty. Another component in the decision process is the institutional ethics committees, which are responsible for insuring the safety of participants in trials conducted at their institutions. These review boards also can require trials to forgo a placebo control group for a group using the alternative effective strategy.
The consequence of losing the “placebo window” is that an alternative clinical trial design must be employed. This alternative design is not based on how well a product does compared to the assumed no effect of a placebo; rather, this alternative design requires the test product to be “non-inferior” relative to the standard of care product. This means that new test products evaluated in trials against established products can perform no worse than the established product in order to be approved. One of the consequences of this design in the HIV prevention field is that the already very large placebo controlled trials that are necessary to prove efficacy will need to become significantly larger in order to prove they are non-inferior to another product. This is due to the statistical analyses employed for such trials, which require much larger data sets to establish a sufficient level of certainty for non-inferiority. This will present both financial and resource challenges for the HIV prevention field, which have not yet been fully addressed. There is hope that new technologies can be developed which will be able to provide adequate and alternative forms of data that will be acceptable to regulatory authorities as an alternative means of establishing that a new product is non-inferior to an existing product. However, such technologies are in very early stages of development, and regulatory agencies have not yet indicated if such alternative strategies would be acceptable. More research and development is needed in the field, as are additional discussions with regulatory authorities.
MP: What are your thoughts on novel, post-placebo trial designs?
Joseph Romano: Novel, post placebo trial designs are extremely important to the HIV prevention field. As mentioned above, conventional non-inferiority trial designs require huge numbers of participants, and will have significant costs and capacity burdens. The ability to evaluate large, or even moderate numbers of products in this manner will be greatly hindered. Therefore, it is extremely important to try to develop alternative, yet equally appropriate means of clinically evaluating new products in a post-placebo era. There is reasonable hope that alternative formulations of the same drug will not require full efficacy studies, and that sufficient safety evaluations along with robust pharmacokinetic studies can be used to bridge the new formulation to the old version. It may also be possible to evaluate combination products involving two individual drugs that have established safety profiles by means of novel designs that do not require the combination to be proven superior to the individual products. The use of specific populations in trials may also provide useful options. Hopefully, there can continue to be advances in human pharmacodynamics model systems that provide robust surrogates for efficacy much the way RNA viral load became an acceptable surrogate for efficacy in the treatment field. Importantly, all of these options need to be pursued in parallel along with discussions with regulatory authorities. Mechanisms such as the conditional approval option in Europe need to be further investigated.
Joseph Romano, Ph.D., is President at the NWJ Group, LLC. He provides strategic and operational consulting in the fields of pharmaceutical and biotechnology, with expertise in drug, vaccine, device and diagnostics development.
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