If research and development investment in a given project is directly proportional to the productivity index, anything that increases the cost of a programme or, potentially, decreases the projected revenue (or increases the risk that the revenue projections may not be achieved), will drive investment away from that project. The balance between returns and costs that drive any given productivity index are provided in Fig. 4. Simply using the costs of a phase II–III development programme, along with the bare minimum costs required to support the postapproval regulatory requirements of a new drug product, along with the projected peak fifth year sales, one can create a family of productivity curves. One can see that a product with peak (and sustained) sales of US$500 million would achieve a productivity index of 5.0, but then only if the costs of development remained below approximately US$130 million. Given the data from DiMasi et al. , which suggests that HIV clinical phase costs alone could easily exceed US$200 million, the productivity index for an antiretroviral drug is likely to remain closer to 2.
Although the decision to invest in projects related to HIV will include an assessment of the relative value metrics, it will not be based solely on those metrics. Certain diseases simply demand the attention of the biomedical community, and the devastating global pandemic of HIV is without question one of those diseases. In spite of the potentially challenging market considerations, significant attention has been directed at the problem and highly valuable results have ensued. Without question, the future of HIV drug development will include active pharmaceutical company engagement; the issue remains the degree to which the research and development investments can be sustained.
Within this context, one can begin to appreciate the interest in ensuring that the scope and objectives of a programme to develop an antiretroviral agent are truly aligned with the objective of providing clinically meaningful guidance to patients and physicians. Although answering questions of clinical interest can be justified simply on the basis that more information defines risk better, collection of the data generates an inherent trade-off between the resource commitment demanded now and the potential research and development investments of the future. Similarly, although solutions that improve access to life-saving antiretroviral drugs for all HIV-infected patients should involve every sector of society, these solutions must be sensitive to the delicate balance between costs and return that underscore the drug discovery process within the private sector.
The multifactorial nature of access
Access to drugs depends on a number of considerations: the presence of suitable drugs to meet a defined medical need; a functional regulatory process focused on bringing the best medicines to patients; the ability to manufacture the drugs locally or an ability to import drugs manufactured outside the region; a distribution channel that provides the drug to the site of patient care; the appropriate training of personnel to ensure appropriate use in a clinical setting; and, importantly, the price of the finished product to the patient.
The sustainability of the drug supply is critical, especially for the provision of the chronic therapies needed for the treatment of HIV. Among other things, sustainability is dependent on the ability to forecast demand accurately, matching the potential need for medicines with the ability to integrate that need into the medical infrastructure. Accurate forecasting of demand is essential in order to avoid either shortages of medicine or the production of supplies that then expire in warehouses. Whether such forecasting is achievable given the limited tools available in some resource-poor regions has yet to be determined. Sustainability also requires stable social and political conditions, measures to prevent both diversion of the supplies and counterfeiting of drugs and, in regions with lower resource commitments to healthcare, appropriate long-term commitments from funding sources.
Regulatory processes that support access to antiretroviral drugs in the developing world are still evolving. To date, the regulatory review process existing within the United States and Europe has guided the introduction of new antiretroviral agents. While recognizing the tremendous contribution of those efforts, there remain some concerns that the needs of individuals within developing countries may not be fully addressed by a review process that cannot take into consideration conditions within those communities. The result of this discordance is a fragmented review and approval process within Africa resulting in delays in the introduction of new drugs. The regulatory burden taken on by companies choosing to make these regulatory filings is not insignificant, and this resource commitment adds to the cost of the drug development process. Measures have recently been introduced to attempt to harmonize this regulatory process outside the United States and Europe. A streamlined review and approval process for antiretroviral drugs in developing countries would be a welcome advance.
The factors that help to establish the price of drugs in developed countries were discussed previously. On the basis of those established prices, pharmaceutical companies have set prices of antiretroviral drugs differently in regions of the world based on their socioeconomic status, as determined by third party agencies such as the World Bank . Compared with the developed world, prices in middle markets are provided at discounts of up to 75–85%, whereas prices in the least developed countries are discounted by 95% or greater. In some circumstances, depending on the drug involved, these discounts may provide the drug at or below cost. It should be noted, however, that the final price of an antiretroviral agent to a patient is not set solely by the pharmaceutical company, but rather is a compilation of charges that include taxes and tariffs as well as margins from distributors and pharmacists.
The regimens that are presently being made available in developing countries include nevirapine and two nucleosides. The cost of this regimen is approximately US$200 , still very expensive relative to the annual income of individuals in these regions, but potentially manageable with global support. As these regimens fail, however, the cost of the subsequent regimens is likely to go up considerably, given the pharmaceutical properties of those agents. This concern regarding the cost of goods for certain antiretroviral drugs may actually create a market for agents that are both safe and effective but are less expensive to produce. New drugs with either improved potency or simpler synthesis routes may meet this unmet need and would be especially attractive in these resource-limited regions.
Access to antiretroviral drugs has improved over time but there is still much to be accomplished. Access begins with regulatory approval, but maneuvering within the global regulatory environment is complicated and resource intensive, especially within the developing world. Patient access to antiretroviral agents should be offered in a setting where basic healthcare needs can also be met. Reliable access requires distribution mechanisms that prevent counterfeiting and the diversion of product across national borders, often presenting significant challenges within developing countries. Finally, pricing strategies need to be carefully considered, given the hurdles that pricing may put before access to care.
In conclusion, the global threat of HIV infection requires solutions driven from many sectors of society. Optimally, this set of solutions should be complementary, reinforcing the value of each contribution. Further advances in our ability to treat or prevent HIV are dependent on success in overcoming scientific and technical challenges in our understanding of HIV pathogenesis, applying that success towards the creation of new therapies, integrating these therapies into treatment regimens that can both durably suppress the development of resistant virus and be tolerated for long periods of time, and providing these therapies into a system that maximizes access for those in need. For the drug development process to support these efforts, both the public and private sectors need to prioritize resources appropriately to a healthcare agenda and then, within healthcare, agree that the treatment and prevention of HIV infection is a priority. The extent to which the other key actors have a clear and supportive understanding of the scientific, clinical, regulatory and economic calculus that is at the heart of the private biomedical enterprise model will also contribute to a sustained research effort in this critical therapeutic area.
The method for the allocation of resources within the private sector is based on perceptions of relative value. Although there is a clear and pressing medical need for a continual stream of new antiretroviral drugs, other unmet acute and chronic conditions also compete for a fixed pool of resources. Efforts to direct resources to investments in antiretroviral agents are significantly enabled to the extent that they remove uncertainty around the profile of a desired agent, streamline the process of development so that resource commitments are devoted to answering only essential scientific and clinical questions, integrate global regulatory commitments in a setting that fully considers the risk/benefit equation for these types of agents in the targeted subpopulations and allows for confidence in a reliable funding stream especially in areas where there is limited resource for healthcare spending, while removing barriers to trade that prevent medicines from reaching patients.
The author would like to acknowledge Andrew Schmeltz and Philip Hedger for their generous feedback and careful review of the manuscript. Michael Dunne is an employee of Pfizer Global Research and Development.
Disclaimer: The production of this special Supplement was supported by the World Bank, the Joint United Nations Programme on HIV/AIDS and the World Health Organization. The findings, interpretations and conclusions presented in this paper do not necessarily reflect the views of these institutions or their constituent agencies or governments.
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Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
AIDS; healthcare; pediatrics