As pediatricians are quick to point out, the treatment of children with HIV infection brings with it additional considerations not faced in adult medicine. Those related to drug therapy include the adjustment of dose, the development of child-friendly formulations, as well as the assessments for side effects that may impact a child's physical development from infancy to puberty. Pediatric formulation development typically follows a successful adult programme, at the earliest after the results of a phase II programme and in some cases after the establishment of an acceptable risk–benefit ratio in adults. Arguments for moving the pediatric development programmes sooner in the development cycle are often met with concern about the testing of new agents in this vulnerable population. In the setting of HIV infection, however, greater flexibility in the timing of the introduction of new therapies for children should be entertained, especially in those whose virus is resistant to current agents.
Formulation development in children is specifically designed to allow for adjustments in dose to be made by age or weight, determined through carefully designed pharmacokinetic studies. The performance of pharmacokinetic studies in children has historically been limited by a scarcity of research centers capable of managing the technical and ethical complexities involved, although recent private and government-sponsored initiatives have improved this research capacity. A list of some of the challenges to be overcome in the development of pediatric formulations is provided in Table 3.
Although combination therapy is essential to optimize viral suppression, the creation of co-formulations of antiretroviral agents into oral suspensions suitable for children is not straightforward. Antiretroviral drugs must be corrected for age and weight, but each antiretroviral agent may have a different such schedule. Consequently, the choice of agents that can be co-formulated together into one oral suspension may be more restricted than that for adults, as each agent will need to be carefully matched by its pharmacokinetic exposure in children. Even with the availability of appropriate formulations as well as information to guide dosing, there still remain issues in the practical application of these recommendations to actual patient care. Underdosing is still common, either because of the rounding down of doses or delays in the adjustment to the appropriate dose as the child grows . Although this list of considerations may seem formidable, the growing concern for the needs of HIV-infected children is likely to accelerate the translation of advances in drug development to the pediatric population.
Strategies to minimize antiviral drug resistance and the impact on drug development
Although each antiretroviral drug has made its own important contribution to prolonging the life of patients infected with HIV, no treatment approach is curative and all treatments eventually fail, either for reasons related to dose-limiting adverse events, non-compliance, the evolution of resistance or some combination of all these reasons. Strategies that have evolved to minimize the likelihood of failure caused by resistance are centered on the use of antiretroviral drugs in combination and then the continuous sequencing of remaining agents into regimens which retain potency.
From the perspective of drug development, this type of application raises hurdles that must be overcome in order to bring new agents to patients. Each successive new antiretroviral agent must retain potency against both present and, given the 10 or more years time lag time in drug development, future strains of virus. Not only must the type of future resistance be anticipated 10 years in advance, but the selected agent must also be capable of working within a regimen, potentially with agents that have yet to be introduced into clinical practice. The characteristics required for use in a regimen include low rates of adverse events, so that the cumulative adverse event portfolio does not lead to discontinuation of the regimen, low potential for drug interactions, so that pharmacokinetics can be better predicted for any given patient, and high degrees of potency, so that the tablet size can be kept to a minimum, reducing the number of pills and enabling compliance. Whereas all of these characteristics are attractive, not all are easily achieved in one compound; trade-offs of attributes are more the rule than the exception.
The clinical research community is constantly evaluating the available medications in various combinations to determine the best possible treatment regimens for specific patient subsets, an effort in the best interests of the patient and likely to select for regimens that are maximally efficacious while sufficiently well tolerated. Figure 1 displays a snapshot of the mix of regimens used for HIV treatment in the United States in 2004–2005. Consistent with guidelines [2,3], therapy for patients with HIV infection is primarily provided as two nucleoside reverse transcriptase inhibitors coupled with either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor, with the use of non-nucleoside reverse transcriptase inhibitors favored in patients previously naive to treatment and protease inhibitor-based regimens favored as treatment progresses.
Research and development decisions are based on perceptions of productivity
The results of comparative clinical trials lead to the rise and fall of interest in any given compound. Figure 2 outlines the global sales of a number of leading antiretroviral drugs over the past 10 years, sales generated predominantly in the United States and Europe. In the period immediately after the introduction of a new drug into a stable market, there is a period of rapid uptake that continues until the relative clinical utility of the drug establishes some market share. In a more dynamic market such as that for antiretroviral drugs with a fixed number of patients and a continuous flow of new products, the returns for some products will fall as new ones take their place. Although this re-ordering of interest is a natural consequence of optimizing the pool of available antiretroviral drugs for patient care, projections of future demand for new agents are significantly more complicated and, especially in this type of market, carry with them a greater risk that the product will not fully recover its research investment.
Research investments in new HIV therapy can be substantial. Figure 3, taken from a review of the costs of drug development [4,5], outlines a number of the dimensions involved in the decision to invest in a given research and development programme, factors that also contribute to the ultimate market price. The decision to invest in a pharmaceutical research and development programme is made relative to other opportunities available at the time, and is based on the project's technical likelihood of success, the ability to establish safety and efficacy in a clinical setting as well as an assessment of the patient's demand for the product, supported by the ability of society to support that demand. Among the four therapeutic areas of central nervous system diseases, cardiovascular disease, analgesics/anesthetics and infectious diseases, the cost of developing anti-infective products is highest. An anti-infective programme, however, spends the least amount of time in clinical development. This leads to a ‘fully loaded cost’, an accounting method that also factors in the ‘time cost’ of an investment not presently generating revenue, more in line with opportunities in other areas. Even so, the returns for anti-infective products are relatively modest, leading to a sales–cost ratio, sometimes referred to as a productivity index, which is slightly below the average of all opportunities. With sufficient available resources, investments can certainly flow into anti-infective products compared with other, lower yielding projects. As the authors note, however, there has been an increase in the amount of spending recently in the anti-infective area, costs that are driven ‘largely, but not exclusively, by HIV treatments’. If this is the case, the productivity index for antiretroviral agents specifically may actually be significantly lower than the 4.5 average for all anti-infective products, given the modest relative returns seen in Fig. 4, and, as noted, the relatively higher cost of developing HIV therapies.
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