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Laurence A Goldberg
In recent years, the introduction of new and expensive pharmacological agents to hospital formularies has highlighted the need to evaluate the balance between clinical effectiveness and cost. Innovation in drug therapy has an impact on many traditional hospital pharmacy activities – formulary management, drug use studies, drug budgeting, pharmacoepidemiology and pharmacoeconomics – and opens new perspectives for our profession in areas such as pharmacogenomics and biotechnology.
Local production of expensive drugs
Equitable access to treatment is a human rights issue, according to Dr Krisana Kraisintu of the Government Pharmaceutical Organisation (GPO), Thailand. Local production of antiretroviral (ARV) therapy might be the best solution for developing countries, because charitable donations and overseas aid are not sustainable and cheap imports of medicines might be of poor quality, she explained. She went on to describe how this policy has been successfully implemented in Thailand.
Five recommendations were made to help to maintain a supply of ARV medicines in the face of limited financial resources. These were:
Patented medicines are protected for a minimum of 20 years. The protection covers not only the process through which the product is manufactured, but also the product itself. It is therefore not possible to manufacture and sell a patented drug made through a new process. Several measures may be used to reduce prices in developing countries, including:
Thailand is a middle-income country with a population of 62 million and an estimated HIV prevalence of 2.5%. The incidence of HIV infection has stabilised as a result of a successful prevention campaign. Approximately 1.2 million people are infected with HIV and there are 100,000 AIDS patients; 30,000–50,000 new cases are diagnosed each year.
Before the local production of HIV drugs, 5% of AIDS patients had access to ARV double therapy. Very few received triple therapy, which cost about US$600 per month (US$1=e. 1). A typical salary was less than US$120 per month.
The Research and Development Institute of the GPO has been working on formulation development and bioequivalence studies of HIV drugs since 1992. The GPO is a state enterprise under the Ministry of Public Health. It manufactures more than 300 pharmaceutical products, with special emphasis on drugs in the “National List of Essential Drugs”.
The first ARV medicine, manufactured in 1995, was zidovudine (AZT) capsules 100mg. This was followed by pilot-scale production of 16 ARV medicines for 5,000 AIDS patients. Since then there has been a tenfold increase in production, so that now 50,000–100,000 AIDS patients are being treated. In December 2001 prices were reduced by 30–50%, which resulted in the price of triple therapy falling from US$112–140 per month to US$53 per month. One of the most recent developments was the launch of GPO-VIR (a combination of lamivudine 30mg, stavudine 150mg and nevirapine 200mg) at a cost of US$27/person/month. In addition to ARVs the GPO also manufactures a range of drugs for the treatment of opportunistic infections.
It has been estimated that the cost of treating 50,000 AIDS patients using original products is US$279m per year, which falls to US$16.6m per year when GPO products are used, giving a net saving of US$262.5m per year.
Thailand will achieve the goal of improving affordability by increasing local production where costs are lower and quality can be maintained.
Drug use studies in health policy generation
There is a real need for new drugs, but output has actually decreased, according to Professor Hubert Leufkens (Utrecht Institute for Pharmaceutical Sciences). A recent review comparing the periods 1991–95 and 1996–2000 revealed a 41% decrease in the number of new chemical entities (NCEs) released, although expenditure had increased by about 40%. However, innovation goes beyond NCEs; it also includes the development of new drug delivery forms, new concepts, new indications for existing products, better access, and improved prescribing and use of medicines.
Pharmacoepidemiology is the study of disease occurrence among populations exposed to given medicines. As such, it provides a way of putting drug effect data into context. Three types of associations can be identified through pharmacoepidemiological studies. First, real causal associations can be demonstrated. An example is anaphylaxis caused by glafenine, a medicine that was withdrawn in the early 1990s. Approximately 20 years after initial reports of adverse reactions, pharmacoepidemiological studies provided proof that there was a high risk of anaphylaxis with glafenine. Secondly, effect modifications can be identified. One example is the increased risk of hospitalisation for bleeding disorders among patients with pre-existing reasons for bleeding, associated with selective serotonin reuptake inhibitor (SSRI) antidepressants. Another example is the increased risk of Achilles tendon rupture with the use of fluoroquinolones and oral steroids. Thirdly, medicines can induce new, “dangerous” behaviour or circumstances. The increased risk of myocardial infarction in some men taking sildenafil is a good example, said Professor Leufkens.
Measurements or analyses can be performed at the population level or at the individual patient level depending on the issue under investigation. It is important to look at the level of the data, cautioned Professor Leufkens. For example, a study that examined the prevention of asthma deaths with inhaled steroids showed that there was no effect with “any use” of steroids, but when a subgroup that had used six or more canisters during the year was analysed a strongly protective effect was shown. Similarly, a crude analysis of the risk of fractures with oral steroid use suggested a small effect, but when the results were stratified according to dose the significant effects of high doses were revealed. Another study compared the risk of developing extrapyramidal side-effects with haloperidol or risperidone/olanzapine. Again, the crude analysis showed no differences, but when the sample was stratified according to the complexity of previous treatment clear differences emerged. It was subsequently shown that, for antipsychotic agents that are metabolised by CYP2D6, slow metabolisers are significantly more likely to develop side-effects.
Another useful aspect of pharmacoepidemiological studies is to monitor persistence of use of treatment or inappropriate dosing. For example, studies have shown that within one year of follow-up 30% of patients receiving statins discontinue treatment. The corresponding figures for antihypertensives and antidepressants are 60% and 75%. Genetic polymorphism appear to contribute to these effects.
Turning to a different issue, Professor Leufkens said that one in five medicines undergoes a postmarketing dose change, 80% of which are reductions. The likelihood of a dose change is highest with newer drugs. A study of 115 products marketed between 1982 and 2000 showed that the WHO-defined daily dose (DDD) had been increased in 40% and reduced in 60%.
It is important to be aware of secular trends and their potential to mislead, said Professor Leufkens. For example, data from New Zealand showed that a fall in the death rate from asthma coinciding with a reduction in the use of fenoterol appeared to suggest a causal relationship. Only when the increasing use of inhaled steroids was taken into account did the more likely explanation emerge.
The purpose of drug use studies is to provide data relevant to public health policy and drug regulatory decisions, said Dr Francis Fagnani (Institut National de la Santé et de la Recherche Médicale). In addition to safety and effectiveness data, information on quality of care, pharmacoeconomic aspects and the impact on public health and on the healthcare delivery system is needed.
Where there is no previous knowledge of the drug, data about long-term adverse drug events (ADEs) and rare ADEs are required. Where there is already some knowledge, studies are needed to check the frequency and severity of known ADEs and to identify comedications, comorbidities or specific patient factors that could exacerbate ADEs.
The concepts of efficacy and effectiveness are important in this context. Efficacy may be defined as the ability of a treatment to achieve the planned goals under the best possible conditions, whereas effectiveness is the ability of a treatment to achieve the planned goals when used in routine medical practice. Effectiveness studies therefore need to assess patient benefit in the real-life, routine clinical practice situation. It is also important to make assessments in specific subgroups such as the elderly and those with concurrent diseases. In addition, the consequences of poor compliance need to be determined, and a final endpoint needs to be identified to evaluate the benefit to the patient or the population.
The methods used in postmarketing surveillance (PMS) fall into two categories – the generation of new data through ad-hoc surveys and trials, and analyses of databases (see Table 1).
PMS studies are warranted for several groups of drugs:
At present there are numerous problems besetting the successful execution of PMS studies; nevertheless they still provide useful and relevant data that help with rational decision-making. Dr Fagnani hoped that access to new databases in future would improve the quality of many PMS studies, but he also reminded the audience that the results of PMS studies had to be interpreted in light of the setting in which they were performed, bearing in mind local epidemiology and medical practices.
Pharmacogenetics and pharmacogenomics
Pharmacogenetic testing is likely to be useful for 10–20% of drugs and of no use for about 50%, according to Professor Pier Franco Pignatti (Department of Mother and Child Biology and Genetics, University of Verona, Italy).
Understanding of a biological defect could lead to therapy, but identification of the gene responsible for the defect could, in an ideal situation, lead to prevention of the condition.
The “candidate” approach is one strategy for identifying the responsible gene. This involves formulating a hypothesis about which gene (the “candidate” gene) might be involved in drug metabolism or a specific function, identifying polymorphisms, and then performing association studies in cases and controls. An example of this is the b(2)-adrenergic receptor gene, which appears to govern the response to b-agonists. Polymorphisms were identified in an extracellular portion of the protein (Arg16Gly). Genotypes with Arg/Arg at this site responded best to albuterol, and those with Gly/Gly responded worst. Those with Arg/Gly had an intermediate response. If this test could be carried out in clinical practice, then the patients that were unlikely to respond to beta-agonists could be identified immediately, said Professor Pignatti.
A one-to-one correlation between genotype and effect does not always exist, and some conditions are polygenic in origin. There may, for example, be genetically determined variations in drug metabolism, drug receptors and response in differing combinations. In addition, some genetically determined risks may be modified by other factors. An example of this is the risk of cerebral thrombosis with oral contraceptives and a defect in the gene for prothrombin. Oral contraceptives and the presence of this defect each increase the risk of cerebral thrombosis somewhat, but when both are present in one individual the risk is multiplied almost 150-fold.
It has been suggested that pharmacogenetic profiles might be helpful in certain areas such as oncology, cardiology and neurology. A genetic profile can be created from a series of single nucleotide polymorphisms (SNPs) in specific positions in the genome of cases and controls, rather than by the identification of individual genes. An example of this is the HLA-B57 haplotype in abacavir treatment – patients with this haplotype are almost certain to experience adverse reactions if treated with abacavir and should be advised against it, said Professor Pignatti.
Pharmacogenetic testing is useful for confirming risk, but the way in which patients are selected for this procedure is critical. Such tests need to be integrated with genetic counselling and family involvement. There is also a need to guard against “morbidification” – creating a disease in the mind of otherwise healthy individuals. Finally, issues of consent, privacy and sample storage have to be tackled.
Pharmacogenomics in practice
Pharmacists will be at the forefront of the application of pharmacogenomic information in clinical practice, predicted Gilbert Burckhart (Professor of Pharmacy and Surgery, University of Pittsburgh, USA). SNPs will play a large part in these developments. Hitherto they have been used mainly to examine adverse reactions, but in future they will be used to improve efficacy, he suggested.
Some of Professor Burckhart’s work concerns the role of p-glycoprotein in transplant patients. P-glycoprotein pumps certain drugs (eg, some chemotherapeutic agents) out of cells. This reduces the drug’s effect and makes some patients “resistant” to chemotherapy. Studies had been performed to test the hypothesis that the clinical variability in steroid and tacrolimus dosing in transplant patients was partly attributable to genetic polymorphisms in drug disposition markers. SNPs at the MDR1-ex26 site appeared to hold the key: a C/C (cytosine/cytosine) base pair at this site resulted in a “high-pumper”, whereas C/T (cytosine/ thymidine) or T/T pairs resulted in less p-glycoprotein activity. The results had shown that the high-pumpers required steroid treatment for much longer.
Steroid weaning is important in paediatric heart transplant patients and could be achieved more effectively if patients’ MDR1-ex26 status were known in advance. Those patients with the C/T or T/T polymorphism would be tapered off steroids rapidly and be given long-term maintenance therapy with ciclosporin or tacrolimus. Those with the C/C polymorphism would be weaned cautiously against a background of triple drug therapy. In addition, they would be given antibody induction therapy followed by long-term maintenance with non-p-glycoprotein substrates, such as mycofenolate mofetil or sirolimus.
In order to use pharmacogenomics adequately in the future, pharmacists will need educational programmes that allow them to incorporate the information into their patient care patterns. Information systems will also be needed to allow sharing of patients’ critical genetic information, clinical course and outcomes.