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Clinical Division: REPORTS: CPT 2004

Report on CPT2004 in Brisbane, Australia: Access to Medicines & High Quality Therapeutics: Global Responsibilities for Clinical Pharmacology

The 8th World Conference of Clinical Pharmacology held in Brisbane in August, 2004 was unique because of its focus on global equity of access to safe and efficacious medicines, and selected and used effectively and safely. An expressed goal behind the Australian bid to hold the meeting was to involve clinical pharmacologists from our region of the world where access to lifesaving medicines and confidence in their quality are matters of most significance.

We wanted clinical pharmacologists from the developed and developing world to be aware of and feel some responsibility for the serious global inequities around discovery, development, access to and use of medicines of acceptable quality, safety and efficacy for the major infectious diseases such as TB, malaria and HIV AIDs as well as the emerging lifestyle associated disorders notably cardiovascular disease.

Dr Suwit Wibulpolprasert Senior Advisor on Health Economics, Ministry of Public Health, Thailand presented an inspirational and challenging Plenary lecture on "Philanthropy for the Few - Equity of Access for the many?” He demonstrated the increasing gap between rich and the poor in both developed and developing countries and the many interacting social, political and financial influences that conspire to take resources away from the people who most need them. He concluded with practical steps clinical pharmacologists could take to alleviate problems of access to medicines. This theme was reinforced in the Plenary Lecture of Professor Suryawati, Department of Clinical Pharmacology, Gadjah Mada University, Yogyakarta, Indonesia who challenged all clinical pharmacologists to consider how they might become involved in achieving the three ‘As’ of medicines use in their own countries, namely Access, Affordability and Appropriate use. In her talk Prof Suryawati outlined the roles and contributions of the International Network for Rational Use of Drugs (INRUD) and the International Conferences on Improving the Use of Medicines (ICIUM). Both Dr Wibulpolprasert and Professor Suryawati exhorted the international umbrella organization for clinical pharmacology, the International Union of Basic and Clinical Pharmacologists (IUPHAR), to confirm its support for this new direction in its meetings and activities. At the IUPHAR council meeting coincident with the world conference, this paradigm shift was strongly endorsed.

Dr Lembit Rago, Clinical Pharmacologist from Lithuania and Director of the WHO’s Division of Quality and Safety of Drugs, Geneva, delivered an important and timely plenary review of the status of fixed dose combinations (FDC) of medicines around the globe and the very recent acceptance (2004) of WHO guidance regarding their registration by the World Medical Assembly, highly influential in that it governs and advises WHO. The process has been difficult and lengthy, but there is no doubt that this program has very great potential to deliver less expensive yet effective medications for serious conditions such as HIV AIDs worldwide.

A critical and increasing concern is the safety of medicines given the aging population with multiple co-morbidities and increasing exposure to multiple, increasingly potent medicines. The way in which pharmacovigilance for new drugs is to be conducted in the future is being shaped by a number of interesting Therapeutic Risk Management initiatives across the world, some of which were presented in a lively Symposium. These initiatives seek to better identify, evaluate and minimize the impact of adverse reactions and to communicate safety risks at all stages of the life cycle of a drug and, most importantly, to do so pro-actively according to Dr Susana Perez-Guttmann, Pfizer Ltd, Barcelona, Spain. The importance of pharmacoepidemiology and employing advanced information technology to ‘mine’ large automated health databases have revolutionized the way pharmacovigilance can be undertaken.

The problem of the ‘therapeutic orphan’ status of children was examined in depth by speakers from Europe, USA and Australia. Incentives to pharmaceutical companies to evaluate already marketed medicines along with mandatory studies in children for new medicines, provided that they are potentially useful in children, has been a successful strategy in the USA since the mid 1990s and is now having a positive impact in Europe. However, the conference heard that political pressure needs to be maintained to overcome this problem for children.

Attention was given to the rapidly expanding complementary medicines sector. Dr Charlie Xue, Program Leader, Division of Chinese Medicine, School of Health Sciences RMIT University, Victoria Australia gave the WHO’s perspective on traditional medicine, and provided examples of the role of complementary medicine as a mainstay of public health systems in Southeast Asia and the Pacific regions. Professor Chu quoc Truong, Director of The National Hospital of Traditional Medicine, Hanoi, Vietnam explained that in Vietnam the national government has formally integrated traditional medicine with Western conventional medicine, with apparent good effect.

A Symposium on the controversial topic of ‘Direct to Consumer Advertising’ (DTCA) of prescription pharmaceuticals drew great interest as the situations in Canada, Europe, Thailand, New Zealand and Australia were compared. There were two main themes: first, that regulation is difficult and secondly, that there are many and increasing instances of advertisements that skirt the boundaries of existing laws and regulations in jurisdictions where DTCA is illegal. In developing countries, there is in reality often no distinction between supposed prescription and OTC medicines in terms of access. It is very difficult to control DTCA of so-called prescription drugs when prescription-only status is not upheld at law. However, in countries in which DTCA is currently illegal, there appears to be little appetite for the introduction of DTCA because of concerns around quality of use of advertised medicines, consumer demand leading to distortion beyond the ‘reasonable’ need for medicines and finally, morbidity and mortality from the adverse effects of medicines whose use was unnecessary. However, it was emphasized that there is continuous and considerable pressure from industry and advertising interests to reverse this attitude.

Juxtaposed with the burning issues of equity and access concerning medicines, a major theme of the Congress was the increasing evidence base and rationale for individualising drug therapy selection and regimens. This theme was developed by Professor Michel Eichelbaum, Director of the Dr Margarete Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, Germany in his Plenary lecture. Prof Eichelbaum revealed the impact of genomics on all aspects of drug therapy along with many other speakers in related Symposia. Not only is drug metabolism controlled by gene expression but also drug receptor activity and processes of transport into and out of target organs and cells. The rapid advances in understanding the critical roles and effects of transporters of drugs and influences of genetic variation on these transporters was outlined in a very clear way by Professor Yuichi Sugyiama, Chairman, Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of Tokyo, Japan in his Plenary lecture and in an exciting Symposium that followed. In short multiple genes and proteins under their control determine all of the critical processes of drug metabolism, disposition and action. Targeting of therapy based on genome wide screens also will be informative regarding prognosis and will increasingly guide therapy.

The discussions on individualising drug therapy extended to dosing regimes and the importance of understanding relationships between pharmacokinetics, quite variable between individuals, and drug effects i.e. pharmacodynamics in drug development and clinical practice. A fascinating new area of attention discussed by Prof Nick Holford, Auckland, New Zealand, Prof In-Jin Jang, Clinical Pharmacology, Seoul National University, South Korea and colleagues was the quantitation of the effects of medicines on disease progression as distinct from immediate symptom relief. Parkinson’s Disease, hypertension and cardiovascular disease, depression and osteoporosis, prevalent chronic disorders were used to illustrate this important concept.

The impact of the genomic revolution and molecular biology and techniques on target identification and pharmacological strategies to perturb relevant molecular mechanisms was a major strand running through the meeting. For example, in a Symposium on “Picking the winners and avoiding the losers”, Dr Peter Lord of Johnson & Johnson, USA, discussed how the use of molecular technologies is enhancing the ability of pharmaceutical companies and regulatory agencies to identify toxicological issues earlier thereby decreasing time taken and rate of success from discovery to registration of new drugs. Professor Silviu Itescu (Columbia University USA and The University of Melbourne Australia), provided an excellent overview of the potential that stem cells represent as future therapy, addressing the utility of adult stem cell technology (derived from bone marrow stromal mesenchymal cells) to treat cardiac remodelling following myocardial infarction (heart attack). Silviu’s team have obtained remarkable results administering human angioblasts to laboratory animals in which coronary artery ligation has been used to induce infarction. Two weeks after treatment, hearts exhibit new blood vessel formation, and the increased supply of nutrients not only prevents long-term loss (apoptosis) of cardiomyocytes in the peri-infarct area, but actually permits regeneration of cardiac muscle, that is not only viable but is also functional.

An outstanding smorgasboard of clinical pharmacology and therapeutics was presented in the Therapeutics Horizons stream. An update on relevant pathophysiology preceded exposes of advances in drug therapy in malaria, obesity, osteoporosis, COX-2 selective inhibitors, drug dependence, clinical toxicology and antidotes, cardiac arrhythmias and finishing on the optimistic topic of “Drugs and Ageing: can they deliver eternal life” were dealt with in this series! Artemisinin drugs were found by Dr Sanjeev Krishna of the Department of Cellular and Molecular Medicine, St George's Hospital Medical School, London,UK to inhibit a malarial parasite specific ATPase, providing evidence of a direct toxic effect on a vital parasite transport function. Other speakers in the Malaria Symposium including Dr Tran Tinh Hien of The Hospital for Tropical Diseases, Ho Chi Minh City Viet Nam, emphasized the importance of using and investigating combinations of antimalarial drugs including artemesinin and combined this approach with earlier diagnosis with robust, simple and fast field tests. A fascinating series of presentations by Dr Rachel Batterham of the Department of Metabolic Medicine, Hammersmith Hospital, London, UK and Professor Yuji Matsuzawa, Director, Osaka University, Japan dealt with progress in pharmacotherapeutic approaches to obesity, insulin resistance and Type II diabetes and accelerated cardiovascular disease. The complex neurohormonal controls of appetite and body weight, centred around the arcuate nucleus of the hypothalamus, gut and fat cells, presented and increasing array of targets but also challenges.

Professor Nick Buckley, Canberra, Australia and international speakers shocked delegates in their Symposium that outlined the almost complete lack of any targeted drug development strategies to deal with the millions of poisonings and hundreds of thousands of deaths each year from organo-phosphate poisoning in the Asia-Pacific region.

Drug-induced arrhythmias, increasingly recognised in the last decade, initially focused on antiarrhythmic drugs themselves such as lignocaine and quinidine. More recently, the pro-arrhythmic properties of other drugs by virtue of their effects on cardiac ion channels has been a major concern in drug development. Prof Terry Campbell, Sydney Australia and Professor Naomasa Makita, Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan and colleagues discussed developments in understanding the mechanisms, screening methods and implications for therapeutics.

The breadth of clinical pharmacology, and one of its attractions, was exposed in this meeting with Symposia on Drugs in Sport where Harm Kuipers, Professor of Movement Sciences, Maastricht University, Holland challenged the inclusion of many drugs on the current “prohibited list” as there was little or no evidence that they actually enhance performance. Peter Hemmersbach, Scientific Director Hormone Laboratory and School of Pharmacy, Aker University Hospital, University of Oslo, Norway discussed the difficulties inherent in testing for endogenous compounds such as human growth hormone and touched on future likely developments, including gene transfer technology to enhance sporting performance.

Professor Tom MacDonald, Clinical Pharmacology, Ninewells Hospital & Medical School, Dundee, UK delivered an entertaining Plenary Lecture with the important message that large returns in population health outcomes would accrue if we could better implement evidence based guidelines and improve our patient’s adherence to therapy. In the prevalent cardiovascular disorders, lowering blood pressure is the intervention for which there is the best evidence. Despite these proven benefits, BP control is poor worldwide. There are good arguments to support a more aggressive approach to BP management and to treat younger subjects but once again, long-term compliance is sub-optimal. This linked to an important theme running strongly through the meeting namely the concept of “Quality Use of Medicines” or QUM, an acronym developed in Australia in the early 1990s. The conference was an important opportunity for Australia to showcase progress in achieving QUM through our approach and achievements in gathering evidence about what works and then implementing it along with the networks, products and services in support of QUM. The major sponsorship of the world conference by the National Prescribing Service, itself one of the prominent fruits of the QUM movement, effectively emphasised the importance of the QUM in Australia and its potential for the rest of the world.

Professor Tony Smith, Newcastle, Australia in his Plenary lecture spoke of the unfinished business for clinical pharmacology and world health. He reminded us that clinical pharmacology arose as a discipline largely in developed countries and continues to be vital to the stellar advances in drug discovery. However, many of the needs of developing countries remain unmet, partly because there are only limited numbers of clinical pharmacologists working in these environments. He summarised the tasks they need to be involved in including political advocacy for appropriate drug use, the construction and implementation of national medicines policies and specific issues such as the collaborative development of standard treatment guidelines, essential medicines lists and the promotion of rational prescribing, especially through training programs in medical schools. In his view, our umbrella organization, IUPHAR through its division of clinical pharmacology could begin to address training and educational needs possibly through building links with such organisations as WHO, and the International Network for the Rational Use of Drugs. (INRUD). This commitment from IUPHAR was achieved at the meeting and our strong impression was that delegates from developed and developing countries left with a similar perspective.

Ric Day, Don Birkett, John Miners, Gillian Shenfield, David Henry, Paul Seale

11 November, 2004