Faiz Kermani

Despite advances in modern medicine, in practice it remains difficult for physicians to determine a patient's response to a treatment. A drug that is safe and effective for one patient may prove to be dangerous or ineffective in another.

  In some cases, the lack of effectiveness of a drug or the occurrence of side-effects can be linked to factors such as medication errors. However, it is now known that a significant proportion of differential drug response is genetic in origin.

  This genetic angle has often not been fully appreciated, but new developments are driving the use of this information in medicine.

Pharmacogenetics is the study of how genetic variation between individuals affects their response to medicines.

  The term is often used interchangeably with pharmacogenomics, which uses genetic analysis to identify putative targets for medicines or to identify large-scale differences in the patterns of gene expression in response to chemical compounds.

  One of the hopes within the pharmaceutical industry is that pharmacogenomics will enable companies to improve success rates within certain therapeutic classes and develop tailor-made treatments for individuals.

Doctors will be able to examine the genetic make-up of a patient and determine which drugs on the market would be best for them.

  In 2001, a review of major drugs in several major therapeutic classes revealed considerable variation in patient response rates. In this review, patient response rates to asthma drugs were described as being around 60%, whereas the rates were only 30% for Alzheimer's disease therapies and 25% for cancer chemotherapy.

Pharmacogenomics is also predicted to have an impact on reducing the number of medical adverse events.

  Adverse effects remain a problem despite industry efforts to conduct extensive testing of investigational products, and the numerous measures brought in by regulatory agencies to improve safety measures. According to one estimate, 100000 deaths and 2 million hospitalizations occur each year in the US because of adverse drug responses. The continuing controversy regarding drugs such as Vioxx highlights public concern about drug-related side-effects. If pharmacogenomics can be harnessed to identify the genetic basis of these adverse events, lives will be saved and public confidence in the pharmaceutical industry will also be improved. 

Supporters of pharmacogenomics believe that it will revolutionize clinical trials, as more will be known about the compounds being tested in relation to the genetic make-up of participants (Figure 1). In this scenario, pharmaceutical companies could exclude subjects for whom a particular drug would be harmful or ineffective. By then screening patients who would be appropriate for the drug being tested in the trial, considerable resources and time may be saved. This would reduce the costs of clinical development as well as enhancing success rates. From a marketing perspective, companies would be able to provide greater information on how different patients might respond to their drug and this would boost physician confidence in their products.

There have also been suggestions that pharmacogenomics could be used for drugs that were discontinued or withdrawn from major markets, because of safety concerns, so that they could be reintroduced by matching them to a niche patient population.

  One study recently estimated that 38 drugs have been withdrawn from major markets because of such concerns since 1990.

  However, the slow progress in identifying genetic traits that could be associated with the reported toxicity for these withdrawn products means that the full potential of pharmacogenomics in this area is yet to be realized.

Many companies have been very successful in developing drugs that can be used by a variety of patients, and there is a fear that pharmacogenomics will segment markets and drastically reduce revenues.

  Given that it costs pharmaceutical companies a tremendous amount of money to develop a new drug, will they be willing to invest in the R&D process if the end-product is only considered applicable to a small portion of the population? Those in favour of utilizing pharmacogenomics argue that the R&D process will be made more efficient and less expensive through the use of pharmacogenomics, thereby compensating for a reduced patient population.

  Furthermore, the commercial success of drugs such as Glivec (imatinib) and Herceptin (trastuzumab) has shown the power of the genetic approach to drug development.

  These drugs are widely seen as advances in cancer treatment and have been well received by patients. In fact, many see cancer as the area in which pharmacogenomics will have its initial impact within the pharmaceutical industry. 

Another worry of pharmaceutical companies is that they are still unclear about what regulatory agencies are seeking in terms of pharmacogenomic information for heir products. However, this situation is changing, with FDA appearing to be the regulatory leader in this respect. It is developing detailed guidance documents that provide information on its current thinking and the use of pharmacogenomics for regulatory decision making. It has also introduced a genomics training programme for its staff. In conjunction with EMEA, it recently issued guidance documents to encourage the voluntary submission of genomic data by companies to the agencies. 

The completion of the Human Genome Project in 2003 led to a flurry of interest in pharmacogenomics, but many of the predictions regarding its impact in medicine proved premature. Nevertheless there is now a clear move towards applying the principles of pharmacogenomics to drug development. Guidance from regulators will be key to how fast these are incorporated into mainstream pharmaceutical R&D.  

Pharmaceutical Research and Development in the 21st Century., Pharmbiosys

2. Pharmacogenetics and Personalised Medicine — Key Facts.  

www.pharmafocus.com/cda/focusH/1,2109,21-0-0-NOV_2002-focus_news_detail-0-75441,00.html

Articles

The completion of the Human Genome Project in 2003 led to a flurry of predictions regarding the application of pharmacogenomics to drug development. With US and European regulatory authorities finally on the verge of issuing guidance on the use of pharmacogenomics, drug development is all set to change.

The future is pharmacogenomic

Arecent survey by the Organisation for Economic Co-operation and Development (OECD) revealed that pharmaceuticals accounted for more than 10% of total health spending in most countries, but that in France they accounted for over 20% of healthcare spending despite the fact that it has one of the strictest pricing systems in Europe. A combination of low prices and a high level of government-reimbursement have given patients and physicians little incentive to cut consumption.

In France, the top therapeutic categories are cardiovascular (CV), central nervous system (CNS) and alimentary/metabolism.

  However, for the 12 months leading up to December 2006, these classes performed below expectations. The market for CV drugs actually declined by 4%, whilst those for CNS and alimentary/metabolism grew at approximately 2%. However, this picture appeared to mirror the general results for Europe's top five markets (Germany, France, UK, Italy and Spain). Promising categories for the French market include antineoplastic and immunomodulatory agents, and blood agents, which grew at 15% and 29% respectively for the 12 months leading up to December 2006.

Driven by a rapidly ageing population and a known high consumption of pharmaceuticals, the French pharmaceutical market has always appeared buoyant. Yet in practice, pharmaceutical companies have found the operating conditions in France to be tough, as governments continue to exert a downward pressure on profitability.

  For example, there has been visible encouragement for generics and it has been predicted that the French generics market may grow by over 20% per year by 2008.

  In contrast, annual growth for branded pharmaceuticals was less than 5% in 2006 and may be lower than 4% by the end of 2007.

  In recent years, growth rates for the French pharmaceutical market have tended to fall below industry expectations, and it is unclear whether this will improve in the future as cost containment continues to be popular among French politicians.

In 2004, French pharmaceutical production was valued at close to €35 billion and rose by 7.7% in 2006.

  Most French pharmaceutical exports go to the US, followed by Germany and Belgium. Out of total French pharmaceutical production, close to 44% is described as destined for EU member states. Despite continuing growth in production, the French pharmaceutical industry body, LEEM (Les entreprises du medicament) has described the operating environment as fragile.

The change in operating conditions is reflected by a steady decrease in the number of domestic pharmaceutical companies. In the 1950s there were around 1000 companies involved in the pharmaceutical sector, but this dropped to 339 in 2005.

  As in other parts of the world, the French market is dominated by the large multinationals. It has been estimated that the top 10 pharmaceutical companies represent over 50% of the French pharmaceutical market.

LEEM has also expressed concerns about the state of French pharmaceutical R&D, although in some areas the industry still performs well. For example, LEEM estimates the numbers of pharmaceutical staff have tripled in 20 years with 1000 new posts being created by the industry every year.

  At present, the industry employs approximately 100000 personnel with about 18% of these being involved in R&D functions.

  The number of personnel involved in R&D has increased from 14% in 2001, indicating favourable conditions for pharmaceutical research in France.

  In particular, demand for clinical R&D staff appears to be at an all time high. Figures from LEEM reveal that a considerable amount of clinical research is being conducted in France — especially in the cancer therapeutic area. They estimate that around 12000 pharmaceutical industry staff work on projects associated with breast cancer alone.

However, other signs are less encouraging and point to an erosion of France's underlying research base. For a start, the industry has seen a marked increase in the taxation of its income — between 1997 and 2001, industry figures reveal that the level of such taxes tripled.

  In an industry where sales growth is often in the double digit range, the French industry's figures have noticeably dipped, and companies link this to government cost containment and taxation policies.

  As the pharmaceutical industry uses its profits to determine the level of reinvestment in R&D, this has led to some multinational companies shifting new investment to foreign markets where they consider the conditions for long-term profitability more favourable.

The French Government has launched several initiatives to sustain innovation, including reforming the R&D tax credit scheme and creating a new fiscal status for emerging innovative companies. France has been examining initiatives launched by the UK and Spain to improve their R&D positions to develop its own national approach. The French government has also been following the progress of the EU-focused G10 Medicines Group, which seeks to improve R&D competitiveness in line with social and public health objectives.

In January 2004, the French government commissioned a fact-finding report entitled 

 detailing measures that could improve France's R&D position (Table 1). To compile the report, a delegation visited several countries representing major R&D centres to hear the views of different companies and organizations involved in the pharmaceutical and biotech sectors. The French government has also attempted to encourage emerging biotech companies through its 'young innovative company' scheme. To qualify for this status, a company must meet certain criteria such as spending at least 15% on R&D. In return they can get a substantive waiver on tax for a period of up to 8 years.

  The French biotech environment appears to be improving, with an estimated 400 start-ups in the country.

  Although this figure is similar to that in the UK and Germany, many of the French start-ups are at a very early stage compared with these European counterparts. 

Table 1 PharmaFrance recommendations.1			

Historically, France has been the major pharmaceutical producer in Europe. If the country is to maintain this position in the future then much will depend on the initiatives that have been undertaken by its government to revitalize the research environment. It will be keen to learn from the mistakes of neighbouring Germany, where the pharmaceutical industry has suffered a clear decline. 

1. R. Jones, The Chemical Industry and Globalization, ACS  Symposium Series, No. 942 (An American Chemical Society  Publication, 2006).  

2. IMS Health, "Drug Retail Monitor, 12 months to December 2006," (2006). 

3. IMS Health, "Generics Market Expected to Soar to $80 Billion by 2008," (2004). 

4. Anon, L'industrie pharmaceutique, Les entreprises du médicament (LEEM [2007]). 

Driven by a rapidly ageing population and a known high consumption of pharmaceuticals, the French pharmaceutical market has always appeared buoyant.

Fostering France's pharmaceutical recovery

A problem for the major pharmaceutical companies is that investors have become accustomed to double-digit growth performance and thus, there is constant pressure on them to develop an ever-greater number of new products with high sales potential. However, the rising costs and risks of drug development combined with the lengthy drug development timescales, and increasing competition have made it difficult for companies to keep pace with such expectations. Clinical trials are a particularly costly and time-consuming part of the R&D process, frequently accounting for over 40% of total R&D spending.

These continuing pressures necessitate a change in R&D strategy, particularly with respect to using external organizations to ensure successful product development.

  Few pharmaceutical companies would attempt to manage every part of the R&D process by themselves, as there is now proven value in outsourcing.

  This change in R&D thinking also requires a response from those who are in line to perform such work.Contract research organizations (CROs) must be able to offer a range of services that can meet a client's objectives for their product, but must also be thinking how they can further expand their offerings to suit the dynamic global market. They must mature beyond being simple service providers and demonstrate themselves as partners who can provide true value to pharmaceutical companies. 

Recent figures show that pharmaceutical companies are increasing their R&D investment in their quest to improve productivity (Figure 1). Figures from Pharmbiosys reveal that this spending rise is particularly evident among the top ten pharmaceutical companies — who dominate the industry's R&D efforts.

  According to the analyses, by the end of 2006, the top ten companies were expected to have invested a massive $54 billion, representing close to 60% of total industry R&D spend.

  By 2008, their investment could rise to $65 billion, representing over 80% of total industry R&D spend.

Although smaller companies may produce innovative compounds, only the larger companies would appear to have the spending power to take these products through the necessary stages of clinical trials. The divide in spending power between these two sets of companies will be further increased by events such as mergers and acquisitions.

  Despite the vast investment at their disposal, the largest companies have become much more cost-conscious when planning projects and using internal resources. As a result, it could be CROs that stand best to benefit from the rises being seen in R&D spending by these pharmaceutical industry leaders. Formalized plans to use contractors for clinical trials are increasingly becoming part of a company's R&D strategy.  

A 2006 report by the Tufts Center for the Study of Drug Development revealed that company sponsors who were more extensive users of CROs tended to complete their projects faster, with this being particularly noticeable during the study close-out period.

  An important additional feature of these findings was that quality comparable to submissions involving minimal use of CROs was maintained.

  Such findings will give confidence to those wishing to outsource projects and counter fears about loss of control over the development of products.  

In 2004, it was estimated that leading CROs managed around 23000 Phase I–IV clinical trials worldwide.

  Such figures demonstrate that the CRO sector is both mature and well-established. Clearly, the major trials will be given to those CROs that have the most services to offer pharmaceutical companies and have an international focus to their work. Previously, many pharmaceutical companies have automatically assumed that they had superior knowledge to CROs in all aspects of clinical development. Provided they can defend their arguments with good reasoning, ambitious CROs should not be shy to challenge such attitudes! 

A pharmaceutical company may indeed have better knowledge regarding certain aspects of clinical development, but this will be biased to the products they have previously developed and the markets with which they are most familiar. As pharmaceutical companies are committed to innovation this means developing new products for a changing global market, and, therefore, requires a fresh approach to R&D and subsequent marketing. This is where a pharmaceutical company can gain value from a CRO, by using them for an objective viewpoint concerning their plans. 

 CROs will have worked with a range of clients across a variety of therapeutic areas and in many different markets. As the CRO sector has evolved steadily, it would be a mistake to overview the experience they have gained over the past two decades. Most CROs have considerable experience of dealing with and resolving a variety of problems encountered during clinical development, and should be able to apply such thinking to the client's product. Frequently, it is not just technical issues that disrupt a clinical trial, but also failure to maintain proper lines of communication. Furthermore, these CROs have their own contacts in regulatory agencies, healthcare systems and patient organizations, and these can ensure smooth progress for a trial. 

In this new era of clinical development, a pharmaceutical company should insist that the CRO provides a comprehensive approach to their trial that challenges any preheld views. Only in this way can a realistic approach be devised that will allow the trial to stay on track if any problems are encountered. The clinical trial process rarely runs according to plan, but many companies are often overambitious at the outset and can pay a heavy price should their product fail. Equally, many CROs have been so eager to take on work they have not taken the time to critically evaluate the trial and this has exacerbated eventual problems. Although the CRO may not wish to draw attention to weaknesses in the intended trial, failing to do so is a great disservice. If a CRO wishes to be seen as a partner it must shake off the notion that it is a passive player in the R&D process. 

Many CROs have been able to demonstrate their value through work in emerging markets. These regions are seen as particularly promising as they have the required patient numbers for large trials and because the work can be done in a cost-effective manner. However, these regions have additional value in adding to the prestige of a pharmaceutical company's products. For a firm to expand its markets, local physicians must have confidence in their products. Clinical trials offer these physicians a chance to familiarize themselves with the product in a setting they trust.

Engaging these healthcare professionals is part of the clinical development process and the experience of CROs in working with these individuals is important to the success of an international trial. As the media often criticize pharmaceutical companies for how they operate in emerging markets, it is vital that CROs ensure standards are maintained. Many CROs have been able to do this by setting up their own investigator networks, which they can access if a trial is to be run in that region. These investigators will be the key opinion leaders in their respective therapeutic areas and have appropriate experience in running global clinical trials. These networks can provide added reassurance for pharmaceutical companies looking to outsource trials internationally. 

Increasing R&D spending will enable the largest pharmaceutical companies to expand their pipelines, but outsourcing will allow them to further extend the benefits that result from the additional investment. The CRO sector has now come of age and has much to offer the pharmaceutical industry in the modern era of drug development. The greater use of outsourcing will aid the transformation of CROs from simple 'service providers' to established partners. Such cooperation can only improve pharmaceutical industry efforts to develop new and innovative drugs to satisfy unmet medical need.  

Pharmaceutical Research and Development in the 21st Century

2. Anon, "CROs Usage Associated With Faster Drug Development Speed At  Comparable Quality, According To Tufts Center For The Study Of Drug Development," 

Although the CRO may not wish to draw attention to weaknesses in the intended trial, failing to do so is a great disservice.

Oursourcing is key to future pharmaceutical R&D strategy

Although it has recently been surpassed by Mexico in terms of value, the Brazilian pharmaceutical market remains of key importance to companies establishing themselves in Latin America. The Brazilian government has focused heavily on improving the healthcare system and this should lead to long-term benefits for its citizens. The Ministry of Health has also attempted to decentralize the management of the healthcare system to more regional and local levels. This has been necessary to account for the different healthcare priorities in different parts of the country. 

Figure 1 Life expectancy in Latin America.			

The population is growing and ageing rapidly (Figure 1), which will result in increased demand for new medicines and thus provide the pharmaceutical industry with great opportunities; for example, between 1970–1991, the Brazilian population grew from 93.1 million to 146.8 million — an increase of nearly 58%.

  The changing epidemiological profile of the population has been accompanied by a rise in chronic diseases, particularly cardiovascular and respiratory conditions, and a persistence of diseases associated with poverty and social inequality.

Despite the potential opportunities for pharmaceutical companies, the Brazilian market will present several challenges, given the government's tough line on pharmaceutical pricing, intellectual property and cost containment. Nevertheless, companies focused on the future will benefit from remaining committed to the Brazilian market. 

Brazil's size makes the provision of affordable healthcare for all citizens a difficult commitment for the government to fulfill. It has been described as a country that exhibits some of the most profound social inequalities to be found across the world. According to figures from the UK's Department for International Development Health Resource Centre, across Brazil there is a 63.4% degree of income inequality.

  The scale of the difference is highlighted by the fact that the median income of the wealthiest 10% of the Brazilian population remains 30 times greater than that of the poorest 40%.  

Successive Brazilian governments have attempted to improve this situation and a key step forward was the 1988 constitution that created a new health system, the Sistema Único de Saúde ([SUS] literally the Single Health System).

  The SUS brought together a number of healthcare institutions and hospitals across the nation under a single body of control for the first time.

  In 1990, Brazil's Congresso Nacional (National Congress) passed additional legislation that detailed how the new system would operate. 

Public health services, in conjunction with the private sector, work under contract to the government and it is estimated that healthcare coverage is now about 75%.

  Much of the work being carried out by the government to improve healthcare services is focusing on the poorest sections of the population in areas such as combating vitamin deficiencies and reducing child mortality rates. Over 75% of the financing for the public health sector comes from the Brazilian treasury, with the remainder provided by states and municipalities.  

Although much has happened since the establishment of the SUS, the healthcare situation in Brazil is changing slowly rather than dramatically. This is partly because of factors such as the country's economic crisis, which disrupted the government's more ambitious plans. In 2002, Brazil's healthcare spending as a percentage of GDP was only 5.2%. This put it behind countries such as Argentina (8.0%), Chile (6.0%) and Mexico (5.5%).

  Brazil's per capita spending on healthcare was estimated at $50 per annum, which put it far below the $500 recommended by the World Health Organization. 

The economic problems that Brazil suffered during 2002 contributed to significant disruption of healthcare services and stagnation of the pharmaceutical market.

  At one point during August 2002, the Brazilian currency, the Real, lost 13% of its value.

  The weakening of the currency made it more difficult for the country to pay its debts and growing unemployment led to further uncertainty. The persistence of this uncertainty contributed heavily to the election of a new President in the subsequent elections, but his social policies appeared to alienate foreign investors. Economic troubles in neighbouring Argentina and Uruguay only served to prolong any recovery in the Brazilian economy, as investors moved funds out of Latin America.  

The economic problems naturally affected the funding of healthcare and the pharmaceutical market. In 2002, Brazil's pharmaceutical net sales were estimated at $3.9 billion, whereas in 2001 they had been around $5.7 billion.

  However, currency fluctuations are reported to have made the drop in pharmaceutical sales appear more dramatic. In December 2002, the government appeared to address some of the pharmaceutical industry's worries by allowing an 8.63% price increase for many products sold in pharmacies.

  Furthermore, although Brazil has now slipped behind Mexico as the leading market in Latin America, it is recovering strongly. IMS Health reported that in the twelve month period leading up to February 2005, sales through retail pharmacies in Brazil rose by 19%, which surpassed the 9% sales increase seen in Mexico and the 13% increase in Argentina.

  The most popular therapeutic categories in terms of sales were cardiovascular, central nervous system (CNS) and alimentary/metabolism. 

There is no doubt that the Brazilian pharmaceutical market offers considerable commercial opportunities to the pharmaceutical industry, but what is of concern to companies is the attitude that the government has taken towards pricing issues and intellectual property. The immense scale of the AIDS crisis in Brazil has largely driven this process (Figure 2) as the country has the highest number of AIDS cases in Latin America.

Figure 2 Expenditure by the Brazilian government on antiretrovirals.			

Brazil has implemented one of the most effective anti-AIDS strategies in the world by making affordable treatments available to sufferers despite opposition from the global pharmaceutical industry on the strategies employed. The pharmaceutical industry has been critical of the Brazilian government's attempts to produce its own generic versions of antiretroviral drugs. Brazil exploited a time lag until international patent rules applied in the country. This has meant that a generic version of an antiretroviral combination cocktail that sells for $10000–15000 a year in the USA can cost $3000 in Brazil.

  This situation came about from enacting a law that "guaranteed every AIDS patient [in Brazil] state-of-the-art treatment".  

In August 2001, there was controversy when Brazil's health minister threatened to strip Roche pharmaceutical's patent on the anti-AIDS drug Nelfinavir after six months of negotiations failed to lower the price. By manufacturing the drug locally, the minister estimated that the price could be reduced by 40%. Although Brazil has manufactured generic versions of antiretrovirals, it was the first time it had openly threatened to strip a patent.  

Although the approach that the Brazilian government has used is highly controversial, its effects have been dramatic. The decline in hospitalizations from opportunistic infections from 1997–1999 is estimated to have saved the country $422 million.  

Another challenge for the pharmaceutical industry is the overt attempt by the government to promote the usage of generics to drive down healthcare costs. In public hospitals, doctors are required to prescribe generically and the government has been running a public campaign to educate consumers about generics.

  The official backing of generics has also been seen in the approval process. The Agencia Nacional de Vigilancia Sanitaria (ANVISA) has visibly increased the number of generic applications that it has approved. 

Brazil represents an important market for the pharmaceutical industry. There is a strong demand from the growing population for new medicines, but any commercial opportunities in this area will be strongly affected by the government's attempts to drive down prices through cost containment measures. Pharmaceutical companies will need to carefully assess the market for their products to deal with these difficult challenges. Dealing with government cost control measures is not a new experience for international companies, and so overall Brazil still has plenty to offer the pharmaceutical industry. 

1. L. Lobato, Reorganizing the health care system in Brazil in S. Fleury, S. Belmartino and E. Baris (Eds.) 

Reshaping health care in Latin America: A comparative analysis of health care reform in Argentina, Brazil, and Mexico

 (International Development Research Centre, Ottawa, ON, Canada, 2000). 

2. UK's Department for International Development Health Resource Centre, Brazil health briefing paper (2004). 

www.dfidhealthrc.org/shared/know_the/publications.html

Financing Health Policies in Brazil: Achievements, Challenges and Proposals

 (The UN Development Programme Poverty Centre, Brasilia, Brazil, 2002). 

5. Brazil: Country Health Profile. The Pan American Health Organization (2001). 

6. E. Sandullo, Latin America lagging behind in health care provision (IMS Health, 2003). 

7. Brazil's looming economic crisis (BBC News, London, UK). http://

8. J. Oliveira, Brazil: Market overview of drugs and pharmaceuticals (US & Foreign Commercial Service and US Department Of State, 2003). http://

9. L. Miranda, El aumento de precios de medicamentos en las farmacias tendrá lugar en diciembre (2002). 

10. IMS Retail Drug Monitor: Pharma Sales Growth Continues at 6 per cent Pace in 13 Major Markets (IMS Health, 2005). 

12. F. Kermani, Neglected and Emerging Diseases: The Next R&D Challenge (Chiltern International, 2004).  

13. AIDS drugs policy — Ministry of Health/Brazil (2000). 

www.aids.gov.br/assistencia/aids_drugs_policy.htm

14. Generics take off in Brazil (IMS Health, 2004). http://

Although it has recently been surpassed by Mexico in terms of value, the Brazilian pharmaceutical market remains of key importance to companies establishing themselves in Latin America. The Brazilian government has focused heavily on improving the healthcare system and this should lead to long-term benefits for its citizens. The Ministry of Health has also attempted to decentralize the management of the healthcare system to more regional and local levels. This has been necessary to account for the different healthcare priorities in different parts of the country.

Pharma battles in Brazil

Strange but true, few who love its taste associate it with good health, but recent reports that a confectionery company was seriously examining the pharmaceutical potential of chocolate achieved widespread international media coverage.

In fact, the health-related properties of chocolate have long been debated and it appears that certain people in the industry believe compounds in chocolate could yield new pharmaceutical approaches to major disorders. In an industry that is seeking new sources of innovative products, this could be one of the most unusual avenues to be explored in a long time. 

Chocolate has a loyal following in most countries (Figure 1), but it has taken a strange route through history to arrive in its modern form. Although its health benefits have been poorly characterized scientifically, there must be little doubt that chocolate's persistence in society through the ages owes much to the general feeling of well-being that it brings to those who consume it. 

The exact origins of chocolate are mysterious, but most historians agree that it was first consumed in Central America. In 2002, residues in a ceramic vessel, found at a Mayan site in north-eastern Guatemala, were found to contain theobromine — considered to be a chemical marker for cacao.

 When these findings were placed in the context of linguistic assessments of the ancient regional cultures it led to the theory that chocolate use could date back to as early as 500 BCE.

  The Aztec and Mayan civilizations were experts at cultivating the cacao tree and using its seeds to produce a chocolate-like substance, which they drank unsweetened. There are numerous hieroglyphs that depict the central role of chocolate in Mayan society, being used by rulers and the priestly classes. The Aztecs took on the beverage, referring to it as xocalatl meaning warm or bitter liquid. Cocoa beans were also used as a currency and exacted as tribute from people ruled by Aztecs.

When the Spanish arrived in the New World they observed the drinking of xocalatl with interest and curiosity. The Aztec Emperor Moctezuma is reported to have consumed several goblets of the drink, believing it to be an aphrodisiac.

 Aztecs also believed that by drinking chocolate they would gain some of the wisdom of Quetzalcoatl, their God of learning and of the wind. 

Following the Spanish conquest of Mexico, chocolate found its way to Europe with other discoveries from the new colony. Yet it remained a guarded secret within the Spanish empire and it did not find its way to other European countries until over a century later. In the 1570s, chocolate was being used by the Spanish in a sweetened form, and gained popularity as a medicine and aphrodisiac. As a result of rising demand, shipments began to arrive from Mexico. Starting in the 1650s, chocolate began to appear across Europe as a beverage for the elite classes. Over the following century, demand grew and this pushed down the price of cocoa beans, thereby bringing chocolate into the reach of wider society. Cocoa production also began to spread with plantations in the West Indies, the Far East and Africa.

Interestingly, a number of the original chocolate manufacturers were apothecaries (early chemists), who wished to take advantage of the reported medicinal properties of cocoa. Apothecaries became a major force in chocolate manufacture, as they possessed the necessary skills and equipment to blend the cocoa ingredients for consumers. In fact, both Fry's of Bristol and Terry's of York, two well-known names in British chocolate history, were founded by apothecaries.

The increased popularity of chocolate led to a series of innovative developments. A major step forward was in its transformation from a beverage to a solid form that retained its taste and so could be eaten. As others experimented with further enriching the taste and developing pastes that could be moulded into bars, businessmen began to mass-produce chocolate using the latest technology of the industrial revolution. Some industrialists, particularly those in Switzerland, who went on to found Nestlé and Lindt, became interested in modifying chocolate's consistency and through the addition of milk created the version of chocolate that is well-known today.

Chocolate's origins hint at medicinal properties, but proving these in a conclusive manner to a modern scientific audience has proved elusive. Nevertheless, this has not dimmed the enthusiasm of those pursuing research in this field. A notable amount of chocolate-based research focusing on a range of medical conditions has appeared in peer-reviewed scientific journals over the last year. Most of this research has centred on chocolate-derived antioxidant flavonols, but additional chocolate compounds and their properties are also being explored. 

In general, reports that chocolate-derived flavanols can reduce the risk of dementia, diabetes, heart attacks and strokes have been based on small studies, with few details on how this approach could be extended into mainstream medicine.

  Critics have pointed out that research in this area is limited and that the nature of the source of flavanols has driven the publicity rather than any positive clinical results. Furthermore, it is important to note that chocolate is not the only source of these compounds. 

appeared in cinemas, a study involving chocolate appeared in 

, the Journal of the American Heart Association. The study was conducted by research groups at University of L'Aquila (Italy) and at Jean Mayer USDA Human Nutrition Research Center on Aging (Tufts University [Boston, MA, USA]). According to the researchers, dark chocolate decreased blood pressure in a number of hypertensive volunteers.

  Furthermore, it had beneficial effects for these volunteers in terms of lowering cholesterol levels and improving sugar metabolism. In contrast, white chocolate did not produce these favourable effects.

The researchers linked the beneficial effects to flavanols, which are found in high amounts in dark chocolate, but not in white chocolate. However, the authors of the study did stress that the dark chocolate used in the study differed from commercially-available milk chocolate products, which are low in flavanols. Although the results of these types of cardiovascular studies are interesting, the researchers involved have often distanced themselves from the ensuing media publicity in case their work is misinterpreted as an open endorsement for people to eat chocolate to lower their blood pressure! As is often pointed out, research into the cardiovascular effects of flavanols from cocoa remains at an early stage. Furthermore, many people already have a diet that is too high in fat and so a large intake of chocolate will not improve their health outcome. 

Another widely-covered chocolate-related study appeared in April 2005 in the 

  Researchers at Georgetown University (Washington DC, USA) reported that pentameric procyanidin, which naturally occurs in cocoa had potential anticancer properties. The work was performed 

 on breast cancer cell lines, where it was found that pentameric procyanidin inactivated various proteins that had a role in regulating the cell cycle.

  In contrast, normal human mammary epithelial cells in primary culture were resistant to the effects of this cocoa-derived compound on their ability to proliferate. The novel aspect of the study was the manner in which pentameric procyanidin exerted its effects, as it appeared to jointly deactivate several regulatory proteins. Nevertheless, the study was performed 

 and so much further work is required before the relevance to human cancer can be ascertained. 

A more unusual study was published online in FASEB Journal  (Federation of American Societies for Experimental Biology [Bethesda, MD,USA]) by a team at Imperial College (London, UK) and focused on the cough-suppressant properties of chocolate.

  Theobromine found in chocolate was found to be nearly a third more effective in stopping persistent coughs when compared with codeine, one of the most well-known cough medicines.

  The initial findings were considered of interest as persistent coughing often affects patients with lung disease. Nevertheless, much remains to be done before chocolate can be developed cough remedy (Figure 2). 

Figure 2 Theobromine levels in chocolate.			

The main driver of the current medical interest in chocolate appears to be Mars Inc., which held a conference in Switzerland where researchers discussed how pharmaceutical products could be derived from cocoa sources.

  Up until now, chocolate research has been a predominantly academic exercise and so the interest of a major company in medical applications could transform the perceptions of this field of study.  

Using chocolate as a medical product itself remains unlikely because of the variation in flavanol levels with respect to cocoa content. It is also important to note that each stage in the processing of cocoa alters its chemistry.

  A study conducted by the scientific research agency of the US Department of Agriculture ranked flavanols and antioxidant capacity in a range of commercially available chocolate products. Natural cocoa powder was ranked highest in terms of antioxidant capacity followed by unsweetened baking chocolate. Milk chocolates were ranked lowest in terms of antioxidant capacity.

Furthermore, most of the research promoting flavanols continues to be sponsored by food companies and observers have suggested that transforming chocolate into a health-related product is not a new concept, but has resulted in little progress over the years. During 1995, Japan held an International Symposium on Chocolate and Cocoa Nutrition, which led to a series of popular television broadcasts called "the surprising effects of cocoa." This stimulated considerable medical research into the potential health benefits of chocolate, as well as huge sales of cocoa products.

Mars Inc. remains publicly upbeat about its latest developments and believes it possesses intellectual property of interest to pharmaceutical companies. It claims to be discussing licensing deals and joint venture agreements based on developing products from cocoa-derived compounds. As the second-largest chocolate manufacturer in the US and one of the world's largest food-processing companies, and with a reported value of over $30 billion, its move towards the pharmaceutical sector cannot be ignored.  

However, whether it gives rise to extra sales of chocolate (Figure 3) and gives the media more to think about than amusing headlines remains to be seen. For the moment, though, pharmaceutical researchers can stick to eating chocolate. 

Figure 3 Total confectionary sales of major chocolate manufacturers.			

is European marketing manager business development at Chiltern International Ltd, UK. 

1. Mars Talks Up Cocoa's Medicinal Potential 

2. Ancient Chocolate Found in Maya "Teapot" http://

5. Chocolate May be Healthy for Your Heart 

6. A Small Portion of Dark Chocolate a Day Keeps Heart Attacks and Strokes Away 

gumc.georgetown.edu/communications/releases/ramljak_paper.pdf

10. Researchers Find That Chocolate Compound Stops Cancer Cell Cycle in Lab Experiments http://

11. Chocolate Could be Cough Medicine http://

12. Questions and Answers — Chemistry of Cocoa and Chocolate 

13. Study Reveals Differing Amounts of Naturally Occurring Flavanols in Chocolate and Cocoa Powder 

14. Health Benefits of Cocoa and Generic Promotion of Benefits in Japan 

Could compounds in chocolate yield new pharmaceutical approaches to major disorders?

Chocolate medicines

Latin America has become a promising region for the pharmaceutical industry in terms of both R&D and sales. Nowhere has this been more apparent than in Mexico, which has become a top priority market for many of the major multinational pharmaceutical companies. Furthermore, the Mexican government is increasing its investment in healthcare resources and there is a strong, growing demand from the population for access to newer and better medical treatments. 

Mexico's potential was highlighted during 1999, when the Latin American region was affected by recession. Mexico's oil-based economy and close links to the US helped it survive this period of economic uncertainty, while other countries in the region suffered. At present, it is the ninth largest economy in the world and the leading trading nation in Latin America.

  Having established bilateral accords with 32 countries, Mexico has become ideally placed for international trade and commerce.

  In particular, Mexico's participation in the North American Free Trade Agreement (NAFTA) with the US and Canada puts it in a very powerful trade position with respect to its Latin American neighbours. 

In pharmaceutical terms, Brazil had always been the major Latin American market, but by 2003, continuing economic problems led to it being surpassed by Mexico in terms of sales. In 2004, IMS Health estimated that Mexico accounted for 32.6% of the regional pharmaceutical market, with Brazil accounting for just over 31%.

 Mexico's growing importance as a pharmaceutical market is not surprising given its large population. As their financial situation improves, many in the population are seeking access to new and better medicines. In addition, the government is attempting to reform its healthcare system to provide poorer sections of its society with affordable treatments.

  Many Latin American countries, including Mexico, have taken an interest in how the British National Health Service is organized when embarking on such reforms.

Similar to many other Latin American countries, Mexico has been re-examining its approach to healthcare to expand coverage for its citizens.

  By law all workers in the mainstream economy must be registered with one of the social security institutions.

  These include the Instituto Mexicano de Seguro Social (IMSS), which provides healthcare to about 34 million Mexicans, mostly in the private sector, and the Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), which provides healthcare to about 9 million Mexicans, mostly federal government employees.

  The national oil company, PEMEX, and the military run their own health insurance schemes. The system for the uninsured population includes the Ministry of Health's (SSA) services, which operate throughout the country, and the IMSS Solidarity Program, which covers the population in certain rural areas.

Mexico's public healthcare system provides services to about two-thirds of the population, but the government recognizes that the current service level is far from ideal.

  To improve coverage for those that require it most, the government is attempting to persuade employed citizens to use their private medical insurance more effectively. Although the Federal government sets the overall standards and has the major say in regulating the healthcare service, since 1996 there has been a considerable amount of decentralization, with individual states taking on more responsibilities. 

One of the major problems in reforming Mexican healthcare is that despite certain advances in the past, there remain areas where little improvement has been made. In addition, the country has been keen to improve the quality of the healthcare being delivered and make such information available to the public via the established media and the internet.

  The government has encouraged the establishment of codes of practice for health professionals, the use of clinical guidelines in public institutions, and the certification of professionals and healthcare institutions.

Nevertheless, healthcare in Mexico is improving and the government hopes to make further advances. For example, between 1940 and 2000, life expectancy rose by 30 years for both men (from 40 to just over 70 years) and women (from 42.6 to just over 76 years) (Figure 1).

  Furthermore, between 1970 and 2000 infant mortality more than halved to (from 72 per 1000 births to 26).

The country has been making ambitious reforms through its National HealthCare Programme (El Programa Nacional de Salud). Through this programme 2001 to 2006, the government hopes to define the type of national healthcare system the country needs to have for the future.

  The aim is to establish a system that will guarantee all citizens free healthcare by 2025, independent of their ability to pay for it. As of 2002, government projects had extended healthcare coverage to over 8 million low-income citizens.

As well as constructing new hospitals, and improving existing ones, government projects are also focusing on the procurement of pharmaceuticals and other medical supplies.

  At present, although the public health system provides services to a majority of the population, it accounts for somewhere between a tenth to a fifth of the total value of the market for pharmaceuticals (Figure 2). If healthcare reforms are successful, this figure should rise. 

Figure 2 Public share of pharmaceutical expenditure (2002 estimate).			

Latin America has become a promising region for the pharmaceutical industry in terms of both R&D and sales. Nowhere has this been more apparent than in Mexico, which has become a top priority market for many of the major multinational pharmaceutical companies. Furthermore, the Mexican government is increasing its investment in healthcare resources and there is a strong, growing demand from the population for access to newer and better medical treatments.