DRUG DEVELOPMENT IN EUROPE Early Days

Clinical pharmacology, the science of drug actions in humans, started its development in the 19th century. Test animals were increasingly used in pharmacology research. In France, Francois Magendie (1783–1855) played a prominent role. He is known to many for his description of the foramen of Magendie in the brain but could be thought of also as one of the most important founders of modern pharmacology. Czech Jan Evangelista Purkinje (1787–1869), whose name is linked to large nerve cells in the brain (Purkinje cells) and to conducting tissue in the heart (Purkinje fibers), was one of the first to study drugs in healthy subjects, an unusual step, to avoid interference by illnesses when studying drug characteristics [4]. In 1805, German pharmacist Friedrich Serturner isolated the pure active ingredient in opium. He named this chemical morphine, after Morpheus, the Greek god of dreams. Serturner’s discovery was the first isolation of an active ingredient. For many years he experimented on himself and others to explore the effects of the alkaloid.

In the 17th century, a controlled study design was described. Jan Baptista van Hellemont (1578–1644), a physician in Brussels, had proposed to his opponents to settle a dispute about wound treatments. Several hundred patients were to participate in an experiment, with vitriol or bloodletting treatments assigned by lottery to each individual patient. Results were to be judged by “the number of funerals” on each side. It is only in the 20th century that the randomized controlled study design became generally accepted. The double blind randomized study conducted in the late 1940s by the British Medical Research Council confirming the effect of streptomycin on tuberculosis was to become a classical example. With the emergence of the chemical industry in the second half of the 19th century, drug manufacturing by chemical synthesis became possible and a number of pharmaceutical companies emerged.

Several drugs to treat serious diseases were discovered. Due to insufficient pharmacological knowledge those drugs were probably too easily introduced. The American government realized an important role to play. Legislation in 1938 and later in 1962 required manufacturers to show respectively safety and efficacy of drugs. The American example was followed in Europe with some delay. In the Netherlands the first such legislation was introduced in 1958. But it was only after the thalidomide tragedy in the 1960s that an official agency to evaluate drugs started to operate efficiently in this country. Similarly, in the United Kingdom it was not until the Medicines Act was introduced in 1972 that evidence of efficacy as well as safety was required as a condition for granting a product license.

The legal obligation to demonstrate safety and efficacy before market introduction stimulated the development of clinical pharmacology as a new scientific discipline. The development of clinical pharmacology is a logical consequence of the pharmaceutical revolution in the beginning of the 20th century and the increasing contribution that drug treatments have made to medical practice in the second half of the century [4, 5].

Clinical Pharmacology

Clinical pharmacology, the science of interactions between men and drugs, was forged as an established medical discipline in the late 1950s and early 1960s in the United States, the United Kingdom, and Scandinavia. By 1970, it had been recognized by World Health Organization (WHO) and in the same year the Clinical Pharmacology section of the British Pharmacological Society was formed. In 1974 the British Journal of Clinical Pharmacology was launched. Clinical pharmacology has developed unevenly within the European region and indeed throughout the world. It has developed rather at a faster pace in some countries (e.g., the United Kingdom, Scandinavia) but slower in others. The functions of clinical pharmacology were defined 30 years ago in a WHO report as research, teaching and service functions to enhance the “scientific study of drugs.” Pharmacological service functions are referred to functions aiming to solve problems in drug therapy, not to traditional clinical work. In retrospect it is felt in Europe that most clinical pharmacology groups who lived up to the recommendation of this WHO report have evolved favorably, while many of those who did not, have disappeared [6].

There are different descriptions of clinical pharmacology. It is considered as both a research discipline (interdisciplinary) and a clinical specialty (specified training of MDs). Under ideal circumstances they work closely together, and there is a career ladder for both. At times, there has been tension between a conservative clinical specialist approach, at the cost of isolation, and a broader multidisciplinary-in-touch approach. However, to meet various challenges in Europe, old barriers divided along traditional subject lines, are being replaced in both academia and industry by interdisciplinary teams [6].

Four decades of clinical pharmacology research (1960–2000) have emphasized different aspects of the discipline (see Table 1) from controlled clinical trials and drug metabolism during the early 1960s to molecular pharmacogenetics and pharmacoeconomy during the late 1990s [6] (also In Europe, clinical pharmacology continues to be driven by a thriving pharmaceutical industry, much of which is West-European based. Its see Section 2 of this chapter).

development has been underpinned by the recognition that newly available drugs must be assessed in unbiased controlled clinical trials designed, conducted, and analyzed to the highest possible standards. Meanwhile, understanding of potential mechanisms of drug actions has improved, increasing the number of target sites for new drug development. Improved measurement techniques of both drugs and their metabolites, and the body’s response to them, have increased the understanding of pharmacokinetics and pharmacodynamics [7].

Evolution in Clinical Drug Development Globalization

Drug development is undertaken today mostly in a globalized industry where companies tap international sources of technology. European companies nurture U.S. as well as European scientific bases and vice versa.

Traditional domestic companies are mostly less innovative and rather persist through marketing based strategies and protection [8]. Current trends in drug development are therefore global in nature. The items described in this section however reflect insights and opinions from European sources.

New Needs and Concepts

The implementation of genomic research combined with progress in discovery techniques has significantly increased the number of potential drug candidates for a series of diseases for which there are currently no or only insufficient treatments. Due to the present system, many of these candidates never reach the patient because of bottlenecks in, and limitations to, the drug development process (see Table 2). In the early 2000s, an TABLE 1 Four Decades and Different Aspects of Clinical Pharmacology [8]

apparent downturn in productivity in pharmaceutical R&D has been observed. This is illustrated by the fact that the European Medicines Evaluation Agency (EMEA) has willingly given back part of its approved budget in 2002 because the anticipated number of new drug applications had not been forthcoming. European scientists from industry, academia, and drug regulators have been discussing the so-called “crisis.” Many share the opinion that the rational way to reverse the trend of dwindling productivity is to introduce new faster methodologies and modern technology at every step of the development process [9–12].

To address new needs, a series of new concepts and techniques have been introduced in European drug development:

The need to predict the “developability” in the selection of potential drug candidates to go forward to full drug development. Early testing is expected to be discriminating while predictive of potential future problems, especially with respect to toxicity in humans [11].

The need to predict the probability of therapeutic and commercial success. Due to increasing costs of drug development and marketing competition, companies need an early answer to the likely clinical and commercial success with abandonment of the compound if the target profile is not likely to be met, ideally after the first human study [13].

In the end, economics are key considerations in drug development [14].

The increasing use of well-established techniques of PK modeling and the evaluation of dose-concentration-effect relationships (PK/PD) for both desired and undesired effects.

The use of rapidly evolving computer modeling and simulation techniques especially into difficult areas such as cancer and pediatric studies [11].

The need to optimize the dosing regimen early in clinical development.

Traditional drug development, based on the “maximal tolerated dose”

TABLE 2 Bottlenecks in Traditional Drug Development [6]

approach or fractions thereof, has often resulted in overdosing.

However, clinical trials at too high a dose may attribute an unacceptable safety profile to an otherwise good drug [13]. Moreover, European regulatory authorities typically require an appropriate dose-finding study and demonstration of both the maximal tolerated and minimal effective dose.

Clinical development divided into two parts. “Exploratory”

development or “proof-of-concept” which may require as little as one study and typically covers Phase I and Phase II (typically, Phase I studies conducted in healthy volunteers and Phase II in patient population) in the traditional theme, followed by “full” development and completion of the registration dossier. This approach is particularly important to innovative biotechnology companies which are considered of great value for the future. The probability of attracting a partner, and the value of partnership to the initial company, will depend heavily on whether the “proof-of-principle”

point has been reached [13].

The use of well-validated surrogates which can substantially shorten clinical development time or time to reach a critical decision point.

Biomarkers (less validated) may be useful in decision making, although a larger amount of data is usually required to offset the uncertainty. New biomarkers are explored in preclinical development and link preclinical pharmacology and toxicology with the design and interpretation of early human studies [13].

Pharmacogenetics gives researchers a powerful tool in the understanding of how genetic variation contributes to variations in response to medicines [15, 16]. Many individual and ethnic variations in drug metabolism have already been shown to be due to genetically determined variations in metabolic enzyme activity, particularly cytochrome P450 enzyme subtype polymorphisms. European regulators therefore require the testing of relevant drugs in target groups of poor or extensive metabolizers [17].

Integration of Knowledge

Projected needs of the pharmaceutical industry are related to the need for broad expertise to deal with increasingly complex projects and the integration of specialist knowledge. Optimization of the drug development process requires technical and scientific expertise in many areas. In some disciplines, such as genetics (human polyphormism), mathematics (modeling, simulation), bioinformatics (prediction), and information technology (including pharmacometrics and information management), there is a lack of well-trained experts. Moreover, due to the

multidisciplinary nature of drug development, knowledge covering a range of disciplines is required [9].

An expected central challenge of the pharmaceutical industry in the coming years is the management of complex information. Many shortcomings in drug development can be attributed to insufficient use of available knowledge. The interfaces between the various phases of the R&D process have to be eliminated and a seamless discovery-development process established, ensuring that all knowledge and data are maintained and put to maximum use throughout (Fig. 1). New standards for handling complex data and standardization of the format for knowledge-exchange are required (A.Cohen, personal communication, 2001). This involves, developing IT-supported information data management and decisionmaking process [9]. For example, very promising new standards are to be used in view of the International Harmonization (ICH) initiatives, the Common Technical Document (CTD), and the Electronic Common

FIGURE 1 Integration of functions. Courtesy of A.Cohen, Center for Human Drug Research, Leiden, The Netherlands, Phase I studies tailored towards proof-of-concept. Personal communication, 2001.

Technical Document (e-CTD). The aim is to provide a harmonized format and content for new product applications to be used with regulatory authorities in different regions of the world.

New Approaches in the Real World

The initial goals of drug evaluation have been modified to include new questions directed at goals other than drug safety and efficacy. For example, testing a drug in a population representing the “real” world setting has become a major basis for phase III trials and for establishing “evidence-based” pharmacotherapy.

Other new questions that have been asked are “How should the physician and patient be advised to use the drug?” and “Is the drug better or similar to a drug already available?” In a sense, clinical trials have evolved from a role in drug development to physician education and competitive marketing [18].

A frequently forgotten aspect of drug development, which in some respects is the most important of all, is defining the drug labeling, the European Summary of Product Characteristics (SmPC). This document should provide essential information for the health care professional and is the basis for patient instructions and prescribing guidelines. This document must be accurate but needs also to be easily understood [5].

Risk and Benefit

The standards of safety expected for an agent which may be lifesaving and one which relieves minor symptoms should not be the same. Perceptions on the appropriate balance of risk and benefit however vary widely, including nationally. Based on evidence of efficacy, which may be uncertain, together with limited safety data, licensing decisions may need to be made on as much a judgmental as a scientific basis [5]. While formal analysis of risk and benefit for a particular drug can be carried out, comparative risk assessment with similar drugs is also considered useful (see next paragraph).

Efficacy and safety have traditionally been the most important influential bases to make decisions. In the future, priorities may also be more influenced by costs and expected benefits of drugs on the market. At present pharmacoeconomic data are required for requesting reimbursement in countries such as Netherlands, United Kingdom, Denmark, Finland, Norway, and Portugal. In the future more information regarding the efficiency of the drug as compared to available drugs may be needed, thus magnifying the social value of the resources invested on drug expenditure [19].

At the end, drug development should contribute to the use of the most appropriate drug to the right patient in an optimal dosage schedule with the right information and at a reasonable cost.

Considerations on Study Design

During the 1990s, the importance of properly designed early trials (Phase I and II) has led to dramatic changes in their design. These changes have included both proper randomized, double blinded designs and increased sample sizes. Although there are different opinions on how best to use data from Phase II in the present process, there is little doubt concerning the high level of information likely to be available at the end of Phase II and the conduct of too many Phase III and IV trials may be considered redundant or unethical [18].

There are global concerns that activities carried out during the later stages of clinical trials are balancing on the edge of inappropriate activities.

Regulatory authorities in Europe have in a sense addressed these issues by their request, in specific situations, for comparative trials of marketed drugs.

As the goal of these trials is often to show equivalence, they, however, tend to be more difficult to conduct and to require larger number of patients.

Occasionally, global pharmaceutical companies have sought approval on the basis of placebo-controlled trials in the United States and have added active control comparative trials to register in Europe [18].

Problem Solving by the Entire Community

Mistakes in the design of a drug trial are usually reported as drug failure rather than insufficient expertise, marketing influence, inadequate regulatory management, or improper patient enrolment and follow up. The assumption has been made that these are problems for the pharmaceutical companies to solve. The regulatory role is simply to identify them and reject the failed studies. This might be considered false. It might be considered a problem created by the process of clinical trials, which should be solved by the entire healthcare community [18]. To address this and to reinforce the success of the European Agency, specific changes have been proposed to the European Commission to enlarge the scope of the Agency’s activities beyond the evaluation of medicinal products, by strengthening its role as a scientific adviser.

“New Safe Medicines Faster” in Europe Competitiveness of the Industry

Pharmaceutical companies based in Europe have traditionally played a leading role in developing new drugs, the industry making a significant

contribution to the health and economy of European Union (EU) communities. Many of the top pharmaceutical companies reside in the EU and Switzerland and the European pharmaceutical industry has traditionally held a world-leading position. The trend in the late 1990s, however, indicated that U.S. companies have perhaps taken over the leadership role, showing the U.S. industry’s superior ability to translate new technologies into marketable medicines [9].

However, initiatives to improve the EU competitive situation are the topic of agendas and programs of EU professional and trade organizations and a

“New Safe Medicines Faster” initiative has been recognized for support by the European Commission [11]. Within Europe, medicinal development may still be hampered by barriers put up by the legislation of individual nations, by fragmentation and by suboptimal cooperation among the industry, academia, and authorities. The need for new revised European standards and for pan-European interdisciplinary networks is recognized and addressed [9].

Initiatives to Exploit Huge Opportunities

Proposed key actions are to promote basic research, new leading technologies, and new interface research, including management of the enormous quantity of diverse data that the development of drugs delivers.

Networking is considered essential and the creation of centralized databases and database networks at a European level is suggested. New European platforms for regulators and researchers are recommended to design the necessary changes to the drug development process in partnership and bring about improvements in capacity, efficacy, and speed (Table 3). The purpose is to exploit the enormous opportunities created by the genomic revolution and modern drug discovery for the generation of new medicines to the benefit of the European citizen [9].

TABLE 3 Objectives of New Safe Medicines Fast in Europe [7]

The European System for Approving Medicines Coordinating Scientific Resources

The role of national regulatory authorities in Europe has changed since the EMEA came into operation in 1995, after several years of cooperation among national authorities at a European level. The EMEA is a technical agency coordinating the scientific resources made available by the national authorities to provide high quality drug evaluations, to advise on development programs and to provide useful and clear information to the users. In addition to their country specific responsibility, national authorities now also investigate medicines for decisions at the EU level, in close collaboration with the drug regulatory authorities in other European countries [20].

To Promote Public Health and Free Circulation of Medicines

The European System offers two routes for granting authorizations. A company can or must, depending on the type of product, seek centralized approval, which means an authorization valid for the whole EU. The centralized procedure is compulsory for biotechnology products and optional for innovative conventional products. In this case the application is dealt with administratively by the EMEA. Independent evaluations are conducted by two selected members of the European scientific committee (named CPMP, Committee for Proprietary Medicinal Products).

Multidisciplinary teams, coordinated by the selected members, perform those evaluations and discuss their conclusions with the other members. The European Commission makes final decisions after the CPMP has expressed an opinion following its scientific debate.

For innovative conventional products a company can instead choose the

For innovative conventional products a company can instead choose the