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Evolution of Drug Development and its Regulatory Process

Henry J.Malinowski and Agnes M.Westelinck* Food and Drug Administration Rockville, Maryland, U.S.A.

The history of clinical pharmacology over the past 100 years may be thought of as a gradual progression from the use of potions and other sometimes dubious concoctions to the complex drug development process seen today [1]. The future of clinical pharmacology has been described as academia, industry, and government working together to advance science, develop new drugs, and improve the quality of life of mankind [2]. Efforts such as the International Conference on Harmonization (ICH) have promoted unification of regulatory policies, including those related to clinical pharmacology. More than 35 harmonized ICH Guidelines are available [3] and the recently harmonized Common Technical Document provides for a common format for new drug and biological regulatory submissions. Following are perspectives from Europe and the United States on the progress of clinical pharmacology over the years, in these two major regions of the world.
* Current affiliation: Barrier Therapeutics, Princeton, New Jersey, U.S.A.

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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 (17831855) 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 (17871869), 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. Serturners 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 (15781644), 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.

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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 (19602000) 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 see Section 2 of this chapter). In Europe, clinical pharmacology continues to be driven by a thriving pharmaceutical industry, much of which is West-European based. Its

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TABLE 1 Four Decades and Different Aspects of Clinical Pharmacology [8]

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 bodys 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

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Drug Development and its Regulatory Process TABLE 2 Bottlenecks in Traditional Drug Development [6]

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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 [912]. 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

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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 dosefinding 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

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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-ofconcept. Personal communication, 2001.

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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 evidencebased 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].

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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 Agencys 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

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

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. industrys 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].

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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 route based on mutual recognition of national decisions. The European System affords many advantages. New medicines come to market faster, which of course benefits patients and industry. Also, by utilizing the collective competence of several national drug authorities, the quality and objectivity of evaluations can be improved, duplication of work is avoided, and harmonized opinions and labeling throughout the EU becomes available. An important part of this European-oriented work also revolves around developing new standards and requirements in the face of rapid scientific discoveries and development of new medicines. The intended end result is to promote public health and free circulation of medicines [20]. Broad Level of Satisfaction In 2000, an extensive consultation [21] was carried out on behalf of the European Commission to review the operation of the new European System

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since 1995. It has revealed that there is a broad level of satisfaction about the system from ministries, patient and professional associations, regulatory authorities, and industry, although improvements can be made and new challenges exist. There is a general feeling that the system has contributed to the creation of a harmonized EU market for medicinal products and that it provides a strong foundation for an efficient regulatory environment. There is also a general perception that assessment of products to date has provided a high degree of protection to the public health. This is despite the fact that there have been withdrawals from the market of products already authorized. This is considered consistent with increasingly effective pharmacovigilance procedures and the bias toward products developed on the leading edge of science. Comparative Observations From the same consultation in Europe, comparative observations upon the regulatory frameworks in the EU and United States have revealed a perception that the EU is taking a more risk-adverse approach to assessment as compared with the FDAs policy of risk management. Specific instances would exist where products were removed, or threatened with removal, from the EU market because of perceived safety concerns, while the same products were dealt within the United States by the imposition of specific warnings in the label [21]. Comments were made about a similar level of conservatism in the EU in the approach to the review of products in specialist areas such as oncology and a greater willingness to embrace new therapies in the United States [21]. Analysis of Outcomes An analysis of outcomes of applications in the Central Procedure from 1995 to 1999, published by the EMEA [21], has shown 72% (97/135) positive outcomes, i.e., drug approvals. For applications with a negative outcome, methodological concerns over study design, choice of endpoint, comparator, and selected population were raised more frequently than over those with a positive outcome. FDA had authorized 13 (34%) of the 38 applications that had a negative outcome in the EU. This may be explained by a different attitude toward data requirements e.g., requirements for controlled data, by the availability to FDA of additional regulatory tools, e.g., conditional approvals, and by the limited use of EMEA scientific advice (11%) prior to submission [22]. It is expected that the Reform of EU Pharmaceutical Legislation, proposed in 2001, will influence the regulatory environment significantly [23].

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DRUG DEVELOPMENT IN THE UNITED STATES The modern uses of clinical pharmacology data in the United States may be thought of as having several phases, beginning with early efforts in the 1970s, which related to the increased availability of sensitive and specific analytical methods around that time. This was followed by application of these capabilities to various areas such as the study of specific subpopulations. Further implementation has emphasized the link of pharmacokinetic data to clinical safety and efficacy data. Most recent emphasis has included better understanding of drug interactions and optimal dose adjustment for various sub-populations. Communication of information and recommended approaches has been facilitated by the preparation of FDA Guidances as well as ICH Guidelines. Era of Pharmacokinetic Studies The modern era of drug development related to clinical pharmacology studies may be thought to have begun in the 1970s. A key component was the development of bioanalytical methods needed to accurately detect plasma concentrations of administered drugs. This aspect has continued to improve until it is now possible to measure plasma levels for nearly every drug under development. This is an important factor in the study of the relationships of dose, exposure, and effect. An important regulatory milestone was the creation of the distinct Human Pharmacokinetics and Bioavailability Section of NDAs [24]. This established a section in each NDA in which are contained all clinical pharmacology and biopharmaceutics studies. Prior to what is called the NDA rewrite, NDAs were not very consistent in content, and information to be included was not very precisely defined or well organized. When this Format and Content Guideline was first introduced in 1987, the types of studies were identified as: Pilot or background studies carried out in a small number of subjects as a preliminary assessment of ADME. BA/BE studies. Pharmacokinetic studies. Other in vivo studies such as those using pharmacological or clinical endpoints in humans or animals. In vitro studies such as dissolution and protein binding studies.

While the original focus was on in vivo studies in healthy subjects, this has expanded to include plasma sampling in patients as part of population pharmacokinetic studies, exposure response studies and pharmacokinetic/ pharmacodynamic studies.

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There are numerous types of clinical pharmacology studies conducted during the development of a new drug. These include both studies on healthy subjects without the disease intended for treatment (Phase I) and studies involving patients (Phase II and III). Studies in healthy subjects primarily focus on safety aspects of the drug, in establishing dose-toxicity relationships. These studies also investigate the pharmacokinetics for the drug under development, dose proportionality, absolute bioavailability, mass balance, effect of food, different formulations, as well as special populations. Studies conducted in patients primarily relate to establishing efficacy and dose/response. In addition, optimal dosing interval, effect of severity of disease, tolerance, and adverse reactions are determined. One significant example from this era involved a once-a-day extended release theophylline product which was shown to have a significant change in bioavailability when administered with a high fat meal. This important safety information resulted in the following precaution being added to the products labeling:
Drug/Food Interactions Taking (this product) less than one hour before a highfat-content meal, such as 8 oz whole milk, 2 fried eggs, 2 bacon strips, 2 oz hashed brown potatoes, and 2 slices of buttered toast (about 985 calories, including approximately 71 g of fat) may result in a significant increase in peak serum level and in the extent of absorption of theophylline as compared to administration in the fasted state. In some cases (especially with doses of 900 mg or more taken less than one hour before a high-fat-content meal) serum theophylline levels may exceed the 20mcg/mL level, above which theophylline toxicity is more likely to occur.

A CDER Guidance [25] is available which describes current recommendations related to food effect studies and labeling based upon the results of such studies. Drug administration relative to meals is sometimes of great importance. The labeling for atovaqone serves to illustrate a situation where drug must be taken with food for optimal efficacy:
Failure to administer (atovaquone) with meals may result in lower plasma atovaquone concentrations and may limit response to therapy.

Era of Special Populations With the ability to conduct pharmacokinetic studies well established, attention advanced to additional applications. One such area was the study of various sub-populations, including the elderly, males compared to

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females and possible racial differences in pharmacokinetics. These aspects have continued to be emphasized and currently, it is expected that all NBAs will include analysis of data related to age, gender, and race. CDER has used numerous methods to move forward the science of drug regulation. This includes involvement in Workshops to discuss current drug regulatory issues and the development of Guidances to put forward recommendations to sponsors as to how to proceed in many areas including clinical pharmacology studies. These Guidances include both CDER-developed documents [26] and ICH Guidelines [27]. The importance of age-related differences in response to drugs is discussed in a CDER Guidance [28]. A pharmacokinetic screen [29] is recommended, consisting of obtaining blood samples from patients in Phase II and Phase III clinical investigations. This is a means of identifying subgroups of patients, such as the elderly, in whom the drug may have unusual pharmacokinetic characteristics. Procedures such as the pharmacokinetic screen have evolved into current methods of population pharmacokinetics [30]. An example, from about 20 years ago, of a drug which proved to have serious toxicity among some elderly patients was benoxaprofen, a nonsteroidal anti-inflammatory drug, used to treat arthritis. It was promoted as perhaps capable of arresting the disease process in rheumatoid arthritis. While it was certainly effective for labeled indications, for certain elderly patients it was associated with fatal cholestatic jaundice among other serious adverse reactions. If the pharmacokinetics of benoxaprofen had been studied in the elderly, it is possible that a dose adjustment for elderly could have been recommended and withdrawal of benoxaprofen from the market, which occurred in 1983, might have been avoided [31]. While for most drugs, males and females can safely receive the same dose, for a few drugs, differences in pharmacokinetics related to gender can be important. In 1993, the Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs [32] was published. This recommended inclusion of patients of both genders in drug development, assessment of clinical data by gender, assessment of potential pharmacokinetic differences between genders, and the conduct of specific additional studies in women, when appropriate. Patients with impaired renal or hepatic function are also important subpopulations. Consideration of the need for dosage adjustment in situations of renal or hepatic impairment has received considerable attention. Guidances [33, 34] addressing these topics are available from FDA.

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Era of Drug Interactions and PK/PD Relationships In 1991, a Workshop was held to discuss current thinking related to the rational integration of pharmacokinetics, pharmacodynamics, and toxicokinetics [35]. This was an important milestone along the path of closer relationships between clinical data and pharmacokinetic data. In CDER, a reorganization establishing the Office of Clinical Pharmacology and Biopharmaceutics in conjunction with increased resources related to User Fees, promoted communication among medical reviewers and clinical pharmacology reviewers. Co-location of these reviewers provided for increased discussions, data sharing, and consultations. The importance of the relationship of changes in pharmacokinetics to drug safety and efficacy is a continuing topic of much discussion. One related area is drug interactions, which sometimes are extremely important. The interaction of fluorouracil and sorivudine, which caused a number of deaths in Japan [36] in the 1990s, served as an important reminder of the potential consequences of drug-drug interactions. Sorivudine was withdrawn in Japan after 15 patients who were prescribed both sorivudine and fluorouracil died. They had developed aplastic anemia, after taking sorivudine with fluorouracil. Knowing the situation that had occurred in Japan, sorivudine was not approved in the United States because of this potentially fatal drug interaction and the fact that alternative drugs to sorivudine were available, without the serious drug interaction potential. Serious interactions between mibefridil and certain cholesterol lowering statin drugs resulted in the removal of mibefridil from the market. Mibefradil is a potent inhibitor of the metabolism of lovastatin and simvastatin and if either of these drugs is taken together with mibefridil, they can cause potentially life-threatening rhabdomyolysis related to much higher exposure to the statin drug due to inhibited metabolism caused by mibefridil [37]. In response to the significance of drug interactions, Guidances for the study of potential drug interactions, both in vitro [38] and in vivo [39], are available from FDA. Study continues on establishing in vitro/in vivo correlations for metabolically related drug interactions, in order to increase the predictability of in vitro drug interaction data. An important new law went into effect in 1997. The Food and Drug Administration Modernization Act (FDAMA) [40] contained many new provisions including a section describing the number of required clinical investigations needed for approval. If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical

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investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence. The confirmatory evidence described can be obtained from earlier clinical trials, pharmacokinetic data, or other appropriate scientific data. This indicates further reliance on pharmacokinetic data in conjunction with clinical studies in the overall development of a new drug. Year 2000 and Onward As we continue to move forward in the area of clinical pharmacology aspects of drug development, we are faced with worldwide pharmaceutical companies, an explosion of data, and increased knowledge of the importance of optimal drug administration and the consequences of less than optimal drug use. In this context, computer-based systems increasingly provide an essential means of communication, as well as an effective tool for modeling and simulation. From the internet to personal information managers and Pocket PCs, we are nearly always close to a source of drug information. An increasingly common utterance is that there is so much information available but there are also increasing difficulties in sorting through this avalanche of information to find what is useful and thereby translating information into useful knowledge. But, there can be no question that computer-based information will continue to expand and progress as one of the most important means of communication and sources of information. Clinical trial simulation [41] has matured to a point where all available information about a drug under development can be used efficiently to promote more rapid drug development. The entire process of drug development has been estimated to take up to 12 years and cost upwards of $350 million. About one-third of this cost and half the time is spent on clinical development. Simulation techniques can provide valuable information related to optimal dosing schedule, expected range of response, effects of changes in exclusion criteria on expected outcome, optimal frequency to measure response, and the impact of compliance. Effective labeling has become an important topic, as large amounts of information become available for newly approved drugs. Drug interactions studied for a new drug have implications for the other drugs involved in the interactions and keeping labeling up to date for all drugs is a difficult task. As difficult is the task of healthcare providers being aware of all patient situations where dose adjustment may be appropriate, related to age, gender, race, renal or hepatic function, or drug interactions. FDA has proposed a new labeling format [42] in the effort to present important dosing and other safety information more clearly and obviously.

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The use of population pharmacokinetics [30] allows for the study of differences in safety and efficacy among population subgroups. This approach, which involves obtaining plasma samples from patients participating in clinical studies, can permit the identification of important factors, such as age, gender, weight, renal function, hepatic function, and concomitant medications which can affect the safe and effective use of a drug. A topic of interest and considerable discussion recently is the Global Clinical Trial. Clinical trials conducted in the United States. Europe, or Japan often need some type of bridging study to allow the existing clinical data to be used in the approval process in a different region of the world. A Global Clinical Trial would include patients from the three ICH regions and might allow the results of the trial to be directly applicable for approval in all three regions and thereby speed worldwide drug approval. Risk management is a frequently heard term in the current and future era of a complex healthcare environment, with many potent new drugs being approved, and an emerging global market. The FDAs Task Force on Risk Management [43] has recommended that a new framework for risk management activities is needed. The current system, which involves not only the FDA but also pharmaceutical manufacturers, healthcare practitioners, and patients, is more fragmented rather than part of an integrated systems effort. One important recommendation relates to risk confrontation, which involves community-based problem solving and involves all stakeholders in the decision-making process. Regarding postmarketing surveillance and risk assessment, it has been suggested that new approaches be considered such as increasing reliance on computer-based, perhaps global, health information databases, as well as gathering data from identified sentinel facilities where staff are trained to recognize rapidly, and report accurately, adverse reactions. In conclusion, one of the most striking developments in this area over the past 30 years has been the change from independent clinical studies conducted in patients with the goal of determining safety and efficacy, and independent pharmacokinetic studies conducted in healthy subjects, to the current situation where these studies are viewed together. Over the years, these two sources of data have become increasingly associated and utilized together in numerous approaches to efficient drug development. By obtaining some additional plasma samples from patients in clinical studies, all studies in humans can be viewed as a continuum and a more complete evaluation of a drug can be obtained. By the integration of all available drug development data, dose can be better optimized for each patient, thereby minimizing adverse reactions and promoting effective treatment of diseases.

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ACKNOWLEDGMENT Dr. A.Cohen, Center for Human Drug Research, Leiden, The Netherlands and Dr. P.Neels, Member of the Commission for Proprietary Medicinal Products, Brussels, Belgium. REFERENCES
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