Roger J. Porter MD
Vice President, Clinical Pharmacology, Clinical Research and Development, Wyeth-Ayerst Research; and Adjunct Professor of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania
The major pharmaceutical companies of the world are involved in all aspects of drug development; these large companies are concerned with everything from the conceptual foundations of drug discovery to postmarketing development of additional indications. Antiepileptic drugs have benefited from the Antiepileptic Drug Development (ADD) Program, a program that has been especially effective early in the process, attempting to act as a catalyst to motivate the machinery of industry to “carry the ball” through some of the tricky and expensive stages of early development (1). All this is part of the altruistic effort to hasten the day when the drug will be available to the patients who need it to control their seizures. This chapter concentrates on those factors that typically are the burden of the pharmaceutical company in the development of a new molecule. We assume that the new molecule appears—at least at first—to be efficacious and safe in animals and that the company has chosen to invest its efforts and resources in this molecule; in reality, however, every molecule in the company's pipeline is continuously scrutinized to see if it comes close to its target profile.
THE DEPARTMENTS IN A PHARMACEUTICAL COMPANY
It might be thought that the major effort of a pharmaceutical company is simply to test a drug in humans to see if it is safe and effective. Indeed, this is the single most expensive part of drug development. But before and during the clinical testing, a critical array of other departments make other decisions about the drug. Some of these decisions are relatively routine, but some can decide whether the drug survives to reach the marketplace.
Typically, the departments that are involved with the drug (assuming it is a small molecule) are (a) Discovery, (b) Pharmaceutical Sciences, (c) Drug Safety, (d) Drug Metabolism, (e) Regulatory Affairs, and (f) Clinical Research; in addition, certain departments coordinate projects, such as Project Management, or coordinate information flow, such as Information Management. The roles of only the first six are reviewed in this chapter. These departments have roles that not only are sequential, as listed here, but in most cases parallel to any ongoing clinical work.
The Discovery Departments of most large pharmaceutical companies have become quite large because the need for a continuous flow of new compounds is required to maintain the growth rate of the company. In most large companies, the internal discovery efforts are supplemented by a continuous effort to in-license promising compounds and by active interactions or collaborations with academic laboratories and smaller firms (including biotech companies). Critical to the decision for in-licensing are factors such as patent protection, ability of the compound to “fit” into the portfolio of the big company, projected time of development, expected toxicities, timing of competition, and so forth.
Paramount to the decision process is whether the new compound—internal or external—will have an advantage over existing therapy. One of the most important ways that the Discovery Department addresses this issue is continuously to seek compounds with new mechanisms of action (i.e., novel mechanisms or novel targets, or both). An excellent example of an in-licensed compound with a novel mechanism is retigabine. When Wyeth-Ayerst Research first in-licensed the compound, there was good evidence that the drug activated potassium currents in neuronal cells; although we knew that this was a novel approach, we did not know which channels were specifically affected. Later work, in part by Discovery scientists at our partner Asta Medica in Germany, showed that retigabine is an M-channel agonist that is related to a hereditary epilepsy syndrome (2) and to a fundamental excitability current. This additional information
may affect the eventual clinical program at later stages. In other words, retigabine was attractive as an in-license candidate in part because of this novel mechanism of action. Later work refined this mechanism and made the drug even more attractive as a potential antiepileptic drug.
One of the typical Discovery activities, when a compound involves receptors or channels, is to characterize the drug against many other potential targets—to analyze the drug's unique characteristics; this permits a full profile of that drug to evaluate potential therapeutic benefits or liabilities. Further, working with drug metabolism, the Discovery team characterizes the metabolites (if any) of the drug to ascertain the level of pharmacologic activity present in each. In addition, the Discovery team may test the drug for other indications to assess activity. Gabapentin is a good example of an antiepileptic drug that has pain as a major secondary indication. These are some of the examples of how the Discovery team “follows along” with the clinical development and assists with the overall progress toward final approval.
Chemical and Pharmaceutical Development
Although early synthesis of small quantities of the drug are performed in the Discovery laboratory, larger quantities soon are required, and Chemical Development is called on to make increasingly larger batches of increasingly pure material. To do this properly requires great knowledge of chemical synthesis and scale-up procedures, if for no other reason than to be efficient and safe in the procedure to be used. The demands for drug substance come from all sides of the organization: Discovery has more tests to run; Drug Safety has to begin work to see if the drug is safe; Drug Metabolism needs to work on the assay of blood and urine levels, and Clinical Research needs drug to mount clinical trials.
As noted previously, besides making the bulk drug (which eventually may be contracted to an outside vendor), Pharmaceutical Development is responsible for the delivery system of the drug to the patient. Unfortunately, this rarely is a simple process. The oral form may require bioavailability enhancement, or it may involve complex multiple drug combinations or delayed release. Pediatric formulations [which may be mandated by the U.S. Food and Drug Administration (FDA)] may necessitate taste masking, solutions, suspensions, sprinkles, or chewables. Parenteral formulations may be needed, although some drugs simply cannot be solubilized sufficiently for intravenous or intramuscular use. All of these efforts must be produced under strict quality control. The product must meet rigid criteria for stability at various temperatures and conditions. All this is to ensure that the eventual marketed product is of the highest possible quality.
The Drug Safety Department is responsible for the preclinical safety testing and evaluation of the compound. The department provides information to the company about toxicologic risks and sets the stage for introduction into humans. Although animal testing is required, an increasing number of studies are accomplished without using live animals, and every effort is being made to limit such studies and the number of animals used to those that are absolutely necessary to support safe development in humans.
The sophistication and variety of the toxicity studies to be performed are quite remarkable. Typically, the studies begin with general acute, subchronic, and chronic effects of the drug in experimental animals. These may be combined with plasma levels to establish the relationship between the toxic effects and the exposure (3). During this time, a dose-response relationship may be sought if this appears to be clinically relevant, and end points for monitoring adverse effects in animals that also may be helpful in the clinic are determined. Specific areas of interest include carcinogenicity, reproductive and developmental toxicity, genotoxicity, cardiovascular toxicity, immunotoxicity, and neurotoxicity (3).
All of this process is aimed at a continuum of establishing the risk of carrying the compound further into development, even though some of the tests are not completed until just before the clinical program is finished.
The Drug Metabolism Department is responsible for describing what happens to the drug in animals and humans—that is, how the various species modify and eliminate the drug. This includes the classic measurements of absorption, distribution, metabolism, and elimination (ADME). In addition, in vitro systems are used to predict the metabolic profile and identify the enzymatic systems that may be involved in metabolism. The department is responsible for creating a sensitive and validated assay for the drug and relevant (active) metabolites in biologic fluids, first for the ADME and animal toxicokinetic studies and later for the studies in humans.
The data derived from these animal studies are used to predict what will happen when the drug is administered to humans (i.e., data such as the degree of absorption, the plasma protein binding, the routes of metabolism, the potential for drug-drug interactions, and the mechanisms of elimination). Toxicokinetic studies combine various doses of the drug with blood sampling and permit scaling for predicting the appropriate starting dose for the first-in-human studies.
Although not an in-line function of drug development (i.e., this department does not actually handle the compound), Regulatory Affairs is very influential in the flow of the paperwork that creates worldwide approval and eventual marketing. Each company has its group of experts (sometimes combined
with clinical research) that orchestrate the complex and numerous submissions to the health agencies in each country.
After Discovery has chosen the best compound from its series, Chemical and Pharmaceutical Sciences has made and formulated enough pure compound, Drug Safety has done at least the early toxicologic studies, and Drug Metabolism has a sensitive assay in plasma, then Regulatory Affairs can submit a document (which usually contains at least one research protocol from Clinical Research) to the country health authorities to commence clinical investigation. How companies organize their clinical departments varies widely, but the simplest prototype is described here
The first few studies of the new drug typically are carried out by Clinical Pharmacology, a specialized team in each company. The first study usually is a single-dose study, often in human volunteers, with gradually increasing doses to test human tolerability to the compound. If a sufficient safety range of single doses is tolerated, the next study is the multiple-dose study, with gradually increasing doses to evaluate tolerability. Plasma levels are drawn with each dose, and a pharmacokinetic profile is available at the end of these studies. If all goes well in this so-called phase I, the drug may then be evaluated for efficacy and safety in patients by the appropriate team of clinical experts in the company, typically designated the Therapeutic Area (TA). Clinical Pharmacology continues its work throughout development, with studies on the effect of food, age, and sex; it also carries out specialized studies such as dose proportionality, 14C metabolism/disposition, distribution, bioequivalence, and drug interaction studies.
FIGURE 5.1. Compound success rate by stage. As can be seen, only 250 compounds of 5,000 to 10,000 screened enter preclinical testing, and only 5 of these enter the clinic. Only one of these five is approved for marketing. Although this figure emphasizes approval by the U.S. Food and Drug Administration, all large companies now emphasize worldwide registration, and most attempt, insofar as is possible, simultaneous approvals worldwide. (From Pharmaceutical Research and Manufacturers of America. 1999 Industry profile. Washington, DC: Pharmaceutical Research and Manufacturers of America, 1999, with permission.)
The TA in Clinical Research houses the specialists in the disease area to be studied. These physicians and clinical scientists supplement their own knowledge by making frequent contacts with experts outside the company—usually from academia. These contacts may be as simple as a phone call or as complex as a formal consultants' meeting.
The TA takes the information provided by Clinical Pharmacology and begins cautious studies in humans with the disorder in question. These early clinical efficacy and safety studies are often called phase II of development, and usually are designed to accomplish certain goals. First, the drug must continue to be safe in the patient population, just as it was in volunteers. Second, from these studies some estimate of efficacy needs to emerge: Does the drug really do what is intended within its nontoxic range? Third, the appropriate dose must be determined—how much, and how often to dose.
If the drug still looks promising at this stage, and only a tiny percentage of potential drugs screened for initial acting get this far (Figure 5.1), then broader trials, often involving thousands of patients, further test the effectiveness and safety of the drug; this stage is termed phase III. The TA is responsible for this very expensive process and for carrying the drug to registration and approval. Every other department noted
previously remains active in the process right to the end, but the final clinical data in patients are of utmost importance.
CHALLENGES TO THE PHARMACEUTICAL INDUSTRY
Many of the internal challenges are inherent in the process of development as reviewed in the preceding section. But some may not be obvious at first glance. The following are some examples of potential challenges at each departmental level:
The external challenges to the pharmaceutical industry are well summarized in the March, 1999 document published by the Pharmaceutical Research and Manufacturers of America (4). Only a few of the relevant issues are included in this portion of the chapter.
Challenges in Research and Development
Only half a century ago, the concepts of sickness and health were quite different from those of today. Parents generally expected that some of their children would die in infancy, and in the pre-antibiotic era, it was more or less expected that some of those who made it through infancy would die of infections such as bacterial pneumonia. Death and disability were still relatively common occurrences at all ages. Expectations about health were tempered by discouraging statistics (5).
In the new millennium, primarily in developed countries, expectations are completely different:
The loss of a child is uniformly tragic and unexpected. Death in middle age is similarly distressing. The vast majority of us live a healthy life and expect to do so into old age, rather naively fearing only accidents in our youth, and cancer and vascular disease as we get older. We expect that children will be born healthy, that infections will disappear with antibiotic treatment, and that artificial hips, heart valves, and knees will replace our natural parts if needed (5).
These optimistic expectations are based on the reality of the health of the majority of people in economically developed countries. Profiting from improved sanitation, safe drinking water, antibiotics, life-style changes, pharmaceuticals—both vaccines and drugs (Figure 5.2)—and many other factors, everyone expects to enjoy life to an old age (5).
These expectations put pressure on all aspects of the health care delivery system. People who are “robbed” of their full lifetime are quick to identify a nonnatural cause for the personal loss and to seek redress, often within the legal system. For the pharmaceutical companies, the pressure is to identify drugs that not only are effective for the disorders under treatment but extraordinarily safe. To accomplish this task, companies are spending record amounts of money on research (Figure 5.3)—outspending, in the past few years, even the National Institutes of Health. The absolute amount of research investment also is remarkable from the standpoint of research and development as a percentage of sales (Figure 5.4), with other industries averaging only 3.7%; by comparison, research-based pharmaceutical companies average over 20%. Considering the steady incursions of generic drugs in the marketplace (Figure 5.5)—generic companies perform virtually no research—the pressure is on big companies to maintain a flow of patented drugs in the marketplace to maintain the research momentum.
FIGURE 5.2. Some of the impacts of pharmaceutical agents on death rates in the United States. Vaccines have caused an even more impressive decline. (From Pharmaceutical Research and Manufacturers of America. 1999 Industry profile. Washington, DC: Pharmaceutical Research and Manufacturers of America, 1999, with permission.)
FIGURE 5.3. The expenditures for research and development (R&D) by research-based pharmaceutical companies, including both U.S. and foreign company spending in the United States, and U.S. company spending abroad. (From Pharmaceutical Research and Manufacturers of America. 1999 Industry profile. Washington, DC: Pharmaceutical Research and Manufacturers of America, 1999, with permission.)
FIGURE 5.4. The research-based pharmaceutical companies in the U.S. and R&D as a percent of sales. About 80% of this R&D is devoted to new products; the other 20% is spent on improvements of existing products. (From Pharmaceutical Research and Manufacturers of America. 1999 Industry profile. Washington, DC: Pharmaceutical Research and Manufacturers of America, 1999, with permission.)
FIGURE 5.5. Generic drugs have dramatically increased their share of the market in the past few years. Although some large research and development (R&D)-oriented pharmaceutical companies operate generic subsidiaries, the generic business is primarily driven by volume and cost of goods. Virtually no R&D is sustained by this portion of the market. (From Pharmaceutical Research and Manufacturers of America. 1999 Industry profile. Washington, DC: Pharmaceutical Research and Manufacturers of America, 1999, with permission.)
Challenges in Regulatory Aspects of Development
Not all of the challenges of developing a new drug are scientific. Many difficulties arise as a result of the regulation of the industry by various governmental bodies. The effect on drug development is, at first glance, more subtle than the scientific questions of safety and efficacy; the impact can be powerful and often is viewed negatively by the company.
FIGURE 5.6. The time of development of a drug has almost doubled since the 1960s. The length of approval phase has actually decreased in recent years (in large part because of “user fees”), but the clinical and preclinical phases continue to lengthen. (From Pharmaceutical Research and Manufacturers of America. 1999 Industry profile. Washington, DC: Pharmaceutical Research and Manufacturers of America, 1999, with permission.)
Before discussing the regulatory aspects of drug development, it is important to recognize the remarkable contributions of governmental regulatory agencies—primarily the FDA in the United States—to the science of drug development, especially in the design of clinical studies. Before the thalidomide disaster in 1963, a drug merely needed to be proven safe to obtain a place in the market. Since then (in the United States), a drug must be proven safe and effective. The insistence of the FDA on controlled clinical studies (usually randomized and often blinded) has greatly advanced the science of clinical trials. The result has been a heightened standard for drug approval. This standard has not been achieved, however, without additional costs.
The cost is measured in both time and money. As the sophistication of the process increases, more time is required to take a molecule from discovery to the drug store. As can be seen in Figure 5.6, the time of development has greatly lengthened since the 1960s. Regulatory approval was an early culprit, but more recently, the need for larger
and more extensive clinical trials has caused the process to lengthen. This extension of time-to-market is costly not only because of the added studies conducted, but because it steals from the product's patent life.
FIGURE 5.7. The increase in clinical trials per drug application, from 1977 to 1995. (From Pharmaceutical Research and Manufacturers of America. 1999 Industry profile.Washington, DC: Pharmaceutical Research and Manufacturers of America, 1999, with permission.)
Are more clinical trials actually being performed? As can be seen in Figure 5.7, the average number of clinical trials in each drug application has dramatically increased; this is mostly a response based on the expectations of the regulatory agencies. Whether this expectation is warranted is a matter of considerable debate. In any case, the most expensive aspect of drug development, the clinical trials process, has expanded greatly. This is further documented by the concomitant increase in the number of patients provided in each dossier (Figure 5.8).
Even the largest pharmaceutical companies have finite resources. When the cost of development of a drug increases, this means that fewer drugs can be pursued. Further, each individual drug, when it reaches the drug store, must now be more expensive—not only to cover the costs of its own development, but to fund future research.
FIGURE 5.8. As expected from the increase in the number of clinical trials (Figure 5.7), the number of patients studied for each drug application has dramatically increased. (From Pharmaceutical Research and Manufacturers of America. 1999 Industry profile. Washington, DC: Pharmaceutical Research and Manufacturers of America, 1999, with permission.)
FIGURE 5.9. The United States outspends other developed countries on health care not only in absolute terms, but as a percentage of gross domestic product. (From Pharmaceutical Research and Manufacturers of America. 1999 Industry profile. Washington, DC: Pharmaceutical Research and Manufacturers of America, 1999, with permission.)
Challenges in the Global Environment
The United States is not reluctant to invest in health care. Relative to other comparable countries, the United States devotes enormous resources, as shown in Figure 5.9. This is not to say that most of the costs are from drugs; clearly this is not the case, as is shown in Figure 5.10. The average person in the United States, as a matter of fact, spends on prescription drugs (Figure 5.11) somewhat less than on alcohol, but somewhat more than on tobacco!
The key to long-term success in pharmaceutical development lies in the ability of the companies to continue to be innovative to compete successfully in what has become an intensely competitive environment.
The United States is, fortunately, in a position to benefit from this new international competition. We currently have the most highly developed biomedical research enterprise, many
technological advantages, and a healthy biomedical industry. The opportunity is enormous if we can maintain an open trading system, free movement of capital and technology, and protection of intellectual property rights (5).
FIGURE 5.10. The United States is only average in the share of gross domestic product devoted to pharmaceuticals, compared with other developed countries. (From Pharmaceutical Research and Manufacturers of America. 1999 Industry profile. Washington, DC: Pharmaceutical Research and Manufacturers of America, 1999, with permission.)
FIGURE 5.11. Prescription drugs are relatively low on the scale of spending priorities in the United States. (From Pharmaceutical Research and Manufacturers of America. 1999 Industry profile. Washington, DC: Pharmaceutical Research and Manufacturers of America, 1999, with permission.)
Further, “we must adopt policies that will help avoid the double-whammy of both paying for highly expensive health care and paying those costs in the form of profits to foreign companies” (5).
We are in the midst of one of the most exciting times in human history. The pace of development of new, more effective, drugs have never been faster. Whether the issue is approached from the viewpoint of the United States or a more global view is taken, one can only hope that the resources now devoted to finding new drugs—to combat both old and new diseases—will continue unabated.