Development & Regulation of Drugs: Introduction

A few useful drugs have been known since humans first began ingesting or injecting substances and recording the results (see The History of Pharmacology in Chapter 1), but the majority of agents in current use have been methodically discovered and developed during the last 100 years. To expedite the development of effective drugs and to protect patients against the toxicity of dangerous ones, a variety of pharmacologic and toxicologic techniques have been invented. The resulting avalanche of new chemicals and the efforts to market them have in turn required a variety of methods of legal regulation. This chapter describes the methods of new drug development and the aspects of governmental drug regulation in the United States.

Among the first steps in the development of a new drug is the discovery or synthesis of a potential new drug compound or the elucidation of a new drug target. When a new drug is discovered, subsequent steps seek an understanding of the drug's interaction (mechanism of action) with its biologic targets. Repeated application of this approach leads to compounds with increased efficacy, potency, and selectivity (Figure 5–1). By law, the safety and efficacy of drugs must be defined before marketing. In addition to in vitro studies, relevant biologic effects, drug metabolism, pharmacokinetic profiles, and particularly an assessment of the relative safety of the drug must be characterized in vivo in animals before human drug trials can be started. With regulatory approval, human testing may then go forward in three phases before the drug is considered for approval for general use. A fourth phase of data gathering and safety monitoring is becoming increasingly important and follows after approval for general use.

Enormous and increasing costs, with estimates from $150 million to several billion, are involved in the research and development of a single new drug that reaches the marketplace. Only 2 of 10 marketed drugs return their research and development (R&D) investments, thus providing considerable motivation to develop "blockbusters." Thousands of compounds may be synthesized and hundreds of thousands tested from libraries of compounds for each successful new drug lead, which then frequently needs to be further optimized for reasons of potency, selectivity, drug metabolism, and dosing convenience before each drug reaches the market. Increasing regulatory challenges and litigation resulting from real or suspected drug toxicity after approval further increase the cost of developing new drugs. Because of the economic investment required and the need to efficiently access and integrate multiple technologies, most new drugs are developed in pharmaceutical companies.

Nevertheless, the incentives to succeed in drug development can be enormous. The global market for pharmaceuticals in 2007 was estimated to be $712 billion. The 2007 worldwide sales of the top-selling drug (Lipitor) exceeded $12 billion. In the USA, approximately 10–12% of the health care dollar is presently spent on prescription drugs. At the same time, the investment in drugs can have enormous health benefits: For example, for every patient dollar spent on drugs that control diabetes, cholesterol, or blood pressure, there is a health care cost savings of $7, $5, and $4, respectively.

Drug Discovery

Most new drugs or drug products are discovered or developed through one or more of six approaches: (1) identification or elucidation of a new drug target; (2) rational drug design of a new drug based on an understanding of biologic mechanisms, drug receptor structure, and drug structure; (3) chemical modification of a known molecule; (4) screening for biologic activity of large numbers of natural products, banks of previously discovered chemical entities, or large libraries of peptides, nucleic acids, and other organic molecules; (5) biotechnology and using genes to produce peptides, proteins and information useful as targets, drugs or diagnostics; and (6) combinations of known drugs to obtain additive or synergistic effects or a repositioning of a known drug for a new therapeutic use.

Drug Screening

Regardless of the source or the key idea leading to a drug candidate molecule, testing it involves a sequence of iterative experimentation and characterization called drug screening. A variety of biologic assays at the molecular, cellular, organ system, and whole animal levels are used to define the activity and selectivity of the drug. The type and number of initial screening tests depend on the pharmacologic and therapeutic goal. For example, anti-infective drugs may be tested against a variety of infectious organisms, some of which are resistant to standard agents; hypoglycemic drugs may be tested for their ability to lower blood sugar, etc.

In addition, the molecule will also be studied for a broad array of other actions to establish and confirm the mechanism of action and selectivity of the drug. This can reveal both suspected and unsuspected toxic effects. Occasionally, an unsuspected therapeutic action (sulfonamides, lidocaine, sildenafil) is serendipitously discovered by the careful observer. The selection of compounds for development is most efficiently conducted in animal models of human disease with pharmacogenomics increasingly valuable in producing relevant models. Where good predictive preclinical models exist (eg, antibacterials, hypertension or thrombotic disease), we generally have adequate drugs. Good drugs or breakthrough improvements are conspicuously lacking and slow for diseases for which preclinical models are poor, or not yet available, eg, Alzheimer's disease.

Studies are performed during drug screening to define the pharmacologic profile of the drug at the molecular, cellular, system, organ, and organism levels. The value of these tests is highly dependent on the reproducibility and reliability of the assays. For example, a broad range of tests would be performed on a drug designed to act as an antagonist for a new vascular target for the treatment of hypertension.

At the molecular level, the compound would be screened for activity on the target, for example, receptor binding affinity to cell membranes containing the homologous animal receptors (or if possible, on the cloned human receptors). Early studies would be done to predict effects that might later cause undesired drug metabolism or toxicologic complications. For example, studies on liver cytochrome P450 enzymes would be performed to determine whether the drug of interest is likely to be a substrate or inhibitor of these enzymes or to interfere with the metabolism of other drugs. Effects on cardiac ion channels such as the hERG potassium channel, possibly predictive of life-threatening arrhythmias, are considered.

Effects on cell function determine whether the drug is an agonist, partial agonist, or antagonist at the relevant receptors. Isolated tissues, especially vascular smooth muscle, would be used to characterize the pharmacologic activity and selectivity of the new compound in comparison with reference compounds. Comparison with other drugs would also be undertaken in other in vitro preparations such as gastrointestinal and bronchial smooth muscle. At each step in this process, the compound would have to meet specific performance and selectivity criteria to be carried further.

Whole animal studies are generally necessary to determine the effect of the drug on organ systems and disease models. Cardiovascular and renal function studies of all new drugs are generally first performed in normal animals. Where appropriate, studies on disease models are performed. For a candidate antihypertensive drug, animals with hypertension would be treated to see whether blood pressure was lowered in a dose-related manner and to characterize other effects of the compound. Evidence would be collected on duration of action and efficacy after oral and parenteral administration. If the agent possessed useful activity, it would be further studied for possible adverse effects on other major organs, including the respiratory, gastrointestinal, endocrine, and central nervous systems.

These studies might suggest the need for further chemical modification (compound optimization) to achieve more desirable pharmacokinetic or pharmacodynamic properties. For example, oral administration studies might show that the drug was poorly absorbed or rapidly metabolized in the liver; modification to improve bioavailability might be indicated. If the drug was to be administered long-term, an assessment of tolerance development would be made. For drugs related to or having mechanisms of action similar to those known to cause physical or psychological dependence, abuse potential would also be studied. Drug interactions would be examined.

The desired result of this screening procedure (which may have to be repeated several times with analogs or congeners of the original molecules) is a lead compound, ie, a leading candidate for a successful new drug. A patent application would be filed for a novel compound (a composition of matter patent) that is efficacious, or for a new and nonobvious therapeutic use (a use patent) for a previously known chemical entity.

Preclinical Safety & Toxicity Testing

All drugs are toxic at some dose. Seeking to correctly define the limiting toxicities of drugs and the therapeutic index comparing benefits and risks of a new drug is an essential part of the new drug development process. Most drug candidates fail to reach the market, but the art of drug discovery and development is the effective assessment and management of risk versus benefit and not total risk avoidance.

Candidate drugs that survive the initial screening procedures must be carefully evaluated for potential risks before and during clinical testing. Depending on the proposed use of the drug, preclinical toxicity testing includes most or all of the procedures shown in Table 5–1. Although no chemical can be certified as completely "safe" (free of risk), the objective is to estimate the risk associated with exposure to the drug candidate and to consider this in the context of therapeutic needs and duration of likely drug use.

The goals of preclinical toxicity studies include identifying potential human toxicities, designing tests to further define the toxic mechanisms, and predicting the specific and the most relevant toxicities to be monitored in clinical trials. In addition to the studies shown in Table 5–1, several quantitative estimates are desirable. These include the no-effect dose—the maximum dose at which a specified toxic effect is not seen; the minimum lethal dose—the smallest dose that is observed to kill any experimental animal; and, if necessary, the median lethal dose (LD₅₀)—the dose that kills approximately 50% of the animals. Presently, the LD₅₀ is estimated from the smallest number of animals possible. These doses are used to calculate the initial dose to be tried in humans, usually taken as one hundredth to one tenth of the no-effect dose in animals.

It is important to recognize the limitations of preclinical testing. These include the following:

1.      Toxicity testing is time-consuming and expensive. Two to 6 years may be required to collect and analyze data on toxicity and estimates of therapeutic index (a comparison of the amount that causes the desired therapeutic effect to the amount that causes toxic effects, see Chapter 2) before the drug can be considered ready for testing in humans.

2.      Large numbers of animals may be needed to obtain valid preclinical data. Scientists are properly concerned about this situation, and progress has been made toward reducing the numbers required while still obtaining valid data. Cell and tissue culture in vitro methods and computer modeling are increasingly being used, but their predictive value is still limited. Nevertheless, some segments of the public attempt to halt all animal testing in the unfounded belief that it has become unnecessary.

3.      Extrapolations of therapeutic index and toxicity data from animals to humans are reasonably predictive for many but not for all toxicities. Seeking an improved process, a Predictive Safety Testing Consortium of five of America's largest pharmaceutical companies with an advisory role by the Food and Drug Administration (FDA) has been formed to share internally developed laboratory methods to predict the safety of new treatments before they are tested in humans. In 2007, this group presented to the FDA a set of biomarkers for early kidney damage.

4.      For statistical reasons, rare adverse effects are unlikely to be detected.

Evaluation in Humans

Less than one third of the drugs tested in clinical trials reach the marketplace. Federal law in the USA and ethical considerations require that the study of new drugs in humans be conducted in accordance with stringent guidelines. Scientifically valid results are not guaranteed simply by conforming to government regulations, however, and the design and execution of a good clinical trial require interdisciplinary personnel including basic scientists, clinical pharmacologists, clinician specialists, statisticians, and others. The need for careful design and execution is based on three major confounding factors inherent in the study of any drug in humans.

Confounding Factors in Clinical Trials

The Variable Natural History of Most Diseases

Many diseases tend to wax and wane in severity; some disappear spontaneously, even, on occasion, cancer. A good experimental design takes into account the natural history of the disease by evaluating a large enough population of subjects over a sufficient period of time. Further protection against errors of interpretation caused by disease fluctuations is provided by using a crossover design, which consists of alternating periods of administration of test drug, placebo preparation (the control), and the standard treatment (positive control), if any, in each subject. These sequences are systematically varied, so that different subsets of patients receive each of the possible sequences of treatment.

The Presence of Other Diseases and Risk Factors

Known and unknown diseases and risk factors (including lifestyles of subjects) may influence the results of a clinical study. For example, some diseases alter the pharmacokinetics of drugs (see Chapters 3 and 4). Concentrations of blood or tissue components being monitored as a measure of the effect of the new agent may be influenced by other diseases or other drugs. Attempts to avoid this hazard usually involve the crossover technique (when feasible) and proper selection and assignment of patients to each of the study groups. This requires obtaining accurate diagnostic tests, medical and pharmacologic histories (including use of recreational drugs), and the use of statistically valid methods of randomization in assigning subjects to particular study groups. There is growing interest in analyzing genetic variations as part of the trial that may influence whether a person responds to a particular drug.

Subject and Observer Bias and Other Factors

Most patients tend to respond in a positive way to any therapeutic intervention by interested, caring, and enthusiastic medical personnel. The manifestation of this phenomenon in the subject is the placebo response (Latin, "I shall please") and may involve objective physiologic and biochemical changes as well as changes in subjective complaints associated with the disease. The placebo response is usually quantitated by administration of an inert material, with exactly the same physical appearance, odor, consistency, etc, as the active dosage form. The magnitude of the response varies considerably from patient to patient and may also be influenced by the duration of the study. Placebo adverse effects and "toxicity" also occur but usually involve subjective effects: stomach upset, insomnia, sedation, and so on.

Subject bias effects can be quantitated—and minimized relative to the response measured during active therapy—by the single-blind design. This involves use of a placebo as described above, administered to the same subjects in a crossover design, if possible, or to a separate control group of subjects. Observer bias can be taken into account by disguising the identity of the medication being used—placebo or active form—from both the subjects and the personnel evaluating the subjects' responses (double-blind design). In this design, a third party holds the code identifying each medication packet, and the code is not broken until all the clinical data have been collected.

Drug effects seen in clinical trials are obviously affected by the patient taking the drugs at the dose and frequency prescribed. In a recent phase 2 study, one third of the patients who said they were taking the drug were found by blood analysis to have not taken the drug. Confirmation of compliance with protocols is a necessary element to consider.

The Food & Drug Administration

It is the responsibility of those seeking to market a drug to test it and submit evidence on its relative safety and effectiveness. The FDA is the administrative body that oversees the drug evaluation process in the USA and grants approval for marketing of new drug products.

Outside the USA, the regulatory and drug approval for marketing process is generally similar to that in the USA.

The FDA's authority to regulate drugs derives from specific legislation (Table 5–2). If a drug has not been shown through adequately controlled testing to be "safe and effective" for a specific use, it cannot be marketed in interstate commerce for this use.*

Unfortunately, "safe" can mean different things to the patient, the physician, and society. Complete absence of risk is impossible to demonstrate, but this fact may not be understood by the public, who frequently assume that any medication sold with the approval of the FDA should be free of serious "side effects." This confusion is a major factor in litigation and dissatisfaction with aspects of drugs and medical care.

The history of drug regulation (Table 5–2) reflects several health events that precipitated major shifts in public opinion. The Pure Food and Drug Act of 1906 became law mostly in response to revelations of unsanitary and unethical practices in the meat-packing industry. The Federal Food, Drug, and Cosmetic Act of 1938 was largely a reaction to deaths associated with the use of a preparation of sulfanilamide marketed before it and its vehicle were adequately tested. Thalidomide is an example of a drug that altered drug testing methods and stimulated drug regulating legislation. This agent was introduced in Europe in 1957–1958 and, based on animal tests then commonly used, was marketed as a "nontoxic" hypnotic and for morning sickness treatment during pregnancy. In 1961, reports were published suggesting that thalidomide was responsible for a dramatic increase in the incidence of a rare birth defect called phocomelia, a condition involving shortening or complete absence of the limbs. Epidemiologic studies provided strong evidence for the association of this defect with thalidomide use by women during the first trimester of pregnancy, and the drug was withdrawn from sale worldwide. An estimated 10,000 children were born with birth defects because of maternal exposure to this one agent. The tragedy led to the requirement for more extensive testing of new drugs for teratogenic effects and played an important role in stimulating passage of the Kefauver-Harris Amendments of 1962, even though the drug was not then approved for use in the USA. In spite of its disastrous fetal toxicity and effects in pregnancy, thalidomide is a relatively safe drug for humans other than the fetus. Even the most serious risk of toxicities may be avoided or managed if understood, and despite its toxicity thalidomide is now allowed by the FDA for limited use as a potent immunoregulatory agent and to treat certain forms of leprosy.

^*Although the FDA does not directly control drug commerce within states, a variety of state and federal laws control interstate production and marketing of drugs.

Clinical Trials: The IND & NDA

Once a drug is judged ready to be studied in humans, a Notice of Claimed Investigational Exemption for a New Drug (IND) must be filed with the FDA (Figure 5–1). The IND includes (1) information on the composition and source of the drug, (2) chemical and manufacturing information, (3) all data from animal studies, (4) proposed clinical plans and protocols, (5) the names and credentials of physicians who will conduct the clinical trials, and (6) a compilation of the key data relevant to study the drug in man made available to investigators and their institutional review boards.

It often requires 4–6 years of clinical testing to accumulate and analyze all required data. Testing in humans is begun after sufficient acute and subacute animal toxicity studies have been completed. Chronic safety testing in animals, including carcinogenicity studies, is usually done concurrently with clinical trials. In each of the three formal phases of clinical trials, volunteers or patients must be informed of the investigational status of the drug as well as the possible risks and must be allowed to decline or to consent to participate and receive the drug. These regulations are based on the ethical principles set forth in the Declaration of Helsinki. In addition to the approval of the sponsoring organization and the FDA, an interdisciplinary institutional review board (IRB) at the facility where the clinical drug trial will be conducted must review and approve the scientific and ethical plans for testing in humans.

In phase 1,  the effects of the drug as a function of dosage are established in a small number (20–100) of healthy volunteers. Although a goal is to find the maximum tolerated dose, the study is designed to prevent severe toxicity. If the drug is expected to have significant toxicity, as may be the case in cancer and AIDS therapy, volunteer patients with the disease are used in phase 1 rather than normal volunteers. Phase 1 trials are done to determine the probable limits of the safe clinical dosage range. These trials may be nonblind or "open"; that is, both the investigators and the subjects know what is being given. Alternatively, they may be "blinded" and placebo-controlled. The choice of design depends on the drug, disease, goals of investigators, and ethical considerations. Many predictable toxicities are detected in this phase. Pharmacokinetic measurements of absorption, half-life, and metabolism are often done. Phase 1 studies are usually performed in research centers by specially trained clinical pharmacologists.

In phase 2, the drug is studied in patients with the target disease to determine its efficacy ("proof of concept"), and the doses to be used in any follow-on trials. A modest number of patients (100–200) are studied in detail. A single-blind design may be used, with an inert placebo medication and an established active drug (positive control) in addition to the investigational agent. Phase 2 trials are usually done in special clinical centers (eg, university hospitals). A broader range of toxicities may be detected in this phase. Phase 2 trials have the highest rate of drug failures, and only 25% of innovative drugs move on to phase 3.

In phase 3, the drug is evaluated in much larger numbers of patients with the target disease—usually thousands—to further establish and confirm safety and efficacy. Using information gathered in phases 1 and 2, phase 3 trials are designed to minimize errors caused by placebo effects, variable course of the disease, etc. Therefore, double-blind and crossover techniques are frequently used. Phase 3 trials are usually performed in settings similar to those anticipated for the ultimate use of the drug. Phase 3 studies can be difficult to design and execute and are usually expensive because of the large numbers of patients involved and the masses of data that must be collected and analyzed. The drug is formulated as intended for the market. The investigators are usually specialists in the disease being treated. Certain toxic effects, especially those caused by immunologic processes, may first become apparent in phase 3.

If phase 3 results meet expectations, application is made for permission to market the new agent. Marketing approval requires submission of a New Drug Application (NDA) (or for biologicals, a Biological License Application [BLA]) to the FDA. The application contains, often in hundreds of volumes, full reports of all preclinical and clinical data pertaining to the drug under review. The number of subjects studied in support of the NDA has been increasing and currently averages more than 5000 patients for new drugs of novel structure (new molecular entities). The duration of the FDA review leading to approval (or denial) of the NDA may vary from months to years. Priority approvals are designated for products that represent significant improvements compared with marketed products; in 2007, the median priority approval time was 6 months. Standard approvals, which take longer, are designated for products judged similar to those on the market—in 2007, the median standard approval time was 10.2 months. In cases in which an urgent need is perceived (eg, cancer chemotherapy), the process of preclinical and clinical testing and FDA review may be accelerated. For serious diseases, the FDA may permit extensive but controlled marketing of a new drug before phase 3 studies are completed; for life-threatening diseases, it may permit controlled marketing even before phase 2 studies have been completed. Roughly 50% of drugs in phase 3 trials involve early, controlled marketing.

Once approval to market a drug has been obtained, phase 4 begins. This constitutes monitoring the safety of the new drug under actual conditions of use in large numbers of patients. The importance of careful and complete reporting of toxicity by physicians after marketing begins can be appreciated by noting that many important drug-induced effects have an incidence of 1 in 10,000 or less and that some adverse effects may become more apparent after chronic dosing. The sample size required to disclose drug-induced events or toxicities is very large for such rare events. For example, several hundred thousand patients may have to be exposed before the first case is observed of a toxicity that occurs with an average incidence of 1 in 10,000. Therefore, low-incidence drug effects are not generally detected before phase 4 no matter how carefully the studies are executed. Phase 4 has no fixed duration.

The time from the filing of a patent application to approval for marketing of a new drug may be 5 years or considerably longer. Since the lifetime of a patent is 20 years in the USA, the owner of the patent (usually a pharmaceutical company) has exclusive rights for marketing the product for only a limited time after approval of the NDA. Because the FDA review process can be lengthy, the time consumed by the review is sometimes added to the patent life. However, the extension (up to 5 years) cannot increase the total life of the patent to more than 14 years after NDA approval. As of 2005, the average effective patent life for major pharmaceuticals was 11 years. After expiration of the patent, any company may produce the drug, file an ANDA (abbreviated NDA), demonstrate required equivalence, and, with FDA approval, market the drug as a generic product without paying license fees to the original patent owner. Currently, 67% of prescriptions in the USA are for generic drugs. Even biotechnology-based drugs such as antibodies and proteins are now qualifying for generic designation, and this has fueled regulatory concerns.

A trademark is the drug's proprietary trade name and is usually registered; this registered name may be legally protected as long as it is used. A generically equivalent product, unless specially licensed, cannot be sold under the trademark name and is often designated by the official ("generic") name. Generic prescribing is described in Chapter 65.

The FDA drug approval process is one of the rate-limiting factors in the time it takes for a drug to be marketed and to reach patients. The Prescription Drug User Fee Act (PDUFA) of 1992, reauthorized in 2007, attempts to make more FDA resources available to the drug approval process and increase efficiency through use of fees collected from the drug companies that produce certain human drugs and biologic products.

The traditional sequential and linear drug development process previously described is being increasingly modified in an attempt to safely accelerate clinical trials that provide "proof of mechanism" of action and "proof of concept" that the drug does work in the target disease. In these newer approaches, certain development activities such as full dose-response studies, final drug formulation work, and long-term toxicology studies may be deferred. It is hoped that this approach will focus resources on drugs more likely to succeed and minimize later-stage failures. In one example, a phase 0 (phase zero) clinical trial is designed to study the pharmacodynamic, pharmacokinetic properties of a drug and its links to useful biomarkers and measures of mechanism. Unlike a phase 1 trial with dose-response studies, in a phase 0 trial, a limited number of low doses are administered. These trials are not designed to be therapeutic.

Adverse Drug Reactions

An adverse reaction to a drug (ADR) is a harmful or unintended response. Adverse drug reactions are claimed to be the fourth leading cause of death, higher than pulmonary disease, AIDS, accidents, and automobile deaths. The FDA has further estimated that 300,000 preventable adverse events occur in hospitals, many as a result of confusing medical information. Some adverse reactions, such as overdose, excessive effects, and drug interactions, may occur in anyone. Adverse reactions occurring only in susceptible patients include intolerance, idiosyncrasy (frequently genetic in origin), and allergy (usually immunologically mediated). During the IND and clinical phase 1–3 trials and before FDA approval, all adverse events (serious, life-threatening, disabling, reasonably drug-related, or unexpected) must be reported. After FDA approval to market a drug, surveillance, evaluation, and reporting must continue for any adverse events in patients, which are related to use of the drug, including overdose, accident, failure of expected action, events occurring from drug withdrawal, and unexpected events not listed in labeling. Events that are both serious and unexpected must be reported to the FDA within 15 days. In 2008, the FDA began publishing quarterly a list of drugs being investigated for potential safety risks. The ability to predict and avoid adverse drug reactions and optimize a drug's therapeutic index are an increasing focus of pharmacogenetic and personalized medicine.

Orphan Drugs, Treatment of Rare Diseases, and Philanthropy

Drugs for rare diseases—so-called orphan drugs—can be difficult to research, develop, and market. Proof of drug safety and efficacy in small populations must be established, but doing so is a complex process. Furthermore, because basic research in the pathophysiology and mechanisms of rare diseases receives relatively little attention or funding in both academic and industrial settings, recognized rational targets for drug action may be few. In addition, the cost of developing a drug can greatly influence priorities when the target population is relatively small. Funding for development of drugs for rare diseases or ignored diseases that do not receive priority attention from the traditional industry has received increasing support via philanthropy or similar funding from not-for-profit foundations such as the Cystic Fibrosis Foundation, the Huntington's Disease Society of America, and the Gates Foundation.

The Orphan Drug Act of 1983, provides incentives for the development of drugs for treatment of a rare disease or condition defined as "any disease or condition which (a) affects less than 200,000 persons in the U.S. or (b) affects more than 200,000 persons in the U.S. but for which there is no reasonable expectation that the cost of developing and making available in the U.S. a drug for such disease or condition will be recovered from sales in the U.S. of such drug." Since 1983, the FDA has approved for marketing more than 300 orphan drugs to treat more than 82 rare diseases.

References