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 sometimes 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). Other drugs and some foods alter the pharmacokinetics of many drugs. 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. It has been shown that age, gender, and pregnancy influence the pharmacokinetics of some drugs, but these factors have not been adequately studied because of legal restrictions and reluctance to expose these populations to unknown risks.
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. In some conditions, a positive response may be noted in as many as 30–40% of subjects given placebo. 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 well-matched 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 (also known as adherence) is a necessary element to consider.
The various types of studies and the conclusions that may be drawn from them are described in the accompanying text box. (See Drug Studies—The Types of Evidence.)
Drug Studies—the Types of Evidence*
As described in this chapter, drugs are studied in a variety of ways, from 30-minute test tube experiments with isolated enzymes and receptors to decades-long observations of populations of patients. The conclusions that can be drawn from such different types of studies can be summarized as follows.
Basic research is designed to answer specific, usually single, questions under tightly controlled laboratory conditions, eg, does drug x inhibit enzyme y? The basic question may then be extended, eg, if drug x inhibits enzyme y, what is the concentration-response relationship? Such experiments are usually reproducible and often lead to reliable insights into the mechanism of the drug's action.
First-in-human studies include phase 1–3 trials. Once a drug receives FDA approval for use in humans, case reports and case series consist of observations by clinicians of the effects of drug (or other) treatments in one or more patients. These results often reveal unpredictable benefits and toxicities but do not generally test a prespecified hypothesis and cannot prove cause and effect. Analytic epidemiologic studies consist of observations designed to test a specified hypothesis, eg, that thiazolidinedione antidiabetic drugs are associated with adverse cardiovascular events. Cohort epidemiologic studies utilize populations of patients that have (exposed group) and have not (control group) been exposed to the agents under study and ask whether the exposed groups show a higher or lower incidence of the effect. Case control epidemiologic studies utilize populations of patients that have displayed the end point under study and ask whether they have been exposed or not exposed to the drugs in question. Such epidemiologic studies add weight to conjectures but cannot control all confounding variables and therefore cannot conclusively prove cause and effect.
Meta-analyses utilize rigorous evaluation and grouping of similar studies to increase the number of subjects studied and hence the statistical power of results obtained in multiple published studies. While the numbers may be dramatically increased by meta-analysis, the individual studies still suffer from their varying methods and end points and a meta-analysis cannot prove cause and effect. Large randomized controlled trials are designed to answer specific questions about the effects of medications on clinical end points or important surrogate end points, using large enough samples of patients and allocating them to control and experimental treatments using rigorous randomization methods. Randomization is the best method for distributing all foreseen confounding factors, as well as unknown confounders, equally between the experimental and control groups. When properly carried out, such studies are rarely invalidated and can be very convincing.
*I thank Ralph Gonzales, MD, for helpful comments.
The Food & Drug Administration
The FDA is the administrative body that oversees the drug evaluation process in the USA and grants approval for marketing of new drug products. To receive FDA approval for marketing, the originating institution or company (almost always the latter) must submit evidence of safety and effectiveness. Outside the USA, the regulatory and drug approval process is generally similar to that in the USA.
As its name suggests, the FDA is also responsible for certain aspects of food safety, a role it shares with the US Department of Agriculture (USDA). Shared responsibility results in complications when questions arise regarding the use of drugs, eg, antibiotics, in food animals. A different type of problem arises when so-called food supplements are found to contain active drugs, eg, sildenafil analogs in "energy food" supplements.
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.*
Table 5–2 Some Major Legislation Pertaining to Drugs in the United States. |Favorite Table|Download (.pdf)
Table 5–2 Some Major Legislation Pertaining to Drugs in the United States.
|Law||Purpose and Effect|
|Pure Food and Drug Act of 1906||Prohibited mislabeling and adulteration of drugs.|
|Opium Exclusion Act of 1909||Prohibited importation of opium.|
|Amendment (1912) to the Pure Food and Drug Act||Prohibited false or fraudulent advertising claims.|
|Harrison Narcotic Act of 1914||Established regulations for use of opium, opiates, and cocaine (marijuana added in 1937).|
|Food, Drug, and Cosmetic Act of 1938||Required that new drugs be safe as well as pure (but did not require proof of efficacy). Enforcement by FDA.|
|Durham-Humphrey Act of 1952||Vested in the FDA the power to determine which products could be sold without prescription.|
|Kefauver-Harris Amendments (1962) to the Food, Drug, and Cosmetic Act||Required proof of efficacy as well as safety for new drugs and for drugs released since 1938; established guidelines for reporting of information about adverse reactions, clinical testing, and advertising of new drugs.|
|Comprehensive Drug Abuse Prevention and Control Act (1970)||Outlined strict controls in the manufacture, distribution, and prescribing of habit-forming drugs; established drug schedules and programs to prevent and treat drug addiction.|
|Orphan Drug Amendments of 1983||Provided incentives for development of drugs that treat diseases with less than 200,000 patients in USA.|
|Drug Price Competition and Patent Restoration Act of 1984||Abbreviated new drug applications for generic drugs. Required bioequivalence data. Patent life extended by amount of time drug delayed by FDA review process. Cannot exceed 5 extra years or extend to more than 14 years post-NDA approval.|
|Prescription Drug User Fee Act (1992, reauthorized 2007)||Manufacturers pay user fees for certain new drug applications.|
|Dietary Supplement Health and Education Act (1994)||Established standards with respect to dietary supplements but prohibited full FDA review of supplements and botanicals as drugs. Required the establishment of specific ingredient and nutrition information labeling that defines dietary supplements and classifies them as part of the food supply but allows unregulated advertising.|
|Bioterrorism Act of 2002||Enhanced controls on dangerous biologic agents and toxins. Seeks to protect safety of food, water, and drug supply.|
|Food and Drug Administration Amendments Act of 2007||Granted FDA greater authority over drug marketing, labeling, and direct-to-consumer advertising; required post-approval studies, established active surveillance systems, made clinical trial operations and results more visible to the public.|
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 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. The Kefauver-Harris amendments of 1962 were, in part, the result of a teratogenic drug disaster involving thalidomide. This agent was introduced in Europe in 1957–1958 and, based on animal tests then commonly used, was marketed as a "nontoxic" hypnotic and promoted as being especially useful 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 arms and legs. 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 stimulated 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 approved 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 new 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 plans for clinical trials, (5) the names and credentials of physicians who will conduct the clinical trials, and (6) a compilation of the key data relevant to study of the drug in humans that has been 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 only 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 (1966). 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 often 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—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 new drug application 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 new drug application 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. If problems arise, eg, unexpected but possibly serious toxicities, additional studies may be required and the approval process may extend to several years.
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. Such "accelerated approval" is usually granted with the requirement that careful monitoring of the effectiveness and toxicity of the drug be carried out and reported to the FDA. Unfortunately, FDA enforcement of this requirement has not always been adequate.
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 apparent only 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. As with monitoring of drugs granted accelerated approval, phase 4 monitoring has often been lax.
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 new drug application. 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 approval of a new drug application. 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 abbreviated new drug application (ANDA), 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 other 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. In 2009, the FDA approved 19 new molecular entity drug applications for new nonbiologic entities and six biological license applications, one more than in 2008. 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.
Several factors in the development and marketing of drugs result in conflicts of interest. Use of pharmaceutical industry funding to support FDA approval processes raises the possibility of conflicts of interest within the FDA. Supporters of this policy point out that chronic FDA underfunding by the government allows for few alternatives. Another important source of conflicts of interest is the dependence of the FDA on outside panels of experts that are recruited from the scientific and clinical community to advise the government agency on questions regarding drug approval or withdrawal. Such experts are often recipients of grants from the companies producing the drugs in question. The need for favorable data in the new drug application leads to phase 2 and 3 trials in which the new agent is compared only to placebo, not to older, effective drugs. As a result, data regarding the efficacy and toxicity of the new drug relative to a known effective agent may not be available when the new drug is first marketed.
Manufacturers promoting a new agent may pay physicians to use it in preference to older drugs with which they are more familiar. Manufacturers sponsor small and often poorly designed clinical studies after marketing approval and aid in the publication of favorable results but may retard publication of unfavorable results. The need for physicians to meet continuing medical education (CME) requirements in order to maintain their licenses encourages manufacturers to sponsor conferences and courses, often in highly attractive vacation sites, and new drugs are often featured in such courses. Recognition of the obvious conflicts of interest is leading some clinical specialty organizations to reject industry support of such conferences. Finally, the common practice of distributing free samples of new drugs to practicing physicians has both positive and negative effects. The samples allow physicians to try out new drugs without incurring any cost to the patient. On the other hand, new drugs are usually much more expensive than older agents and when the free samples run out, the patient (or insurance carrier) may be forced to pay much more for treatment than if the older, cheaper, and possibly equally effective drug were used. Finally, when the patent for a drug is nearing expiration, the patent-holding manufacturer may try to extend its exclusive marketing privilege by paying generic manufacturers to not introduce a generic version ("pay to delay").
Unfortunately, the rate of introduction of new drugs has fallen during the last two decades. This has raised concerns about our ability to deal with the increasing prevalence of resistant microorganisms, and the problems of degenerative diseases in an aging population. In an effort to facilitate this process, the National Institutes of Health are currently (2011) considering the establishment of a new institute specializing in translational research.
An adverse drug event (ADE) or 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 or lack of information (for example, regarding drug incompatibilities). 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 IND studies and clinical trials 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 that 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 is an increasing focus of pharmacogenetic and personalized medicine. It is hoped that greater use of electronic health records will reduce some of these risks (see Chapter 65).
Orphan Drugs & Treatment of Rare Diseases
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 Amendments 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.