The discovery, development, and clinical introduction of new drugs is a process involving close cooperation among researchers, medical practitioners, the pharmaceutical industry, and the United States Food and Drug Administration (FDA). The drug development process begins with the synthesis or isolation of a new compound with biological activity and potential therapeutic use. This entity must then pass through preclinical, clinical, and regulatory review stages before becoming available as a therapeutically safe and effective drug. Similar governmental agencies regulate the development and distribution of drugs in other countries.
The FDA authority over drug review and approval began with the Federal Pure Food and Drug Act of 1906. This first drug law established standards for drug strength and purity. This legislation was followed by the Federal Food, Drug, and Cosmetic Act of 1938, which prohibited the marketing of new drugs unless they were adequately tested and shown to be safe under the conditions indicated on their labels. The 1938 act was amended by Congress in 1962 to state that pharmaceutical manufacturers must also provide scientific proof that new products are efficacious and safe before marketing them. The amendment also required that the FDA be notified before the testing of drugs in humans. Additional legislation implemented since that time includes controls on the manufacture and prescribing ofhabit-forming drugs (Comprehensive Drug Abuse Prevention and Control Act, 1970), drug development for treating rare diseases (Orphan Drug Act, 1983), new drug applications for generic drug products (Drug Price Competition and Patent Restoration Act, 1984), and incentives for pediatric drug testing (Best Pharmaceuticals for Children Act, 2002).
Other regulations that have been passed are relevant to drug use and aimed at reducing health care costs from unnecessary, inappropriate, and unmonitored prescription drug use. These regulations require all states receiving Medicaid dollars to submit a plan to carry out prospective and retrospective drug utilization reviews and to counsel Medicaid patients on drug use to the Health Care Finance Administration for approval (Federal Omnibus Budget Reconciliation Act of 1990, activated in 1993).
Drug Enforcement Administration
Food and Drug Administration
Investigational new drug
Institutional Review Board
New drug application
National Institutes of Health
CLINICAL TESTING AND INTRODUCTION OF NEW DRUGS
Potential new drugs or biological products must first be tested in animals for their acute and chronic toxicity, influence on reproductive performance, carcinogenic and mutagenic potential, and safe dosing range. Early research and preclinical testing often takes 5 to 8 years and costs millions of dollars. Long-term safety testing in animals continues during subsequent trials in humans.
After successful preclinical pharmacological and toxicological studies, the sponsor files an Investigational New Drug (IND) application with the FDA. In addition to animal data, the IND contains protocols for clinical testing in humans. Approximately 2000 INDs are received each year by the FDA. If the IND passes FDA review, clinical trials in humans are initiated. These studies are generally conducted in three phases:
Phase 1: Conducted on a small number of normal volunteers to determine safe dosage range and pharmacokinetic parameters
Phase 2: Conducted on several hundred patients with specific diseases to determine short-term safety and effectiveness of the drug
Phase 3: Conducted on several thousand patients with specific diseases to determine overall risk-benefit relationships
These studies provide the basis for drug labeling. The completion of these clinical studies may take 3 to 10 years and typically costs more than $300 million. Only one out of every five drugs that enter clinical trials receives FDA approval. When that one drug is marketed, it often represents an average $800 million investment, because the pharmaceutical company must pay for the thousands of failed drugs that did not meet approval (Fig. 4-1). The patent protection (17 years) of new drugs may be increased on some drugs, based upon delays in FDA approval (Patent Term Restoration Act, 1984). Extensions in patent life may also occur for products that provide pediatric studies to support pediatric labeling (Best Pharmaceuticals for Children Act, 2002).
FIGURE 4–1 Stages of new drug development and the approval process, patent protection, and generic competition.
Before initiating a study of an investigational drug in humans, an investigator must also obtain approval from the local Institutional Review Board (IRB) of the hospital, university, or other institution where the planned study will be conducted. The IRB is responsible for ensuring the ethical acceptability of the proposed research and approves, requires modification, or disapproves the research protocol. To approve a clinical research study, the IRB must determine that the research design and procedures are sound and that the risk to subjects is minimized. In addition, the IRB must also approve the informed consent document that must be signed by each prospective subject or the subject’s legally authorized representative. IRB approval is usually valid for 1 year.
The basic elements of informed consent include: (1) explanation of the purposes and procedures of the research; (2) description of foreseeable risks; (3) description of expected benefits; (4) statement of available alternative procedures or courses of treatment; (5) statement on confidentiality of records; (6) explanation of compensation or available medical treatments, if injury occurs; (7) description of whom to contact about the research and the subject’s rights and the procedure to follow in the event of injury to the subject; and (8) statement that participation is voluntary and refusal to participate does not involve penalty to the subject.
If suitable preclinical and clinical findings demonstrate efficacy with minimal toxicity, the sponsors can submit a New Drug Application (NDA) to the FDA (see Fig. 4-1). In approving an NDA, the FDA ensures the drug’s safety and effectiveness for each use. Usually, the sponsor and the FDA review the data and negotiate on the detailed information to accompany the drug for its use. This includes contraindications, precautions, side effects, dosages, routes of administration, and frequency of administration. The NDA approval process usually takes 1 to 2 years, with drugs having the greatest potential benefit given priority. Drug applications are identified and placed into specific categories under an FDA classification system (Table 4-1). Postapproval research may be requested by the FDA as a condition of new drug approval. Such research may be used to speed drug approval, uncover unexpected adverse drug reactions, and define the incidence of known drug reactions under actual clinical use.
TABLE 4–1 FDA Drug Classification System
Drugs for AIDS or complications related to AIDS
AIDS, Acquired immunodeficiency syndrome.
After NDA approval, the manufacturer promotes the new drug for the approved uses described on the label. During the post-NDA approval or marketing period (Phase 4), the safety of the new drug must be monitored during clinical use. The label information does not include all conditions in which a released drug is safe and effective. It should be noted that the FDA does not restrict use of approved drugs to those conditions described on the label; the physician is allowed to determine its most appropriate use. However, from both an ethical and liability standpoint, there should be compelling scientific evidence before a drug is used for an unapproved indication. Examples are β-adrenergic receptor blocking drugs, which often are used interchangeably for various indications, though not all have identical FDA-approved indications (Table 4-2).
TABLE 4–2 Varied FDA Approved Uses of Several β-Adrenergic Receptor Antagonists
Early clinical testing of new drugs does not provide an absolute assurance of safety, as evidenced by later discoveries of adverse effects after drugs are used clinically, and thus much larger patient populations are exposed. In some instances, released drugs are withdrawn from the market after toxic or fatal adverse effects are discovered during large-scale clinical use. There are also instances in which a new drug is not found to be efficacious for a specific indication until it is in large-scale clinical use in selected patient populations. The goal of postmarketing surveillance (PMS) is also to define the true side effect profile of a new drug.
New safety information obtained during large scale clinical testing is used to update the current NDA and make changes in the drug label. Side effect profiles in patients with multiple diseases are often incomplete during early studies, and such information is vitally important for improving subsequent use. Reporting of rare and unexpected side effects not listed on the drug label is an important responsibility for prescribers; such information is supplied to the FDA on the Drug Experience Form (FDA form 1639). Med Watch is a voluntary reporting program initiated by the FDA to encourage and facilitate monitoring by pharmacists and other health professionals of adverse effects and problems with medications, medical devices, and other products regulated by the FDA. Any adverse effects or suspect problems may be reported on FDA form 3500.
Several sources of information are available to the physicians concerning the safety of new drugs. These include the Medical Letter on Drugs and Therapeutics, Facts and Comparisons, AMA Drug Evaluations, and the Physician’s Desk Reference (PDR), a compilation of FDA-approved drug package inserts.
Orphan Drugs, Pediatric Drug Testing, and Treatment INDs
There is little economical incentive for pharmaceutical manufacturers to develop and file an IND or NDA for new drugs that may benefit only a small number of patients with rare diseases, defined in the United States as fewer than 200,000 people. The Orphan Drug Act of 1983 provides special incentives, such as tax advantages and marketing exclusiveness, to compensate companies for the developmental costs of such agents. The NIH also participates in the development of orphan drugs. More than 300 drugs have been given orphan status.
Most drugs are studied, approved, and labeled for use in adults. At present, fewer than 25% of all drug labels include pediatric information. Young children often metabolize drugs at different rates than adults (see Chapter 3), and therefore testing is needed to clarify which doses work best in children. These studies would also help define the types of adverse reactions that are likely to occur. Current legislation allows for incentives to drug manufacturers for pediatric testing and provides funding to the NIH for research on drugs for which additional pediatric studies are needed.
The FDA has also established guidelines to help make promising investigational drugs available for the treatment of patients with immediate life-threatening diseases, such as AIDS. These drugs receive highest priority at all stages of the drug review process. The Treatment IND application enables patients not qualified for participation in ongoing studies to be treated with investigational drugs outside controlled clinical trials. The FDA generally considers Treatment INDs for drugs in later stages of clinical testing. The initial criteria include the following:
• The drug is intended to treat a serious life-threatening disease.
• There is no comparable or satisfactory alternative to treat the disease.
• The drug is under investigation in a controlled clinical trial under an IND.
• The sponsor is actively pursuing marketing approval of the investigational drug.
When no Treatment IND is in effect for an investigational drug, a physician may obtain the drug for “compassionate use.” In such cases the physician submits a Treatment IND to the FDA requesting authorization to use an investigational drug for that purpose.
Prescriptions are written by the prescriber to instruct the pharmacist to dispense a specific medication for a specific patient. These include precompounded medications (prepared by the pharmaceutical manufacturer) and extemporaneously prepared medications. It is vitally important that a prescription communicate clearly to the pharmacist the exact medication needed and how this medication is to be used by the patient. Patient compliance is often related to the clarity of the directions on the prescription, and terms such as “take as directed” should be avoided. Equally important is the necessity for clarity when using proprietary drug names because of their similarities. In these instances the physician should designate the generic name and the brand name to avoid confusion.
Prescriptions contain the following elements to facilitate interpretation by the pharmacist (Fig. 4-2):
• Physician’s name, address, and office telephone number
• Patient’s name and address
• Superscription (Rx how drug is to be taken)
• Inscription (name and dosage of drug)
• Subscription (directions to the pharmacist)
• Signature or transcription (directions to the patient)
• Refill and safety cap information
• Prescriber’s (physician’s) signature
• DEA number of physician required for controlled substances
FIGURE 4–2 Typical prescription form.
Because both apothecary and metric systems are in use, it is important that prescribers become familiar with conversion units. Following are commonly used apothecary weights and measures and their metric equivalents:
2.2 pounds (lb) = 1 kilogram (kg)
1 grain (gr) = 65 milligrams (mg)
1 fluid ounce (oz) = 30 milliliters (mL)
1 tablespoonful (tbsp) = 15 mL
1 teaspoonful (tsp) = 5 mL
20 drops (gtt) = 1 mL
Patient instructions (signature) on a prescription are sometimes written using Latin abbreviations as a shortcut for prescribers, giving concise directions to the pharmacist on how and when a patient should take the medication. Although instructions written in English are preferred, some common Latin abbreviations are as follows:
po: by mouth
ac: before meals
pc: after meals
qd: every day
b.i.d.: twice a day
t.i.d.: three times a day
q.i.d.: four times a day
hs: at bedtime
prn: as needed
Additional instructions may be added to the prescription to instruct the pharmacist to place an additional label on the prescription container (e.g., Take with Food). When a prescriber intends to use a drug for an unauthorized indication, or when two drugs have been prescribed that may cause a clinically significant drug interaction, the prescriber should communicate to the patient and pharmacist that this is indeed the intended therapy.
In the United States, many drugs require a prescription from a licensed practitioner (e.g., physician, dentist, veterinarian, podiatrist) before they can be dispensed by a pharmacist. In addition, use of specific drugs, called schedule drugs, with potential for abuse, are further restricted by the FDA, and special requirements must be met when these drugs are prescribed. These controlled drugs (Table 4-3) are classified according to their potential for abuse and include opioids, stimulants, and depressants. Schedule I drugs have a high abuse potential and no currently accepted medical use in the United States. Schedule II drugs also have a high potential for abuse, but they also have an accepted medical use; these drugs may not be refilled or prescribed by telephone. Other schedule drugs (III to IV) have low to moderate abuse potential and have a five-refill maximum, with the prescription invalid 6 months from the date of issue. Drugs in schedule V, which may be dispensed without a prescription if the patient is at least 18 years old, are distributed by a pharmacist, and only a limited quantity of the drug may be purchased (refer to the Controlled Substance Act of 1970).
TABLE 4–3 Controlled Substances
Many prescribed proprietary (brand-name) drugs are available from multiple pharmaceutical manufacturers under a brand-name, or trade name, or as less costly nonproprietary (generic name) preparations after their patent protection has expired. Pharmacists receiving prescriptions for brand-name products may dispense an equivalent generic drug (except as noted later) without prescriber approval and pass on the savings to the patient. Some states have mandatory substitution laws, and the brand-name product is dispensed only when “Dispense as Written” (D.A.W.) is stated on the prescription. Although generic products are considered to be pharmaceutically equivalent to brand-name counterparts, some may not be therapeutically equivalent, because bioavailability can be less stringently controlled.
Generic products tested by the FDA and determined to be therapeutic equivalents are listed by the FDA in Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). These products contain the same active ingredients as their brand-name counterparts and also meet bioequivalence standards within certain tolerances. The FDA recommends the substitution of only those products listed as therapeutically equivalent (A-rated products). Not all generic drugs listed in the Orange Book are therapeutic equivalents of the brand-name products. Brand-name products, such as Lanoxin (digoxin), Dilantin (phenytoin), Premarin (conjugated estrogens), and Theo-Dur (slow-release theophylline), contain either unique chemicals (Premarin) or exhibit bioavailability characteristics that differ from those of generic products. Therefore these should not be substituted without a physician’s approval. In addition, there are drugs with narrow therapeutic ranges (e.g., warfarin and carbamazepine), where small changes in bioavailability can lead to increased adverse effects or decreased therapeutic efficacy. For a patient who is having difficulty maintaining therapeutic range of a given drug, it may not be appropriate to substitute a pharmaceutically equivalent product, even if it is rated therapeutically equivalent.
Recently the FDA has suggested four initiatives for streamlining the drug approval process. These include the use of outside expert reviewers to reduce the backlog of new applications awaiting approval, elimination of duplicate animal testing, institution of a parallel-track policy to increase patient access to treatment for those who cannot participate in controlled studies, and introduction of the use of surrogate markers (e.g., CD4+ cell count for new drugs to treat HIV infection) for evaluating the efficacy of new drugs.
As noted earlier, the FDA has also instituted a program called Med Watch to encourage and facilitate the reporting of serious adverse events and product problems.
Ascione FJ, Kirking DM, Gaither CA, Welage LS. Historical overview of generic medication policy. J Am Pharm Assoc (Wash). 2001;41:567-577.
Health G, Colburn WA. An evolution of drug development and clinical pharmacology during the 20th century. J Clin Pharmacol. 2000;40:918-929.
Kirking DM, Ascione FJ, Gaither CA, Welage LS. Economics and structure of the generic pharmaceutical industry. J Am Pharm Assoc (Wash). 2001;415:78-84.
McClellan M. Drug safety reform at the FDA–pendulum swing or systematic improvement? N Engl J Med. 2007;356:1700-1702.
Welage LS, Kirking DM, Ascione FJ, Gaither CA. Understanding the scientific issues embedded in the generic drug approval process. J Am Pharm Assoc (Wash). 2001;41:856-867.
For more information about the evaluation and regulation of drugs by the FDA see: http://www.fda.gov/cder/index.html
1. A proprietary (brand-name) drug cannot be prescribed if:
A. The FDA has not approved the use for which you are prescribing it.
B. A generic form of the drug is available.
C. The drug has a very high abuse potential.
D. None of the above restricts prescribing a brand-name drug.
2. Phase I studies are important to:
A. Reveal the adverse and toxic effects of a new drug in people.
B. Determine the efficacy of a new drug in a specific disease.
C. Determine a safe dosage range of a new drug in humans.
D. Indicate the effectiveness of a new drug in animal models of disease.
3. Which of the following controlled drug schedules contains drugs that have no accepted medical use in the United States?
A. Schedule I
B. Schedule II
C. Schedule III
D. Schedule IV
E. Schedule V
4. The Latin abbreviation q.i.d. on a prescription means that the drug is to be taken:
A. Twice a day.
B. Four times a day.
C. Whenever needed.
D. Every day.
E. Every other day.
5. How many milligrams are contained in five grains of aspirin?
A. 30 mg
B. 80 mg
C. 130 mg
D. 325 mg
E. 500 mg