By law, the safety and efficacy of drugs must be defined before
they are marketed in the United States. The development of new drugs
is a multistep process requiring molecular, cellular, animal, and
human clinical trials prior to governmental approval and marketing
(Figure 1–1). New drugs may be developed through a basic
understanding of chemical structure or biologic mechanisms, or based
on the actions of previous drugs. Alternatively, drugs may be developed
from screening a large number of biologically derived or synthesized
The development and testing process required to bring
a drug to market in the United States. Some of the requirements
may be different for drugs used in life-threatening diseases.
Regardless of the source or the key idea leading to a candidate
molecule, testing it involves a sequence of 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 molecule will be studied for a broad array of actions
to establish the mechanism of action and selectivity of the drug.
This has the advantage of demonstrating unsuspected toxic effects
and occasionally discloses a previously unsuspected therapeutic
action. As a result of this research effort, a candidate molecule,
called a lead compound, is investigated further. A patent application
may then be filed for a novel compound that is efficacious, or for
a new and nonobvious therapeutic use for a previously known drug.
As part of the preclinical investigative process, lead compounds
are evaluated for potential toxicity. Several of the toxicity tests
are listed in Table 1–1. No drug can be certified as completely
free of risk, since every drug is toxic at some dosage. These investigations
can estimate the risk associated with exposure to the drug under
specified conditions. In addition to the studies shown in Table
1–1, several quantitative estimates are required and are
discussed in Chapter 3.
Table 1–1. Safety
Tests Conducted in Animals ||Download (.pdf)
Table 1–1. Safety
Tests Conducted in Animals
|Type of Test||Comment|
|Acute Toxicity||Compares single therapeutic dose to that which is lethal
in approximately 50% of animals.|
|Subacute Toxicity||Compares multiple doses at therapeutic and toxic concentrations.
Usually 4 weeks to 3 months in duration.|
|Chronic Toxicity||Compares multiple doses at therapeutic and toxic concentrations.
Conducted when intended clinical use is prolonged. Duration 6 months
|Carcinogenic Potential||Two-year duration. Conducted when drug is intended for prolonged
|Mutagenic Potential||Examines genetic stability and the potential for mutations
in prokaryotic and eukaryotic organisms.|
|Toxicologic Potential||Determines the sequence and mechanisms of toxic actions.|
Less than one-third of the drugs tested in clinical trials reach
the marketplace. Federal law in the United States requires that
the study of new drugs in humans be conducted in accordance with stringent
guidelines. The federal Food and Drug Administration (FDA) is the
administrative body that oversees the drug evaluation process in
the United States and grants approval for marketing of new drugs.
The FDA’s authority to regulate drug marketing is derived
from federal legislation. To receive approval by the FDA for marketing,
a drug must be demonstrated to be “safe and efficacious” through
experimental investigation. Unfortunately, “safe” means
different things to the patient, the physician, and society. A complete
absence of risk is impossible to demonstrate, but this fact is not
well understood by the average member of the public, who assumes
that any drug sold with the approval of the FDA must indeed be free
of serious “side effects.” This confusion continues
to be a major cause of litigation and dissatisfaction with medical
care. Of course it is impossible to certify that a drug is absolutely
safe. Experimental investigation, however, can identify most of
the hazards likely to be associated with use of a new drug and to
place some statistical limits on frequency of occurrence of such
events in the population under study. As a result, an operational
and pragmatic definition of “safety” can usually
be reached that is based on the nature and incidence of drug-associated
hazards compared with the hazard of nontherapy for the target disease.
The new drug approval process involves a systematic series of
investigations. Once a lead compound is judged ready to be studied
in humans, a Notice of Claimed Investigational Exemption for a New
Drug (IND) must be filed and approval of the proposed clinical studies
obtained from the FDA (Figure 1–1).
In phase 1, the effects of the drug, as a function of dosage,
are established in a small number (25 to 50) of healthy volunteers.
If the drug is expected to have significant toxicity, as is often
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 whether humans and animals show significantly
different responses to the drug, and to establish the probable limits
of the safe clinical dosage range. Pharmacokinetic parameters (Chapter 3) are often established in phase 1.
In phase 2, the drug is administered for the first time in patients
with the target disease to determine its efficacy. A small number
of patients (100 to 200) are studied in great detail. The clinical benefits
of the drug and a broader range of toxicities can be determined
in this phase.
In phase 3, the drug is evaluated in much larger numbers of patients
to establish safety and efficacy under conditions of proposed use.
Phase 3 studies can be difficult to design and execute, and are
usually expensive because of the large numbers of patients involved
and the mass of data that must be collected and analyzed.
Often 4 to 6 years of clinical testing are required to accumulate
all the data. Chronic safety testing in animals 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 possible risks, and
must be allowed to decline or to consent to participate and receive
the drug. If the clinical and animal investigative results meet
expectations, an application is made for permission to market the
new drug. The process of applying for marketing approval requires
submission of a New Drug Application (NDA) to the FDA (Figure 1–1).
The FDA review of this material and a decision on approval can take
3 years or longer. If the FDA approves the NDA, the drug manufacturer
in conjunction with the FDA develops a “label” for
the drug. This label describes the medical condition treated by
the drug, adverse effects of the drug and dosages for the drug.
After the drug is approved and marketed, the drug may be prescribed
for other medical conditions not listed on the label. Such usage
is the drug’s “off-label” use.
In cases where an urgent need is perceived, the process of preclinical
and clinical testing and FDA review may be greatly accelerated.
For serious diseases, the FDA can permit extensive but controlled
marketing of a new drug before phase 3 studies are completed.
Once marketing of a drug has commenced, phase 4 begins. This
constitutes monitoring the safety of the new drug under actual conditions
of use in large numbers of patients. Phase 4 has no fixed duration.
The time from the filing of a patent application to approval
for marketing of a new drug can be 5 years or considerably longer.
Since the lifetime of a patent is 20 years in the United States,
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 process 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.
After expiration of the patent, any company may produce and market
the drug as a generic drug, without
paying license fees to the original patent owner. The FDA drug approval
process is one of the rate-limiting factors in the time it takes
for a drug to be marketed and reach patients.