New drugs face long road to approval

May 1, 2002
Only five in approximately 5,000 drugs will even make it to clinical testing.

by Jacqueline N. Brian, LDH, MS

Only five in approximately 5,000 drugs will even make it to clinical testing.

Have you ever wondered where all of those drugs on the pharmacy shelves come from? Perhaps not. In fact, most of us don't give medicines much thought until we need them. But they're expensive and time-consuming to develop, test, and evaluate. That antibiotic that you only had to take for five days or the diabetes drug that allows your friend to live a normal life were discovered, on average, 12 to 15 years before they were available at your local pharmacy.

The process starts with a search for a compound, usually at an academic research center, pharmaceutical company, or biotechnology company. The researchers may have a compound that works in an interesting way, and they want to see if it can be adapted to help cure a different disease. Or, they may have a disease in mind that they want to find a therapy for. In that case, they try many compounds to see if one works. Once they've decided on a compound, it must be tested. On average, only five in approximately 5,000 drugs will make it to clinical testing. Out of those, only one might be approved for marketing by the Food and Drug Administration (FDA).

The first testing is done on animals to see how the drug works and to see how it should be given (oral, IV, IM, etc.). Testing also determines whether the drug can be made in the quantities that will be necessary and if it is stable. This testing is referred to as the "chemical synthesis" stage. Companies use this stage to look at issues of purity, costs, and the ability to produce amounts needed to support sales. During this stage, researchers decide how the drug must be stored to retain its potency - away from light, heat, or moisture - and the type of formulation they will use, such as capsule, tablet, or injection.

Next, the "safety testing" stage begins. The main focus is how the drug is processed in the body. Testing at this stage is done on cultured cells, isolated tissues, and animals. Once the company thinks it has enough information from the animal testing, it applies to the Food and Drug Administration for approval to study the drug in humans. The form used for this request is called an Investigational New Drug application (IND). The FDA then reviews the animal data and any human data available (possibly from other countries). If approval is given, the compound moves on to the "clinical testing" stage. The IND must be continually amended as new information becomes available.

Clinical trials

Clinical drug-testing is referred to in phases. Phase I usually is conducted in healthy volunteers, while Phases II, III, and IV are conducted in patients with the condition under study. The testing in all three phases may overlap.

Phase I trials are small (20 to 80 subjects) and usually are conducted at only a few centers. These studies tend to be short, typically less than one month in duration. They are conducted to collect safety and tolerance information, and they take around one year to complete.

Phase II trials are the beginning of testing in subjects with the disease being studied. They are somewhat larger and longer than Phase I trials, usually include several hundred subjects, and last up to three months. The trials usually are controlled trials, meaning that researchers compare the effects of the compound under study to a placebo or an active "comparator" (a drug that is already marketed and considered to be effective). Trials often are "double blind," which means both the patient and the investigator running the study do not know which patients are taking the actual drug being studied. These tests are designed to evaluate safety and efficacy, and they usually take about two years to complete.

Phase III trials are the next step in development. These studies could include several thousand patients and last up to three years. They are conducted to collect more safety and efficacy information for the selected dosage. Much of the information found on the drug's label is determined during this phase of testing. Drugs entering this phase are expected to mimic real life for the condition being studied, which usually means that the requirements for patients to enter the study become less restrictive.

FDA approval

Once a company has completed Phases I through III, it will seek approval for marketing. In the United States, this is done with a New Drug Application (NDA) that is submitted to the FDA. The NDA includes all available information on the drug, including animal and human exposure data. The FDA gets 180 days to review the NDA. At this point, agreement must be reached on label information. According to analysis by the FDA in 2001, NDA review averages around 18.5 months. If your NDA is approved, you must update it on an annual basis.

The FDA is divided into three offices that handle regulated clinical trials:

1. Biologics, including gene therapy and vaccine studies, are handled by the Center for Biologics Evaluation and Research (CBER).

2. Drug issues are reviewed by the Center for Drug Evaluation and Research (CDER).

3. Medical devices are overseen by the Center for Devices and Radiological Health (CDRH).

Each of the offices accepts complaints and questions regarding clinical trials under its authority. If you are familiar with the CDER, you know it is best known for evaluating drugs prior to marketing authorization. The CDER oversees not only prescription drugs, but also over-the-counter and generic drugs. Its oversight includes such commonly used products as sunscreens and fluoride toothpaste.

Phase IV is the final phase in drug development. This phase usually is conducted after the drug has been approved for marketing. During this phase, long-term safety data is collected, along with information about the effects of the compound in various populations, such as ethnic groups, the elderly, and children. These studies can be very large, often including several thousand patients.

What protections are in place for those who participate in a clinical trial? The FDA has guidelines for the protection of human subjects, which are published in the Code of Federal Regulations (CFR). The CFR generally is considered to be the daily newspaper of the government.

All studies are required to be reviewed by an Institutional Review Board (IRB). IRBs are independent groups that are required by 21 CFR 56 to be "sufficiently qualified through the experience and expertise of its members and the diversity of the members, including consideration of race, gender, cultural backgrounds, and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects."

IRBs must have at least five members with "at least one member whose primary concerns are in the scientific area and at least one member whose primary concerns are in nonscientific areas."

In addition, one member must not have any interest or affiliation with the institution conducting the research. Every study must be reviewed by the IRB at least annually while the research is ongoing.

Although there are a few exceptions, generally all subjects or their legal representative must give their permission to participate in the study. This is referred to as "informed consent," which is usually given by signing an informed-consent form. The guidelines in 21 CFR 50 are listed in Figure 2.

Jacqueline N. Brian, LDH, MS, is a professor of dental hygiene at Indiana University-Purdue University at Fort Wayne, Ind. She can be reached by email at [email protected].

References available upon request.

Figure 1
Should you participate in a clinical trial?

The decision to participate in a clinical trial is very personal. There are benefits and risks to consider. This is where the informed-consent process can help. In addition to providing the information listed in Figure 2 in writing, the process also allows for discussion between the prospective study participant and the health-care provider.

Pharmaceutical developers, as well as the general public, need this extensive drug-development process to provide safeguards for human subjects and health benefits for us all. The evidence is convincing that the system is working. We see increased life expectancies in the face of emerging diseases. As a result, we can feel encouraged that great strides are being made both to save and to extend lives.

Figure 2
Eight required elements of informed consent

1. A statement that the study involves research, an explanation of the purposes of the research, and the expected duration of the subject's participation; a description of the procedures to be followed; and identification of any procedures that are experimental.

2. A description of any reasonably foreseeable risks or discomforts to the subjects.

3. A description of any benefits to the subject, or to others, which may reasonably be expected from the research.

4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.

5. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained. The statement also should disclose the possibility that the Food and Drug Administration may inspect the records.

6. For research involving more than minimal risk, an explanation detailing whether any compensation is involved and an explanation about any medical treatments that might be available if injury occurs. If compensation and/or treatment for complications is available, the statement should spell this out and also tell the patient where further information may be obtained.

7. An explanation detailing the person the patient should contact for answers to pertinent questions about the research and research subjects' rights and whom to contact in the event of a research-related injury to the subject.

8. A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits.

Additional information

Looking for still more information? The following Web sites are good resources:

Centerwatch at - A source for locating sites where clinical research is being conducted.

National Institutes of Health (U.S.) at - A source of information on the NIH.

FDA at - A source for researching regulations that affect clinical studies. Recalls, information from advisory committee meetings, as well as recent approvals can be found.

PhRMA at - A source for information provided by U.S. pharmaceutical research and manufacturers.

Tufts Center for the Study of Drug Development at html - Information relating to drug development.

National Institutes of Health (U.S.) at www. - A source of information on current clinical research studies.