Topic Resources
Drug development is the process of discovering or creating new medications (also called drugs) and demonstrating their effectiveness and safety. Because all medications can cause harm as well as help, safety is relative. The difference between the usual effective dose and the dose that causes severe or life-threatening side effects is called the margin of safety. A wide margin of safety is desirable, but when treating a dangerous condition or when there are no other options, a narrow margin of safety often must be accepted.
Ideally, medications are both effective and largely safe. Penicillin can be used as an example. Penicillin, even in large doses, is virtually nontoxic, except for people who are allergic to it. In contrast, barbiturates were once commonly used as sleep aids but are now rarely prescribed as a medication. When used as either a medication or illicit drug, barbiturates can interfere with breathing, dangerously lower blood pressure, and cause death if taken in excess. Newer sleep aids, such as temazepam and zolpidem, are more commonly prescribed because they have a wider margin of safety than barbiturates.Ideally, medications are both effective and largely safe. Penicillin can be used as an example. Penicillin, even in large doses, is virtually nontoxic, except for people who are allergic to it. In contrast, barbiturates were once commonly used as sleep aids but are now rarely prescribed as a medication. When used as either a medication or illicit drug, barbiturates can interfere with breathing, dangerously lower blood pressure, and cause death if taken in excess. Newer sleep aids, such as temazepam and zolpidem, are more commonly prescribed because they have a wider margin of safety than barbiturates.
Designing effective drugs with a wide margin of safety and few side effects cannot always be achieved. Consequently, some medications are used even though they have a very narrow margin of safety. For example, warfarin (a "blood thinner," or anticoagulant) is taken to prevent blood clotting but can cause excessive bleeding. It is used when the risk of blood clotting is so great that the risk of bleeding must be tolerated. People who take warfarin need frequent monitoring to made sure the dose is adjusted to maintain just the right level of clot prevention without unnecessarily increasing the risk of bleeding. Designing effective drugs with a wide margin of safety and few side effects cannot always be achieved. Consequently, some medications are used even though they have a very narrow margin of safety. For example, warfarin (a "blood thinner," or anticoagulant) is taken to prevent blood clotting but can cause excessive bleeding. It is used when the risk of blood clotting is so great that the risk of bleeding must be tolerated. People who take warfarin need frequent monitoring to made sure the dose is adjusted to maintain just the right level of clot prevention without unnecessarily increasing the risk of bleeding.
To help ensure that their treatment plan is as safe and effective as possible, people should keep their health care professionals well informed about their medical history, current medications (including over-the-counter drugs) and dietary supplements (including medicinal herbs), and any other relevant health information. In addition, they should not hesitate to ask a doctor, nurse, or pharmacist to explain the goals of treatment, the types of side effects and other problems that may develop, and the extent to which they can participate in the treatment plan.
More Information
The following are some English-language resources that may be useful. Please note that The Manual is not responsible for the content of these resources.
The Center for Information and Study on Clinical Research Participation (CISCRP): A nonprofit organization that educates and informs patients, medical researchers, the media, and policy makers about the roles they all play in clinical research
ClinicalTrials.gov: A database of privately and publicly funded clinical studies conducted around the world
Drug Design and Development
Many of the drugs in current use were developed by initial observation of a possible effect of a substance, followed by experiments conducted in animals and humans. However, many drugs are now being specifically designed in a laboratory setting. Abnormal biochemical and cellular changes caused by disease are identified, and then compounds that may specifically prevent or correct these abnormalities are designed. When a new compound shows promise, its structure is usually modified many times to optimize its effectiveness and safety.
Ideally, a drug is
Highly targeted to its target site and has little or no effect on other body systems—that is, it has minimal or no side effects (see Overview of Adverse Drug Reactions).
Very potent and effective: Low doses can be used, even for disorders that are difficult to treat.
Effective when taken by mouth (absorbed well from the digestive tract): For convenient use.
Reasonably stable in body tissues and fluids: So ideally, one dose a day is adequate (shorter-acting drugs may be preferred for disorders that need only brief treatment).
Standard or average doses are determined during drug development. However, people respond to drugs differently. Many factors, including age (see Aging and Drugs), weight, genetic makeup, and the presence of other disorders, affect drug response (see Overview of Response to Drugs). These factors must be considered when prescribers determine the dose for a particular person.
Stages of Drug Development
(See table From Laboratory to Medicine Cabinet for a summary of the stages of drug development.)
Early development
In early development, a drug that initially seems useful in treating a disorder is studied in laboratory animals. Many drugs are rejected at this stage because they are shown to be not effective or too toxic.
If a drug seems promising after early development, an approval process for further study in humans is begun and an application is filed with the U.S. Food and Drug Administration (FDA). If the FDA approves the application, the drug is allowed to be tested in people (a phase called clinical studies).
Clinical studies
These studies occur in several phases and only in volunteers who have given their full consent. Three phases of clinical studies are required for FDA approval:
Phase 1 evaluates the drug's safety and toxicity in people. Different amounts of the drug are given to a small number of healthy adults to determine the dose at which toxicity first appears.
Phase 2 evaluates what effect the drug has on the target disorder and what the right dose might be. Different amounts of the drug are given to up to about 100 people who have the target disorder to see whether there is any benefit.
Phase 3 tests the drug in a larger group of people (often hundreds to thousands) who have the target disorder. These people are selected to be as similar as possible to the people who might use the drug in the real world. The drug's effectiveness is studied further, and any new side effects are noted. Phase 3 tests usually compare the new drug against an established drug, a placebo, or both.
Approval
If studies indicate that the drug is sufficiently effective and safe, a new drug application (NDA) is filed with the FDA, which decides whether the medication is sufficiently effective and safe to be marketed. The whole process usually takes about 10 years. On average, only about 5 out of 4,000 medications studied in the laboratory are studied in people, and only about 1 out of 5 medications studied in people is approved and prescribed.
Each country has its own approval process, which may be different from the process in the United States. Just because a medication is approved for use in one country does not mean that it is available for use in another country.
Phase 4 (postmarketing)
After a new medication is approved, Phase 4 studies are sometimes conducted; the manufacturer must monitor the use of the medication and promptly report any additional, previously undetected side effects to the FDA. Such monitoring is important because important side effects that occur only rarely (perhaps once in every 10,000 people) can be detected only when a large number of people use the drug, that is, after it is on the market.
The FDA will withdraw approval if new evidence indicates that a medication may cause severe side effects. For example, the diet aid fenfluramine was withdrawn from the market because some people who took it developed serious heart disorders.The FDA will withdraw approval if new evidence indicates that a medication may cause severe side effects. For example, the diet aid fenfluramine was withdrawn from the market because some people who took it developed serious heart disorders.
From Laboratory to Medicine Cabinet
Phase | Test Group | Purpose | Typical Length |
Early development | |||
Laboratory settings (such as cell cultures and animals) | To determine the chemical and physical characteristics of the medication and to assess the safety and effects of the medication in living organisms | 2–6.5 years | |
Clinical studies | |||
Phase 1 | 20–80 healthy volunteers | To establish basic safety and blood levels achieved with different doses of the medication | 1.5 years |
Phase 2 | Up to 100 people who have or who might develop the disorder being studied | To establish the medication's effectiveness and dosage range and to identify side effects | 2 years |
Phase 3 | 300–30,000 people who have the disorder being studied | To confirm the most effective dosage regimen, to obtain more information about the medication's effectiveness and side effects not seen during Phases 1 and 2, and to compare the medication with existing medications, a placebo, or both | 3.5 years |
FDA review | |||
Government review of all information from early development and clinical studies | To determine whether the medication has been proven to be sufficiently effective and safe | 0.5–1 year | |
Phase 4 (postmarketing surveillance) | |||
All people taking the medication, particularly subgroups such as pregnant people, children, and older adults | To identify any problems that did not occur in Phases 1, 2, or 3, such as those that take a long time to appear and those that occur rarely | Ongoing | |
Placebos
Placebos are substances that are made to resemble medications but do not contain an active medication.
A placebo is made to look exactly like a real medication but is made of an inactive substance, such as a starch or sugar.
Despite there being no active ingredients, some people who take a placebo feel better. Some others develop "side effects." This phenomenon, called the placebo effect, appears to occur for two reasons. The first reason is coincidental change. Many medical conditions and symptoms come and go without treatment, so a person taking a placebo may just coincidentally feel better or worse. When this change occurs, the placebo may incorrectly be credited with or blamed for the result. The second reason is anticipation (sometimes called suggestibility). Anticipating that a drug will work often actually makes people feel better.
The placebo effect is mainly on symptoms rather than the actual disorder. For example, a placebo will never make a broken bone heal faster, but it may make the pain seem less. Not everyone responds to placebos, and it is not possible to predict who will respond.
When a new medication is being developed, investigators conduct studies to compare the effect of the medication with that of a placebo because any medication can have a placebo effect. The true effect must be distinguished from a placebo effect. Typically, half the study's participants are given the medication, and half are given an identical-looking placebo. Ideally, neither the participants nor the investigators know who received the medication and who received the placebo (this type of study is called a double-blind study).
When the study is completed, all changes observed in participants taking the active medication are compared with those in participants taking the placebo. The medication must perform significantly better than the placebo to justify its use. In some studies, as many as 50% of participants taking the placebo improve (an example of the placebo effect), making it difficult to show the effectiveness of the medication being tested.
Benefits Versus Risks of Medications
Every medication has the potential to do harm (an adverse drug reaction) as well as good. When doctors consider prescribing a medication, they must weigh the possible harms against the expected benefits. Use of a medication is not justified unless the expected benefits outweigh the possible harms. Doctors must also consider the likely outcome of withholding the medication. Potential benefits and harms can never be determined with mathematical precision.
When assessing the benefits and risks of prescribing a medication, doctors consider the severity of the disorder being treated and the effect it is having on the person's quality of life. For relatively minor disorders—such as coughs and colds, muscle strains, or infrequent headaches—only a very low risk of adverse drug reactions is acceptable. For such conditions, over-the-counter medications are usually effective and well tolerated.
When used according to directions, over-the-counter medications for treating minor disorders have a wide safety margin (the difference between the usual effective dose and the dose that produces severe adverse drug reactions).
In contrast, for serious or life-threatening disorders (such as a heart attack, stroke, cancer, or organ transplant rejection), a higher risk of a severe adverse drug reaction is usually more acceptable.
Individuals may have different perspectives on quality of life and the risks they are willing to assume. For example, some people are more willing than others to accept the adverse effects of certain cancer chemotherapy in return for a slight chance of prolonging life.
People also differ on how great a possibility of risk they are willing to accept. For example, a 1 in 50 chance of having serious bleeding from a medication may be unacceptable to some people but seem reasonable to others.
