The FDA's Role
Q&A: Off-Label Drugs
A Short History
Understanding the Approval Process for New Cancer Treatments
Every year, medical researchers develop new cancer treatments or new uses for treatments already on the market. These treatments are most often drugs, chemically produced substances used to treat or prevent disease. But they may also be biologics, treatments that are made from living organisms such as vaccines or recombinant proteins.
The U.S. Food and Drug Administration (FDA) is the division of the U.S. Department of Health and Human Services charged with making sure that drugs and biologics are safe and effective before they go on the market.
FDA regulators face two main challenges during the approval process. First, they must make sure the treatment is safe and effective. For this, regulators rely on the results of clinical trials - research studies that test how well medical treatments or other interventions work in people.
The second challenge is to make promising treatments available as quickly as possible to the people most in need of them. Ordinarily this occurs through clinical trials. The FDA may also allow access to an unapproved investigational treatment outside of a clinical trial, if no approved therapy for the disease exists.
This guide will acquaint you with the main parts of the FDA approval process and point you to other resources for learning more about it.
The FDA's Role
One Example: Herceptin®
Before September 25, 1998, women with advanced breast cancer who wanted to take the drug Herceptin needed to enroll in a clinical trial. But after that date, they could obtain it through their doctors, like any other prescription drug. That's because Herceptin had received official approval from the U.S. Food and Drug Administration (FDA).
In the months leading up to approval, researchers had reported promising results from studies of women with advanced breast cancer whose tumor cells had extra copies of a protein called HER2. Herceptin is designed to target that protein and kill the cancer cells, leaving healthy cells alone. One group of researchers found that women who took the drug along with standard chemotherapy survived longer than those who recieved only the chemotherapy. Another group found that Herceptin alone could help some women whose cancer was not responding to chemotherapy.
A few months later, after carefully reviewing the results and weighing the benefits against the risks of side effects, the FDA approved the drug for use in women with HER2-positive, advanced breast cancer.
Approval is only one step in the process by which new treatments are developed. In fact, the FDA estimates that, on average, it takes 8.5 years to study and test a new drug before it can be approved for the general public. That includes early laboratory and animal testing, as well as the clinical trials that evaluate the treatment in humans. The FDA plays a key role at three main points in this process:
- Determining whether or not the benefits of a new treatment outweigh the risks.
- Once clinical trials begin, deciding whether or not they should continue, based on reports of the treatment's side effects and effectiveness against disease.
- When clinical trials are completed, deciding whether or not the treatment should be sold to the public and, if so, what claims the drug manufacturer can make and what the label should say about directions for use, side effects, and warnings.
To make these decisions, the FDA must review studies submitted by the drug's sponsor (which is usually the company that makes the drug), evaluate any reports of side effects or complications (called "adverse events") from preclinical studies and previous clinical trials, and review the adequacy of the chemistry and manufacturing.
This process is lengthy, but it is meant to ensure that only beneficial treatments with acceptable side effects will make their way into the hands of the public. At the same time, recent laws and streamlined procedures within the FDA have accelerated the approval of effective treatments, especially for serious illnesses such as cancer. In addition, specific provisions make some treatments available to patients with special needs even before the approval process is complete.
From Lab to Patient Care
By law, the FDA must review all test results for new treatments to ensure that products are safe and effective for specific uses. "Safe" does not mean that the treatment is free of possible adverse side effects; rather, it means that the potential benefits have been determined to outweigh any risks. The testing process begins long before the first person takes the treatment, with preliminary research and animal testing.
If a treatment proves promising in the lab, the drug company or sponsor must apply for FDA approval to test it in clinical trials with people. The application is called an Investigational New Drug (IND) application. For drugs and recombinant proteins (such as cytokines and monoclonal antibodies), sponsors submit the IND to the Center for Drug Evaluation and Research, or CDER (see chart). For other biologics, including gene therapies and vaccines, sponsors submit the IND to the Center for Biologics Evaluation and Research (CBER).
Once the IND is allowed to proceed by CDER or CBER, clinical trials can begin. If the treatment makes it through the clinical trials process - that is, if the studies show the treatment is safe and effective - the sponsor may submit to the FDA another application. For drugs, this is a New Drug Application (NDA); for biologics, it's a Biologics License Application (BLA). The application must include the following:
- The exact chemical makeup of the drug or biologic
- Results of animal studies
- Results of clinical trials
- How the drug or biologic is made, processed, and packaged
- Quality control standards
Once the FDA receives the NDA or BLA from the sponsor, the formal New Drug Application Review Process (see chart) or Biologics/Product License Application Review Process begins.
For an overview of the entire drug approval process, see the CDER's visual representation of The New Drug Development Process. For more information about the biologic approval process, see CBER's Frequently Asked Questions Web page.
Speed versus Safety in the Approval Process
During the approval process, the FDA classifies as "priority" those treatments that offer significant medical advances over existing therapies. But even in non-priority cases, the FDA's goal is that no more than 10 months will pass between when a complete application is submitted and the FDA has finished its review, either approving the drug or biologic, or providing the sponsor with a complete list of the issues that need to be addressed.
The process is not always smooth, however. Sometimes the FDA requests (or the FDA's advisory panel recommends) additional research or data. Some new approvals have taken as little as 42 days from the time the last part of the BLA/NDA is received; other more difficult applications have spent years in the approval process.
The FDA relies on a system of independent advisory committees, made up of professionals from outside the agency, for expert advice and guidance in making sound decisions about drug approval. Each committee meets as needed to weigh available evidence and assess the safety, effectiveness, and appropriate use of products considered for approval. In addition, these committees provide advice about general criteria for evaluation and scientific issues not related to specific products. The Oncologic Drugs Advisory Committee (ODAC) meets regularly to provide expert advice on cancer-related treatments and preventive agents.
Each committee is composed of representatives from the the fields of research science and medical practice. At least one member on every advisory committee must represent the consumer perspective.
As the FDA looks at all the data submitted and the results of its own review, it applies two benchmark questions to each application:
- Do the results of well-controlled studies provide substantial evidence of the treatment's effectiveness?
- Do the results show the product is safe under the conditions of use in the proposed labeling? In this context, "safe" means that potential benefits have been determined to outweigh any risks.
The FDA's responsibility for new medical treatments does not stop with final approval. The CDER's Office of Compliance tracks drugs after approval to make sure that drug makers comply with current standards and regulations. CDER's Office of Drug Marketing, Advertising, and Communication monitors new drug advertising to make sure it is truthful and complete. Biologics regulated by CBER are followed with the same vigilance after approval by the Office of Compliance and Biologics Quality as well as the Advertising and Promotional Labeling staff. And through a system called MedWatch, the FDA gets feedback from health professionals and consumers on how the new treatments are working, any adverse reactions, and potential problems in labeling and dosage.
Online FDA Resources
The following information from the FDA should help you better understand the drug approval process:
The Clinical Trials Process
Clinical trials provide the most important information used by the U.S. Food and Drug Administration (FDA) to decide whether a new medical treatment shows "substantial evidence of effectiveness," or whether an already approved treatment can be used effectively in new ways (for example, the drug gemcitabine was at first approved as a treatment for pancreatic cancer but was later tested and approved for use in treating certain types of lung cancer).
The FDA must certify that a treatment has shown promise in the laboratory and in animals before human testing can begin. All clinical trials are supervised by an independent board of experts, which ensures that the sponsor of the treatment can stop the study early if major problems develop or if unexpected benefits are found. (See Monitoring the Safety of Clinical Trials.) The potential benefits and risks of any clinical trial must be carefully weighed by the researchers conducting the study and the patients who decide to participate.
Different Kinds of Clinical Trials
Cancer clinical trials can focus on either treatment or prevention. Treatment trials test new ways of curing or relieving the symptoms of cancer in people who have the disease. Prevention trials enroll people who are at increased risk for developing cancer. In some cases, prevention trials test the effectiveness of an intervention such as a change in lifestyle; others test whether a drug can help to prevent cancer. Using drugs in this way is called "chemoprevention."
Most clinical research that tests a new treatment moves in an orderly series of steps, from early phase I clinical trials to more definitive phase III trials. Each kind of clinical trial asks certain crucial questions.
- A phase I trial asks: how does the treatment affect the human body, how should it be given, and what dosage is safe?
- A phase II trial asks: does the treatment do what it's supposed to do, and how well does it work?
- A phase III trial asks: is the new approach better than current medical practice?
Phase I: What Dosage Is Safe?
In phase I treatment trials, a small number of volunteer patients (usually between 15-30) are given the experimental treatment in gradually larger doses to test for any side effects or complications. The researchers conducting the trial will also try to determine what a safe dose would be and how it should be given.
Laboratory studies during this period also yield information about how the treatment is processed in the body - how the drug or biologic itself changes, which organ systems it affects, how long it stays in the body, and how the body gets rid of it. About 70 percent of drugs tested in phase I trials are successful enough to go on to phase II trials. (See the FDA's Table of Drug Testing in Humans.)
Often, cancer patients who decide to participate in phase I trials are no longer benefitting from the standard drugs that are available, or they have a type of cancer for which there is no effective treatment. They may benefit from the treatment they receive in a phase I trial, but the main goal at this early stage is to see how the new treatment affects the body and to determine the right dose and treatment schedule for further testing in phase II studies.
Phase II: Does the Drug Do What It's Supposed to Do?
Phase II treatment or chemoprevention trials test how well a new treatment (or new use of an existing treatment) works against cancer. In addition, by recording information about the treatment's side effects and complications, researchers learn more about its short-term safety.
In phase II trials, people with specific types of cancer or with certain cancer risk factors are given the medication to see whether or not it has a beneficial effect. Each phase II study usually focuses on 30-50 patients. Phase II bridges the information gap between "is the treatment safe?" to "will it actually work in a specific situation?"
People enrolling in phase II trials may find that beneficial effects, when they occur, may still be mixed with side effects and complications that the researchers did not expect. Only about 33 percent of the drugs tested in phase II trials are found safe and effective enough to go on to phase III. (See the FDA's Table of Drug Testing in Humans.)
Phase III: Is the New Approach Better Than Current Medical Practice?
By the time a new cancer approach reaches a phase III clinical trial, it has been shown to be safe at a certain dosage and to be effective against a certain kind of cancer. Now researchers need to figure out whether it is superior to the approaches currently used against that disease. "Superior" can mean that the treatment has a more powerful anti-cancer effect, or that it works just as well but with more acceptable side effects.
To achieve these goals, phase III trials typically enroll several hundred, or even thousands, of people from across the country or around the world. Through a process called randomization, each person is assigned by chance (usually by computer) either to a group that will receive the current standard treatment or a group that will receive the experimental one. Random assignment ensures that participants in the two groups are as similar as possible; only if the groups are similar can their test results be reliably compared to see which approach worked best. Randomization is ethically acceptable because doctors do not know at this point whether the new approach really represents an advance - it might actually work less well than the current standard.
For more information about phase III trials, see Which Study Results Are the Most Helpful in Making Cancer Care Decisions?.
Frequently Asked Questions About Phase III Clinical Trials
- Does the way phase III trials are designed mean I might enter a trial and receive no treatment at all?
As already discussed, it is very rare for a treatment trial to be designed with a control group that receives no treatment at all. This might happen only in cases of cancer where there is no effective treatment available. In the vast majority of cases, all participants receive at least the standard treatment.
Prevention trials are different because they enroll healthy individuals with an identified risk factor or factors for developing a specific type of cancer, to test whether or not a drug shows promise in lowering the cancer's incidence. Thus, since few drugs have yet been shown to reduce the risk of cancer, phase III prevention trials typically include a group that does not receive the drug under investigation and one that does. However, once the prevention trial shows that the new drug has a significant effect in preventing the development of cancer, the sponsor will stop the study to make sure that all participants can receive the new drug.
- How will I know the risks and benefits before I enter the trial?
Before you can can enter a phase I, II, or III trial, you must go through a process called informed consent. During this process, you would be fully informed about the trial through both a written document and an oral discussion, which review what the trial is meant to test, how long it should last, what procedures will be performed, if randomization is involved, and what is known about the possible risks and benefits. So you would know exactly how the trial is designed and what your chances are of being assigned to any one group.
Those who decide to enroll in a study are willing to accept certain risks (some of which may not even be known) to help evaluate a potentially beneficial new treatment or prevention agent. Some people are not comfortable with this and decide not to enroll. Participation is an individual decision, but in all cases it should be an informed decision. (For more information, see A Guide to Understanding Informed Consent.)
- Let's say I'm in group A in a phase III study and all the patients in group B begin to show marked improvement. What happens to me?
All results are carefully monitored during the trial by a Data Safety and Monitoring Committee, whose members are not connected to the trial in any other way. (See Monitoring the Safety of Clinical Trials.) If early results indicate a clear advantage for one of the groups, the sponsor of the study may choose to end the trial early and establish a protocol allowing wider use of the drug before final approval for marketing. If a drug is shown to have a strongly negative effect, the trial is stopped as soon as this is known.
- After the trial is over, can I find out which group I was in?
At the completion of a trial (which may sometimes include follow-up data collection), all patients have access to the results of the study and to information about their own participation. In many cases, however, this information is not available right away. Participants sometimes need to wait for data to be compiled, for other participants to finish their parts of the trial, and for investigators to analyze the results.
- How do I find out about participation in clinical trials?
You should consult first with your attending physician about whether participation in such a study is appropriate for you. He or she may already know of a study or be able to direct you to a nearby resource. One of the best online resources is NCI's searchable database of clinical trials, which includes information, contact names, and phone numbers for clinical trials being conducted nationwide. Many NCI-designated Cancer Centers across the country also offer access to clinical trials.
Getting Treatments to Patients Who Need Them
Not everyone is eligible to participate in a clinical trial. Some patients do not fit the exact requirements for studies, some have rare forms of cancer for which only a limited number of studies are underway, and others are too ill to participate. Working with the National Cancer Institute (NCI) and other sponsors, the U.S. Food and Drug Administration (FDA) has established special conditions under which a patient and his or her doctor can apply to receive cancer treatments that have not yet been through the approval process. In the past, these special case applications for new treatments were grouped under the name compassionate uses. More recently, such uses have expanded to include more patients and more categories of experimental or investigational treatments.
Access to Investigational Drugs
The process of new drug development has many parts. In the United States, until a drug has been approved by the FDA, it can generally be obtained only through several mechanisms: enrollment in a clinical trial studying the drug, an expanded access program, or special exemption/compassionate use programs. See Access to Investigational Drugs: Questions and Answers for more information.
Group C Drugs
In the 1970s, researchers from the NCI became concerned about the lag between the date when an investigational drug was found to have anti-tumor activity and the time that drug became available on the market. Working with the FDA, the NCI established the Group C classification system to allow access to certain drugs.
Group C drugs are provided to properly trained physicians who have registered using a special form to assure that their patient qualifies under guidelines - or protocols - for the drug. Each Group C drug protocol specifies patient eligibility, drug use, and how information about the patient's use of the drug should be reported.
Group C designation (now called Group C/Treatment INDs) speeds new drugs to patients who need them most. The process also allows the NCI to gather important information on the safety and activity of the drugs as they are used in the "real world" prior to their final FDA approval. Group C drugs are always provided free of charge, and the Centers for Medicare and Medicaid Services provides coverage for care associated with Group C therapy.
In 1987, the FDA began authorizing the use of new drugs still in the development process to treat certain seriously ill patients. In these cases, the process is referred to as a treatment investigational new drug application (Treatment IND). Clinical trials of the new drug must already be underway and have demonstrated positive results that can be reproduced. The FDA sets guidelines about what constitutes serious and life-threatening illnesses, how much must already be known about a drug's side effects and benefits, and where doctors can obtain the drug for treatment. For many seriously ill patients, the risks associated with taking a not-yet-completely proven drug are outweighed by the possible benefits.
Accelerated approval is the short-hand term for the process by which the FDA quickly conducts its review of new treatment applications while also putting new safeguards in place. Accelerated approval is based on surrogate endpoint judgments: the FDA can grant marketing approval to drugs and treatments that, according to certain indicators, prove they are likely to have beneficial effects on a disease or condition, even before such direct benefits have been shown clinically. Accelerated approval does not mean that additional clinical trials are not needed or that the FDA stops gathering information about the effects of the drug; a follow-up study is required to demonstrate activity by more conventional endpoints.
Q&A: Off-Label Drugs
What is off-label use?
Off-label use refers to the use of an approved treatment for any purpose, or in any manner, other than what is described in the treatment's labeling. Off-label use of an approved treatment is not the same as expanded access or special exemption, which are mechanisms allowing patient access to investigational treatments not yet approved by the FDA. (See Access to Investigational Drugs: Questions and Answers for more information.)
New treatments can be legally marketed in the United States only after approval by the U.S. Food and Drug Administration (FDA). Approval is the final stage of a multi-year process of study and testing to establish that the new treatment is safe and effective for the proposed use.
A cancer treatment rarely receives approval for general use against cancer. Instead, a treatment is approved for use in treating a specific stage of a particular kind of cancer, for which it has been tested in patients. The specific approved use is called an indication. The indication is described in the labeling for the drug or biologic, which consists of a printed insert included in the treatment's packaging. The insert also describes in detail the chemical composition of the treatment, how it works in the body, and the possible adverse effects of taking it.
However, the FDA - although responsible for ensuring that a treatment is safe and effective for the specific approved indication - does not regulate the practice of medicine. This means that once the FDA approves a treatment, licensed physicians can prescribe it for any purpose they consider medically appropriate.
Off-label uses may include giving an approved treatment:
- for a disease other than the disease it is approved for,
- at a different dose or frequency than specified in the product's labeling, or
- to treat a child when the product is approved to treat adults.
An off-label use of a product can cease to be off label if the product's maker submits a supplemental application and obtains FDA approval for the new use. The FDA encourages, but does not require, drug makers to do this.
To submit a supplemental application, the drug maker must conduct studies to show that the product is safe and effective for the proposed new use. Unless the drug company expects to gain a significant commercial benefit from expanded approval of a drug already on the market, it may decide not to invest time and money in such additional studies.
Why is off-label use of drugs so common in cancer treatment?
A 1991 study by the U.S. General Accounting Office found that one-third of the drug treatments performed by cancer doctors were off-label; more than half of cancer patients received at least one drug for an off-label indication. A 1997 survey of 200 cancer doctors by the American Enterprise Institute and the American Cancer Society found that 60 percent of them prescribed drugs off-label. Frequently the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs.
Off-label use of drugs is widespread in cancer treatment for several reasons.
- Some cancer drugs are found to be effective against a variety of tumor types.
The mechanism of action of a drug or biologic (the way it works in the body) often suggests that it might be effective against tumor types other than those for which it is approved.
For example, cisplatin (brand name, Platinol®) works to halt the uncontrolled growth of cancer cells by interrupting the copying of DNA in growing cells. Because uncontrolled cell growth is part of most cancers, cisplatin is often used in the treatment of thyroid and lung cancers although it is only approved to treat bladder, testicular and ovarian cancers.
Some cancer drugs are approved because they effectively act on a specific biological target present in a particular type of tumor. Examples of such targeted drugs include:
- imatinib mesylate or STI571 (brand name Gleevec™), which blocks the bcr-abl protein in chronic myelogenous leukemia,
- trastuzumab (brand name Herceptin®), which blocks the HER 2 protein in breast cancer, and
- tamoxifen (brand name Nolvadex®), which blocks the estrogen receptor in breast cancer.
However, once a drug is on the market further research may show that it also acts on different biological targets present in other kinds of cancer. Doctors may then begin to use the drug off label to treat those other cancers.
- Cancer chemotherapy often involves the use of multiple drugs.
Multiple-drug treatment regimens have been shown to be effective in several types of cancer, including lymphoma, leukemia, bladder, testicular, and breast cancer. The regimens might include one or more drugs not approved specifically for that disease. Also, the FDA generally does not approve multidrug regimens themselves, in part because such regimens are so numerous as to make separate approvals impractical. Multidrug regimens change over time as doctors try different combinations and observe which regimens seem to produce the greatest benefit for patients.
- Cancer treatment is always evolving.
Researchers continually conduct studies to determine new uses for already marketed drugs and to find effective combinations of drugs for new indications. The results of these studies are published in peer-reviewed medical journals. When a new treatment approach seems to produce better outcomes for patients, other doctors adopt it and it may become a new standard of care.
Can off-label drug use be harmful?
Use of a drug off label may cause harm when the drug's effect against a kind of cancer has not been demonstrated and there is no medical reason to believe the drug might be an effective treatment for that kind of cancer. All drugs have side effects; the side effects of cancer drugs vary depending on the kind of cancer being treated. When a drug's effect against a type of cancer has not been demonstrated, and its side effects are unknown, the possible risks of giving the drug may outweigh the possible benefits.
For example, the FDA approved the use of Gleevec to treat chronic myelogenous leukemia (CML). However, as of November 2001, its effect against chronic lymphocytic leukemia (CLL) had not been studied. The biological process that leads to the development of CLL is quite different from that which causes CML. Currently, there is little scientific data to support using Gleevec to treat CLL. Furthermore, it is not known what side effects the drug might cause in patients with CLL. For these reasons, the off-label use of Gleevec to treat CLL is generally not advised.
Will my health insurance cover drugs used off label for cancer treatment?
Some managed care organizations and health insurance providers decline to reimburse the cost of drugs used off label to treat cancer. Some insurers argue that when a drug is used for an unapproved indication, the use is experimental and therefore, excluded from coverage.
However, because changes frequently occur in the standard of care for cancer treatment, some insurance providers may be unaware of new combination drug regimens or new uses for approved drugs. In some cases, insurers may attempt to limit a doctor's choice of drugs to those that are lower in cost.
Since drugs used off label are often the standard of care for a particular kind of cancer, insurers' denial of coverage for such treatment means that patients may not receive what their doctors consider the best available treatment for their disease. To address this problem, federal and state lawmakers have passed laws that require coverage of off-label drug use for cancer treatment when the use is documented in certain authoritative drug reference books or in the medical literature.
The U.S. Congress passed a law in 1993 requiring Medicare (http://www.medicare.gov/), the federally funded health care program for elderly and disabled people, to cover off-label drugs used in cancer treatment when the use is supported by:
- a citation in at least one of the following authoritative drug reference books.
- two or more peer-reviewed articles published in respected medical journals.
Medicare coverage policy is not binding on private health insurance providers, although some insurers have adopted coverage policies consistent with Medicare's. Many states (see below) have passed laws or issued regulations requiring state-regulated private health insurers to provide coverage similar to Medicare's for off-label drug use in cancer treatment. However, organizations (usually large companies) funding their own health insurance coverage are exempt from these state laws and regulations, although many comply voluntarily.
The complexity of the laws and regulations governing health insurance coverage means there is no simple answer to the question of whether your own health plan covers drugs used off label for cancer treatment. When considering off-label drug use, you and your doctor should carefully check your plan's coverage policy.
If coverage is initially denied, it may be helpful for the doctor to provide the insurer with copies of peer-reviewed journal articles or other documents supporting the proposed off-label use.
What questions should I ask my doctor about off-label drug use?
The following are some questions you may wish to ask your doctor about off-label drug use in cancer treatment.
- What evidence is there to support the off-label use of this drug to treat the type of cancer that I have?
- Is the off-label use of this drug likely to be more effective that the use of an approved drug?
- What are the risks and benefits of off-label treatment with this drug?
- Will my health insurance cover off-label treatment with this drug?
- If my treatment involves a multidrug regimen and one of the drugs is being used off label, will my health insurance cover it?
What states require insurance coverage of off-label cancer drugs?
As of November 2001, the following states required some state-regulated health insurance providers to cover the off-label use of FDA-approved drugs for cancer treatment. Except where indicated, state law requires the coverage.
Although the wording of these laws varies from state to state, most require off-label uses to be covered when documented in authoritative drug reference books. Many, but not all, laws also require coverage when an off-label use is documented in the peer-reviewed medical literature.
A Short History
FDA Regulations and U.S. Drug Law
The present system of FDA regulation has evolved over the course of this century. Before 1906, there were no laws guaranteeing the quality of medicines and no regulations requiring a doctor's prescription for medications. So-called "patent" medicines, many containing dangerous ingredients, were advertised with outlandish health claims and widely marketed in the United States.
By the turn of the century, it was apparent that some form of regulation was necessary. The following major developments in U.S. drug laws and FDA regulations demonstrate how the federal power to regulate drugs, which began as a simple effort to identify fraudulent medicine, has evolved into a complex system dedicated to ensuring the health and safety of the public. They also suggest how the government has tried to balance public safety with the desire to widen access to promising drugs for life-threatening illnesses.
- Food and Drugs Act (1906): This law targeted false and fraudulent "patent" medicines and required that drugs meet standards of strength and purity. A few years later, this act was extended to cover not only a ban on false or misleading labeling pertaining to ingredients, but also to claims of effectiveness. The 1906 act lacked "teeth"—it was difficult to enforce and was very narrowly applied.
- Federal Food, Drug, and Cosmetic Act (1938): It was not until 1937, when 107 people died from a poison in the patent medicine marketed as "Elixir Sulfanilamide," that Congress passed a more stringent drug law. The so-called FDC Act required manufacturers to prove the safety of drugs, authorized factory inspections, and established penalties for fraudulent claims and misleading labels.
- Durham-Humphrey Amendment (1951): This was the first federal law requiring a physician’s prescription for drugs "unsafe for self-medication."
- Kefauver-Harris Drug Amendments (1962): In Western Europe, thousands of babies were born with birth defects because their mothers had taken the sedative thalidomide during pregnancy. A delayed review process prevented the drug from being marketed in the United States, where it was being studied in a large number of subjects.
In response to this tragedy, the Kefauver-Harris amendment mandated that manufacturers prove their drugs were effective for specific medical purposes, as well as safe, through "adequate and well-controlled" studies. This law applied retroactively to all drugs introduced since the 1938 FDC Act. Firms were also required to report all adverse reactions to the FDA and to include complete information (about adverse effects as well as benefits) for physicians in advertisements. For the first time, informed consent was required from patients participating in studies of a new drug.
- See the A Guide to Understanding Informed Consent for more information about the informed consent process.
- See the A Guide to Understanding Informed Consent for more information about the informed consent process.
- Orphan Drug Act (1983): Orphan drugs are intended to treat rare diseases and conditions for which adequate drugs have not yet been developed. In the past, manufacturers had been reluctant to produce such drugs: the complex process of research and marketing a drug for only a small group of potential users may bring little or no profit. This law provided manufacturers with tax benefits for portions of their research and development costs. Furthermore, if a company developed an orphan drug, it was granted exclusive marketing rights for seven years.
- Drug Price Competition and Patent Term Restoration Act (1984): This law made generics, often sold at lower prices than brand-name drugs, more easily available. It also allowed drug manufacturers to "restore" part of the time spent researching drugs before approval to the patent life of the drug.
- Revision of Regulations for New Drug Application Regulations (1985): Changes in requirements for manufacturers called for better organized applications, clearer data, more information on adverse reactions, quicker problem-solving, and in some instances provided for approval based on foreign studies.
- Treatment Use of Investigational Drugs (1987): New regulations allowed "expanded access" protocols for promising investigational drugs. In less-restricted studies, researchers could learn more about the drug while also providing treatment for people with no effective alternative. These regulations still required researchers to formally investigate the drugs in well-controlled studies and provide reasonable evidence of effectiveness.
- Accelerated Approval (1987): Before this rule, drugs could be judged only according to their effect on the illness or patients’ length of survival. This regulation allowed the FDA to approve drugs based on a reasonable "surrogate endpoint" -- that is, an effect of the drug on some physiological process associated with the disease (an example would be CD4 cell counts, which measure the strength of the immune system).
The "surrogate" is used to predict whether a new drug will offer therapeutic benefit. The regulation offered a way of making an apparently promising drug available without having to wait until the end of the clinical trials process. Under these rules, the FDA approves the drug only on the condition that the sponsor confirm actual clinical benefit through well-controlled studies.
- Procedures for Subpart E Drugs (1988): These procedures were designed to encourage early cooperation among manufacturers, clinical researchers, and the FDA to get new drugs to patients with life-threatening or severely debilitating illnesses as quickly as possible. For example, manufacturers may request to meet with the FDA early in the drug development process to reach agreement on the design of preclinical and clinical studies. Similar meetings may also be called after phase I testing to discuss how to design phase II clinical trials, with the goal that the data from phase II trials will provide sufficient data on the drug's safety and effectiveness for a decision about approval of the drug.
- Parallel Track Mechanism (1992): This U.S. Public Health Service policy made promising investigational drugs for AIDS and other HIV-related diseases more widely available under "parallel track" protocols at the same time that controlled clinical trials continued. The system is designed to make the drugs available to patients who have no therapeutic alternatives and cannot participate in the controlled clinical trials.
- Generic Drug Enforcement Act (1992): This law imposed disbarment and criminal convictions for fraudulent and illegal activities in new drug applications for generic drugs.
- Prescription Drug User Fee Act (1992): Manufacturers were now required to pay fees for certain new drug applications. The funds generated have been used to add review staff at the FDA to accelerate new drug reviews. Review times for new drug applications were set at 12 months for standard applications and at six months for priority applications; in other words, the FDA had to take action on the application within that time frame. The order in which applications are looked at is determined with the aid of a classification system, which gives priority to drugs with the greatest potential benefit.
For example, all AIDS drugs receive the highest priority, and all drugs that offer a significant medical advance over existing therapies for any disease are considered "priority drugs." The breast cancer drug Herceptin, approved in September 1998, was assigned to priority review.
- Food and Drug Administration Modernization Act (1997): Extended the User Fee Act another five years and lowered the review times for standard new drug applications to 10 months.