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The Regulatory Process

Researchers and other scientists involved in the drug development process, including drug companies, government agencies such as the National Cancer Institute (NCI), and academia, must receive regulatory approval from the Food and Drug Administration (FDA) to test drugs in humans and make them available for public use. The FDA reviews specific types of applications from study sponsors.

By law, the FDA must review all test results from tests of 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. This was determined by the testing process begun well before the first person used the treatment, with preliminary research and animal testing.

This section explains more about the types of research, costs, time required, FDA applications, and types of FDA review involved in the drug development process.

  • Application Needed Before A Clinical Trial
  • Application Needed After A Clinical Trial
  • Types of FDA review
  • Other Issues


Applications Needed Prior to Starting a Clinical Trial

1. Investigational New Drug Application (IND)

If a treatment seems to be promising in lab tests, the Drug Company or sponsor must apply for FDA approval to test it in human clinical trials. This application is called an Investigational New Drug (IND) application. The FDA reviews the IND application for safety to assure that research subjects will not be subjected to unreasonable risk. If the application is approved, the candidate drug usually enters a Phase 1 clinical trial.

The application must include:

  • Safety Information - results of animal pharmacology and toxicology studies.
  • Manufacturing information - pertaining to the chemical composition, manufacturing methods, stability and controls used.
  • Clinical protocols and investigator information - detailed protocols for proposed clinical studies and information on the qualifications of clinical investigators.

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There are three IND types:

  • An Investigator IND - submitted by a physician who both initiates and conducts the investigation, and under whose immediate direction the investigational drug is administered or dispensed
  • An Emergency Use IND - authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND
  • A Treatment IND - for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions

Although it may take 6 months or more to prepare an application, once the IND is submitted, the FDA has only 30 days to respond. During this time, the FDA has an opportunity to review the IND for safety to make sure that research subjects will not be exposed to unreasonable risk.


2. Access to Investigational Drugs (faster route than traditional IND process)

Group C Drugs (also called Treatment INDs)

In the 1970's, researchers from the NCI became concerned about the lag time 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 patients access to certain investigational drugs.

Group C drugs are provided to properly trained physicians who have registered using a special form to assure that their patients qualify under guidelines or protocols for the drug. Each Group C drug protocol specifies patient eligibility, drug use, and how information about the patients' 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.


Application Needed After Clinical Trials

The process of new drug development has many stages. In the United States, until a drug has been approved by the FDA, it can usually be obtained only through several mechanisms: enrollment in a clinical trial studying the drug, an expanded access program, or special exemption/compassionate use programs.

1. New Drug Application (NDA)

If the treatment or drug makes it through the clinical trials process - that is, if the studies show the treatment is safe and effective - the sponsor may submit another application to the FDA. In the case of drugs, it's a New Drug Application (NDA); for biologics, it's a Biologics License Application (BLA). The application must include the following:

  • Safety data
  • Efficacy (does it work) data documented through clinical trials
  • Chemical makeup
  • How the drug or biologic is made, processed, and packaged
  • Quality control standards

An FDA Advisory Board Committee analyzes the data in the application to assess if a specific indication (standard use) is worthy of approval for public use.

For more information on the regulatory process go to:
FDA U.S. Federal Food and Drug Administration -
New Drug Application (NDA)


Types of FDA review for a New Drug Application (NDA)

Although the approval process is long and arduous, the FDA has tried to cut through the some of the red tape by providing several different approval routes.

  • Standard Review
  • Priority review
  • Accelerated review
  • Fast Track Review

Standard Review

Standard reviews are given to NDA's that do not represent an advance in the treatment for a disease. A standard review must be completed within 10 months of the application.


Priority Review

A priority review is granted for a new drug that, if approved, would be a significant improvement over current treatment options for a disease fulfilling an unmet medical need. While a standard review must be completed in 10 months, a priority review must be completed in 6 months. Drugs that receive a priority review designation are often approved in much less than 6 months. Gleevec was approved in 8 weeks in June 2001, and Eloxatin was approved in 7 weeks in August 2002.


Accelerated Approval

To be considered for accelerated approval, a drug must treat a serious or life threatening illness and provide a meaningful increase in therapeutic benefit to patients over existing treatments.

Accelerated approval uses surrogate endpoints that measure treatment effects that may correlate with clinical benefit. As an example, tumor shrinkage that occurs when using a drug may or may not correlate with increased survival.

However, even though a new drug may be approved with an accelerated approval, the drug company must conduct Phase IV clinical trials to demonstrate meaningful clinical benefit, such as prolonging patients' lives or improving their quality of life. Generally, any accelerated approval drug receives a priority review.


Fast Track

A drug may receive a fast-track designation if it is intended to treat a serious or life-threatening condition and demonstrate the potential to address an unmet medical need.


Fast tracking actually has little effect on the patient's access to the drug.

It means that the drug company is engaged in continuous discussions with the FDA about the drug's development plan. The company may also submit its NDA to the FDA in sections that can be reviewed while the company prepares other sections of the application for submission to the FDA. This is also known as a "rolling submission."


Other Issues

Funneling Data into Numbers
  • For every 50,000 to 5 million compounds screened, about one thousand will be deemed worthy of pursuing, and only about 10 will be tested using clinical trials.
  • Only about one out of every ten new drugs that enter clinical trials will have adequate safety and efficacy data for FDA approval.


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.

A cancer treatment rarely receives approval for general use against cancer. Instead, a treatment is approved for treatment at 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, consisting 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
  • To treat a child when the product is approved only for treatment of adults.



What questions should I ask my doctor about off-label drug use?

  • What evidence is there to support the off-label use of this drug to treat the type of cancer 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?


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.




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