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The FDA Clinical Trial Approval Process Understanding Clinical Trials Important Questions to Ask About Clinical Trials Finding a Clinical Trial

The FDA Approval Process

    Clinical Trial Doctors
  1. What happens during each stage of the drug discovery and approval process?

    1. Basic Research/Drug Development

    2. Pre-Clinical/Translational Research

    3. Phase 1 Clinical Trial

    4. Phase 2 Clinical Trial

    5. Phase 3 Clinical Trial

    6. FDA Review/Manufacturing

    7. Phase 4 Clinical Trial/Post-Market Surveillance/Report Adverse Events

  2. How long does it take to complete each stage?

  3. How many potential treatments (i.e., drugs, devices, or other study topics) typically need to be tested at each stage before one successful treatment obtains FDA approval?

  4. How much does it cost to bring one FDA-approved product to market?

  5. How many volunteers are enrolled in each stage of the process?

  6. What parts of the clinical trial process are funded by BrightFocus? How are private, non-profit organizations important for keeping innovations “alive” and moving down the clinical trial “pipeline”?

 

  • What happens during each stage of the drug discovery and approval process?

    • Basic Research/Drug Development

      Clincal Researcher Looking Through a MicroscopeNew potential treatments* are discovered at this stage. At this point, the investigators test their ideas at the laboratory bench and in machines or “test tubes,” but the experiments can also involve cells and specially-bred animals.  The potential treatments can be made from all sorts of materials, including natural or synthetic chemical compounds and bioengineered or biological materials, like antibodies. Some are “repurposed,” meaning that they have been approved for treatment of one or more disease(s) and are being tested for their potential to treat another disease.

      Much of this basic research is done to determine more details about the disease studied and what proteins, genes or system processes contribute to the development and/or progression of the disease. These clues to potential avenues for treatment are essential to be able to design drugs for further testing. The clues can also help with designing large “high-throughput” drug screening techniques.

      Only potential treatments that have the best evidence for potential safety and effectiveness in animals and humans move forward to Pre-Clinical/Translational Research. The list of treatments is whittled down to much smaller numbers as some make it past the tests and others do not.

    • Pre-Clinical/Translational Research

      MicroscopeThe potential treatments* identified to have therapeutic potential in the Basic Research stage are then tested in animals for their ability to be delivered to the target organ(s) and tissue(s), to determine how well they are cleared from the system, and to determine their toxicity, safety, and effectiveness. Many potential treatments that do not pass certain tests may be “dropped” at this stage, since they may seem too risky for further development for use in patients.

      Normally, one of the Pre-Clinical tests must involve a type of animal that has a condition similar to one or more symptoms held by human patients of the particular disease for which a treatment is being pursued.

      Translational Research involves studies that give evidence that the effectiveness shown for a particular treatment has a good chance that similar results could occur in humans. Essentially, the research must show that the results can “translate” into helping patients who have the disease or condition.

      Many promising treatments are never tested in clinical trials due to lack of funding or other business difficulties. In many cases, further financial support or partnerships are needed to help “bridge the gap” across the “Funding Valley of Death”** to begin Phase 1 Clinical Trials.

      Once the trial sponsor has identified a promising treatment, they prepare and send an Investigative New Drug (IND) Application to the FDA, for them to review the evidence that a potential treatment is appropriate for testing in human clinical trials. The FDA wants to assure that the proposed drug does not put humans at an unreasonable risk for harm. At this point, the sponsors also submit their plans for future clinical trial testing. The FDA requires that the trial volunteers will have proper protection and informed consent (i.e. participants will be given enough information about the relevant medical facts and potential risks of the proposed treatments, as explained in easy-to-understand language). If a treatment or clinical trial design does not meet the FDA’s standards or requirements, the sponsor will not be given permission to proceed with this treatment to human clinical trials.

    • Phase 1 Clinical Trial

      Doctors Reviewing Clinical Trial InformationThe drug treatments that make it through the Pre-Clinical/Translational Research step, and successfully cross the “Funding Valley of Death,”** then enter what is called the Phase 1 Clinical Trial. There are three phases to complete in the clinical trial process before a sponsor can submit their treatments* to the FDA for consideration to be sold on the market. Each stage of a clinical trial has its own purpose in ensuring that a treatment is safe and effective for use by the public.

      The purpose of Phase 1 is to ensure that the treatment is safe in humans, and to determine how and where it distributes within the body. This testing normally takes place with a small group of healthy volunteers. The trial sponsor monitors for potential “serious adverse events”— that is, any toxic, undesirable, or unwanted effect that causes death or danger to health, like a disability or permanent damage, birth defect, heart attack, or other serious medical condition.

      At the end of Phase 1, the results are collected, analyzed, and submitted to the FDA for permission to proceed to Phase 2 Clinical Trials. However, if the results show that the treatment was associated with one or more serious adverse events, then the FDA may not give permission to proceed to Phase 2. Normally, testing of that treatment is discontinued or “drops out” of the running for making it to the market. If the trial meets the primary outcome(s), as defined in the initial study design, then the FDA permits the treatment to proceed to Phase 2 Clinical Trial(s).

      Sometimes, a potential for treatment of one disease has already been approved for use in treating another disease (for example, a cancer drug may be tested for treatment of Alzheimer’s or macular degeneration). This is called “repurposing” a drug, and sometimes this may shorten the clinical trial, or permit the acceleration into Phase 2 Clinical Trials, because the Phase 1 safety profile has already been tested in the previous clinical trial.

    • Phase 2 Clinical Trial

      Doctors Reviewing a Medical ScanOnce a treatment* is considered to be safe for human consumption in Phase 1, the clinical trials then move into Phase 2. The purpose of a Phase 2 Clinical Trial is to determine the right dosage and effectiveness in treating that particular disease. This testing normally takes place with a larger number of volunteers who have the disease. There are many different ways that a trial sponsor can conduct their trial, but the plan normally involves assigning participants to different treatment groups, where each group can receive different doses or delivery of the treatment. Normally, there is a “control group” that receives either the current standard of care, if another type of treatment is already available on the market for that disease, or they may receive what’s called a “placebo” treatment, such as a sugar pill or harmless injection that does not contain the treatment.

      After completion of Phase 2, the results are collected, analyzed, and submitted to the FDA for approval to proceed to Phase 3 Clinical Trials. The health of the group(s) of patients who received the different types of treatment is compared to the control groups. However, if the results show that the treatment did not work better than the current standard of care or even caused acceleration of the disease or other unexpected serious adverse events, the FDA may not give permission to proceed to Phase 3. Normally, testing of that treatment is discontinued or “drops out” of the running for making it to the market.

    • Phase 3 Clinical Trial

      Doctors Discussing Clinical Trial ResultsA Phase 3 Clinical Trial involves a much larger group of volunteers and primarily focuses on determining whether the treatment* would be safe and effective for a wide variety of people. The plan normally involves assigning participants to treatment or control groups. There can be more than one treatment group, especially if the treatment involves a combination of drugs or different components. Normally, the control group receives the current standard of care, if another type of treatment is already available on the market for that disease, or they can receive a “placebo” treatment, such as a sugar pill or harmless injection that does not contain the treatment.

      After completion of Phase 3 Clinical Trials, the health of the patients who received the different types of treatment are compared to the control groups. However, if the results show that the treatment did not work better than the current standard of care or even caused acceleration of the disease or other unexpected serious adverse events, then the FDA may not give permission to proceed to apply for a New Drug Application (NDA). This special NDA contains all of the discoveries made at every stage of the process (starting from the Basic Research/Drug Discovery through to the results of the Phase 3 Clinical Trials), and is submitted to the FDA for their consideration to approve the sale of the treatment on the market.

    • FDA Review/Manufacturing

      The time it takes for this process is variable due to a number of factors, including whether the treatment* is a new kind of drug or an old drug repurposed for another type of treatment, whether there are less than 200,000 people in the United States who have the disease (called an orphan disease), and other considerations. The FDA only approves drugs that they determine to have solid evidence of safety and effectiveness for public use or consumption. In general, the policy is to review the application (called a New Drug Application or NDA) within 6 months of submission and notify the applicant if it will require more review time to ensure that all of the facts have been taken into consideration for the public’s safety and the treatment’s effectiveness.  A typical application is tens of thousands of pages long.

      This stage also involves a review by the FDA to determine if the professional package labeling of the product adequately educates health professionals and the general public, including information on its proper use and potential risks or side effects. In addition, the FDA inspects the facilities where the drug or product will be manufactured. Even after approval and appearance on the market, the FDA continues to monitor for serious adverse events and other dangers to the public.

    • Phase 4 Clinical Trial/Post-Market Surveillance/Report Adverse Events

      After approval by the FDA and manufacturing of the drug on a large scale by the sponsor, the process enters what is called Phase 4 Clinical Trial/Post-Market Surveillance/Report Adverse Events. For at least the entire time a treatment* is on the market, the FDA monitors for public safety and potential serious adverse events. In particular, the FDA has a service called MedWatch, where health professionals, the sponsor, or anyone in the public can report a serious adverse event they believe is associated with a particular drug or treatment (reports can be made online, by mail or e-mail, or by phone). In addition, there may be mandatory or optional Phase 4 Post-Marketing Clinical Trials to obtain further information about the risks, benefits, and long-term effects, or to test the product in special patient populations. The FDA provides a wide variety of information about all of the drugs currently for sale on the U.S. market (see Sources of Information).

  • How long does it take to complete each stage?

    It can take up to 15 years to bring a product to market and then still require additional post-marketing Phase 4 studies:

    • Basic Research/Drug Development and Pre-Clinical/Translational Research (combined): 3 to 6 years
    • Phase 1, Phase 2, and Phase 3 Clinical Trials (combined): 6 to 7 years
    • FDA Review/Manufacturing: 0.5 to 2 years
    • Phase 4 Clinical Trial/Post-Market Surveillance/Report Adverse Events: 0.5 to 10 years (at least as long as the drug is on the market); Specific Phase 4 trials are optional and can be of variable length if assigned by the FDA as a requirement for a treatment’s approval. For example, some Phase 4 trials could last 5-10 years in order to see the effect of the treatment on populations of specific concern to the FDA. The post-market surveillance for adverse events begins immediately after the drug is available to the public and continues for at least as long as the drug is available on the market.

  • How many potential treatments typically need to be tested at each stage before one successful treatment obtains FDA approval?

    • Basic Research/Drug Development: 5,000 to 10,000 potential treatments
    • Pre-Clinical/Translational Research: 250 potential treatments
    • Phase 1/Phase 2/ Phase 3 Clinical Trials (combined): 5 potential treatments
    • FDA Review/Manufacturing: 1 potential treatment

  • How much does it cost to bring one FDA-approved product to market?

    The final cost of bringing one product to the market depends on a number of variables, including the amount of time needed to obtain promising treatments, the number of subjects enrolled in each phase of the clinical trials, the complexity of the product delivery, the disease being treated, time needed for data assessment, and other considerations. However, various sources indicate that it can cost more than $1 billion to bring one product to the market, including approximately $50-840 million to bring treatments through the stages of Basic Research/Drug Development and Pre-Clinical/Translational Research, and approximately $50-970 million to complete the Clinical Trials (Phases 1, 2, and 3).

  • How many volunteers are enrolled in each stage of the process?

    • Basic Research/Drug Development and Pre-Clinical/Translational Research: There are no human volunteers involved in these stages of the process.
    • Phase 1 Clinical Trials: Typically from 20 to 50 volunteers.*
    • Phase 2 Clinical Trials: Typically from 100 to 500 volunteers.*
    • Phase 3 Clinical Trials: Typically from 1,000 to 5,000 volunteers.*
    • FDA Review/Manufacturing:  No enrollment of volunteers at this stage.
    • Phase 4 Clinical Trial/Post-Market Surveillance/Report Adverse Events: The number of volunteers enrolled in a Phase 4 Clinical Trial will vary, depending on the purpose and experimental design of that particular study.
  • * If the disease to be treated is considered to be of “orphan status” (less than 200,000 people in the U.S. are affected by this disease), then the number of volunteers enrolled at all stages of the trials can be much less.

  • What parts of the clinical trial process are funded by BrightFocus? How are private, non-profit organizations important for keeping innovations “alive” and moving down the clinical trial “pipeline”?

    The BrightFocus Foundation mainly supports the Basic Research/Drug Development and Pre-Clinical/Translational Research stages, noting that it is essential to pursue every promising candidate to determine if that could lead to the next diagnosis method, prevention, treatment, or cure. Since clinical trials can be expensive, BrightFocus has entered into special partnerships with other organizations to support clinical trials. However, BrightFocus has supported portions of human clinical trials with grants awarded through our regular open call for submissions in our three research programs.

    As of July 2013, the latest stage of study supported by BFF has been Phase I Clinical Trials. The seed money provided by BrightFocus has kept many promising leads alive (bridging the "Funding Valley of Death”**) and supported the careers of internationally important scientists and clinicians who have contributed to the discovery and development of many treatments and clinical diagnoses/imaging studies that are currently being used on the market (including involvement with Lucentis®/Avastin® for age-related macular degeneration, optical coherence tomography (OCT) for glaucoma, and the Dominantly Inherited Alzheimer Network (DIAN) for Alzheimer’s disease).

    It should be noted that some analysts believe that one cause of the early stage "Funding Valley of Death" is actually a reflection of “classic supply and demand.” There are more start-up companies, including academic university-based technology transfer offices, focused on their patent portfolios and competing for the same pool of dollars. Organizations like BrightFocus help bring more new potential diagnostic methods, preventions, treatments, and cures across the Funding Valley of Death, by providing the seed money needed to keep the ideas alive.


Definitions

*

Treatment: Although we are using the word "treatment," clinical trials also involve medical research studies in which people participate as volunteers to test new methods of prevention, screening, and diagnosis of disease.

**

"Funding Valley of Death": Many promising potential drugs, devices, or other potential treatments are never tested in clinical trials due to lack of funding or other business difficulties. In many cases, further financial support or partnerships are needed to help "bridge the gap" across the "Funding Valley of Death" to begin Phase 1 Clinical Trials.

Sources of Information

U.S. Food and Drug Administration (FDA); National Institutes of Health (NIH); Center for Information & Study on Clinical Research Participation (CISCRP); Pharmaceutical Research and Manufacturers of America (PhRMA); Tufts Center for the Study of Drug Development [Updated Outlook 2010 and original referenced paper (DiMasi, Joseph A., Ronald W. Hansen and Henry G. Grabowski (2003) “The Price of Innovation: New Estimates of Drug Development Costs,” Journal of Health Economics 22(2):151-85, March)]; and a paper comparing the costs of different studies (Morgan, Steve, et al. “The cost of drug development: A systematic review” Health Policy 100 (2011) 4–17).


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Last Review: 01/17/14