FDA Approval Requirements
Releasing the Results
Improving Cancer Care
Speeding Up Drug Development

Learning Objectives Describe the FDA drug approval process Describe how clinical trial results are released Describe clinical trials that have led to advances in cancer prevention, detection, and treatment Discuss the importance of professional referral and patient participation in the research process

Once phase 1 and 2 treatment trials are completed, the data are analyzed and, if the treatment shows promise, it moves into phase 3 trials. As soon as the treatment sponsor thinks that phase 3 data show it is safe and superior to standard treatment, the sponsor may submit a New Drug Application (NDA) or a Biologics License Application (BLA), to FDA for approval. At this stage, FDA approves only the claim being made about the drug or intervention, not the drug or intervention itself

FDA Approval Requirements

A New Drug Application includes:

• The exact chemical or biological makeup of the therapy and the mechanisms by which it is thought to be effective

• Results of animal studies

• Results of clinical trials

• How the drug or therapy is manufactured, processed, and packaged

• Quality control standards

• Information about drug or intervention samples of the product in the form(s) in which it is to be administered

FDA assesses applications in order of importance, giving first priority to interventions with the greatest potential benefits. All drugs that offer significant medical advances are considered priority drugs in the approval process.

Independent advisory committees of professionals from outside the agency give expert advice and guidance in making decisions about drug approval. By law, these committees include both a patient representative and a consumer representative. One such committee is the Oncologic Drugs Advisory Committee, which meets regularly to consider most cancer-related treatments and preventive drugs. The committee assesses the safety, effectiveness, and appropriate use of products considered for approval.

As FDA looks at the sponsor's data and its own review results, it applies two questions to each application:

1. Do the results of well-controlled clinical trials provide substantial evidence of effectiveness?

2. Do the results show that the product is safe under the proposed conditions of use? (In this context, "safe" means that potentialbenefits outweigh any known risks.)

Once FDA has approved a new drug, the drug is "labeled" for a specific use. This label includes information on eligibility, dose, safety, and adverse effects. The agency's responsibility for new treatments does not stop with final approval. FDA also:

• Implements and tracks programs to make sure manfacturers comply with standards and practice regulations

• Monitors new drug advertising to make sure it is truthful and complete

• Handles feedback from health professionals and consumers about effectiveness, adverse reactions, and potential problems in labeling and dosage

Releasing the Results

The results of a clinical trial are usually reported first in peer-reviewed scientific journals. If the results appear to have significant medical importance, researchers make a public announcement when the formal report is submitted for publication, ensuring that people benefit from the new treatment as soon as possible. Particularly important results are featured by the media and widely discussed at scientific meetings and within advocacy groups.

Clinical trial results are not available to the public as the trial progresses because:

• Knowing interim results could influence medical personnel and participants in the trial, biasing the results

• Statistical analysis might be less meaningful, compromising the accuracy of the findings

In the absence of very clear evidence that a trial should be stopped early for medical reasons, trials are completed before reporting results. Interim results are unavailable to the public, and often to the research teams. Independent data and safety monitoring boards track phase 3 trial data. These boards alert researchers about any safety or effectiveness issues that arise during the trial. Data and safety monitoring plans are also in place for many phase 1 and 2 trials.

Research progresses in small steps, and sometimes publishing the results of a trial is not as important as taking what was learned from the trial and building on it in a new trial. To find the results of a clinical trial, search a medical literature database, like Medline or PubMed, available online through the National Library of Medicine (www.nlm.nih.gov) and at medical institutions' libraries. The "closed protocol" file in NCI's PDQ® (Physician Data Query) may contain related studies (see section 6 for more information on PDQ).

It often takes more than a year for a scientific paper to be written, submitted, reviewed, edited, and published. If an initial literature search turns up nothing, try again after some time has passed.

Improving Cancer Care

Once an intervention is proven safe and effective, it may become the new standard of care. Thus, current cancer care is based on the results of past clinical trials. Recent clinical trials have resulted in the following treatment benefits for people with chronic myelogenous leukemia, cervical cancer, breast cancer, and melanoma.

Chronic Myelogenous Leukemia - A New Treatment Option

In 2001, FDA approved Gleevec^TM, offering a new treatment option for many people with chronic myelogenous leukemia (CML). Until then, bone marrow transplantation in the initial chronic phase of the disease was the only known effective therapy for CML. However, this is not an option for many people and the procedure can cause serious side effects or death. Another option, treatment with the drug interferon alfa, may produce remission (a decrease in or disappearance of signs and symptoms of cancer) for many people. But if the drug is ineffective or people stop responding to it, their prognosis is generally bleak.

In three short-duration, early-phase clinical trials with Gleevec, researchers found that people with CML either had higher remission rates than expected or they had few side effects. Gleevec was designed to target an abnormal version of a cellular protein present in nearly all people with CML. The abnormal protein is much more active than the normal version and probably causes the disease. By blocking the abnormal protein, called BCR-ABL, Gleevec kills the leukemia cells.

Gleevec represents a new class of cancer drugs, which target abnormal proteins that are fundamental to the cancer itself.

Cervical Cancer - Improved Survival Rates

For many years, the standard therapy for invasive cervical cancer was surgery or radiation alone. Five large clinical trials showed that women with invasive cervical cancer have improved survival rates when they receive a cisplatin-containing chemotherapy regimen plus radiation therapy.

Breast Cancer

Less Extensive Surgery, Same Survival Time

For many years, the standard therapy for all breast cancers was a modified radical mastectomy with radiation or chemotherapy. Clinical trials showed that for women with early-stage disease, long-term survival after lumpectomy with axillary lymph node dissection plus radiation therapy is similar to survival after modified radical mastectomy.

Reduced Risk for Women at High Risk

Traditionally, women seeking to reduce their risk of breast cancer had no clear option. A large phase 3 clinical trial assessed risk reduction in women taking the drug tamoxifen. The trial found that high-risk women who took the drug for up to 5 years (an average of 4 years) had 49 percent fewer diagnoses of invasive breast cancer than those taking a placebo.

Melanoma - Improved Survival

According to the findings of a large, randomized clinical trial, compared to low-dose interferon or no therapy, high-dose interferon alfa-2b (Intron-A) significantly prolongs disease-free survival for people at high risk for melanoma recurrence.

Biological Therapy

Biological therapy (sometimes called immunotherapy, biotherapy, or biological response modifier therapy) uses the body's immune system, either directly or indirectly, to fight cancer or to lessen the side effects that some cancer treatments might cause.

The immune system is a complex network of cells and organs that work together to defend the body against attacks by "foreign," or "nonself," invaders. This network is one of the body's main defenses against disease. It works against disease, including cancer, in a variety of ways. For example, the immune system may recognize the difference between healthy cells and cancer cells in the body, and work to eliminate those that become cancerous. Biological therapies are designed to repair, stimulate, or enhance the immune system's responses. Many clinical trials are testing the use of biological therapies, such as monoclonal antibodies and vaccines, to treat cancer.

Monoclonal Antibodies

Monoclonal antibodies (MOABs) are a form of biological therapy now being studied in the laboratory and in clinical trials.

MOABs are designed to fill a critical gap in the body's immune system. Although the human body naturally produces antibodies to identify and fight off viral and bacterial infections, the immune system may not always recognize cancer cells as harmful. This is because some cancer cells do not possess an antigen on their cell membrane that is capable of eliciting an immune response. Therefore, cancer is able to grow and spread unchecked. MOABs are being developed to supplement the body's immune system by recognizing and attacking specific proteins that cancer cells express. These specific antibodies may be active on their own, or they may be linked to a drug to allow specific delivery of the drug to the cancer cell.

Basic immunologic research identified a molecule specific to the surface of B-lymphocytes that also is highly expressed on the surface of most lymphomas. An antibody directed against this molecule was shown to be capable of killing cells. Over several years researchers tried to engineer the antibody and succeeded.

In 1997 FDA approved rituximab, now used to treat people with low-grade lymphoma.

Cancer Vaccines

Cancer vaccines are another form of biological therapy being studied in the laboratory and in clinical trials. Researchers are developing vaccines that may promote the recognition of cancer cells by a person's immune system. These vaccines may help the body reject tumors and prevent cancer from recurring. In contrast to vaccines against infectious diseases, cancer vaccines are designed to be injected after the disease is diagnosed, rather than before it develops. Vaccines given when the tumor is small may be able to eradicate the cancer. Cancer vaccines being tested in clinical trials are designed to treat cancer by getting the immune system to attack existing cancerous cells. Many vaccines are not used alone, but in combination with surgery, chemotherapy, or other interventions that help stimulate the immune response in general.

Early attempts to vaccinate people with cancer against the disease have been directed largely at melanoma, a potentially deadly skin cancer with easily accessible tumors. Researchers are also conducting studies that may lead to the development of vaccines for lymphoma, prostate, lung, breast, colon, and other cancers.

Speeding Up Drug Development

In the recent past, it has taken 15 years, on average, for an experimental drug to travel from the laboratory to U.S. consumers. Often the longest part of the process is finding people to participate in each clinical trial phase. With increased public awareness about clinical trials, more people may be willing to participate, and more professionals may refer people into appropriate trials. This awareness would ultimately reduce the time it takes for researchers to enroll participants in trials and complete them--and speed up the movement of new drugs or treatments into standard care.

Decisions to Advance Drug Development

Investigators make decisions about how to proceed with further research based on scientific evidence and promising basic research leads. Even if some participants in a clinical trial had a positive response to a new treatment, researchers must look at the global experience of all participants when deciding whether or not to continue or expand trials. In some trials, more participants treated with standard therapy may have better results than those treated with the experimental therapy, and the investigator may decide to continue research in a different direction.

The Drug Development and Approval Process in the 1990s
	Preclinical Testing		Clinical Trials			Post-Clinical Trials		Total Years for Drug Approval
	Step 1 Laboratory / Preclinical Testing	Step 2 File IND1 application with FDA2	Step 3 Phase 1	Step 4 Phase 2	Step 5 Phase 3	Step 6 File NDA3 or BLA4 with FDA	Step 7 FDA Approval
Purpose	Assess safety and biological activity in the laboratory and in animal models	Obtain FDA approval to begin clinical testing in humans after promising results in laboratory	Determine what dosage is safe, how treatment should be given	Evaluate effectiveness, looks for side effects	Determine whether the new treatment (or new use of a treatment) is a better alternative to current standard	Inform the FDA of Phase 3 data which supports drug safety and better performance over standard treatment	Review process/ approval
All anticancer drugs (average number of years)	4.4 years		8.6 years				1.4 years	14.4 years
All drugs* (average number of years)	3.8 years		10.4 years				1.5 years	15.7 years

¹IND = Investigational New Drug

²FDA = Food and Drug Administration

³NDA = New Drug Application

⁴BLA= Biologics License Application

*Classified as "new chemical entities," which exclude diagnostic agents, vaccines, and other biological compounds.

Sources: DiMasi, J.A. (2001). New drug development in the United States 1963-1999. Clinical Pharmacology and Therapeutics May; 69(5); Tufts Center for the Study of Drugs Development, Tufts University; adapted from Pharmaceutical Research and Manufacturers of America.

Refer to the case study for a review and summary of content covered in this workbook.

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