2. Advancing Cancer Care through Clinical Trials

Evaluating Clinical Trial Results
Approving New Drugs

Overview

Once a new drug or intervention is proven safe and effective in a clinical trial, it may become the new standard of practice. Everything we can tell people with cancer today about their treatment options is based on the results of clinical trials. Members of the interested public can help speed up the research process.

Evaluating Clinical Trial Results

After a clinical trial is completed, researchers look carefully at the collected data before making decisions about further testing and what their findings mean.

After a phase 1 trial is completed, researchers decide whether:

• There are enough data to support further study with a phase 2 trial

• Further research will be discontinued because the agent was not safe

After a phase 2 trial is completed, researchers decide whether:

• There are enough data to support further study with a phase 3 trial

• Further research will be discontinued because the agent was not safe or effective

After a phase 3 trial is completed, the researchers must look at the data and decide whether the results have medical importance. When the analysis is complete, the researchers will inform the medical community and the public of the trial results.

In most cases, a trial's results are first reported in peer-reviewed scientific journals. But if a trial's results have significant medical importance, a public announcement may be made while the formal report is being submitted to ensure that people can quickly benefit from the new advance. Particularly important results are likely to be featured by the media and widely discussed at scientific meetings and by advocacy groups.

Peer review is a process by which experts critique a study's report before it is published to make sure that the analysis and conclusions are sound.

Once a new drug or technique is proven safe and effective in a clinical trial, it may become the new standard of practice for physicians.

Approving New Drugs

By law, the Food and Drug Administration (FDA), an agency of the U.S. Department of Health and Human Services (HHS), must review all test results for new agents to ensure that products are safe and effective for specific uses.

Once a new agent proves promising in the laboratory, the drug company or research sponsor, such as NCI, must apply for FDA approval through an Investigational New Drug (IND) application. Once FDA gives approval to the sponsor, clinical trials may begin.

Once a trial sponsor feels there are adequate data from the results of the trial to support a certain use for a drug, the sponsor submits a New Drug Application (NDA) or a Biologics License Application (BLA) to FDA.

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.

How FDA Makes Decisions

FDA uses independent advisory committees of professionals and consumers from outside the agency for expert advice and guidance in making decisions about drug approval. By law these committees include both a patient representative and a consumer representative.

As FDA looks at all the data submitted and the results of its own review, it addresses two key questions:

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

2. Do the results show the product is safe under the proposed conditions for use? (In this context, "safe" means that potential benefits have been determined to outweigh any risks.)

How Can the Public Influence the Drug Development Process?

As shown on the Drug Development and Approval Process chart, it takes 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 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 ultimately reduces the time it takes for researchers to enroll participants in trials and complete them-and speeds the movement of new drugs or treatments into standard care.

Advances in Care

Most of the ways we treat cancer today are based on the results of earlier clinical trials. Recent clinical trials have resulted in the following treatment benefits for people with chronic myelogenous leukemia, cervical cancer, breast cancer, and melanoma, for example.

Chronic Myelogenous Leukemia-A New Treatment Option

In 2001, FDA approved Gleevec, 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 the drug, their prognosis is generally poor.

In three short-duration, early-phase clinical trials with Gleevec, researchers found higher remission rates among people with CML than they would have expected, and the people had few side effects. Gleevec was designed to target an abnormal version of a normal cellular protein present in nearly all people with CML. The abnormal protein is much more active than the normal version and is probably the cause of 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 the 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. The results of five large clinical trials showed that women with invasive cervical cancer have improved rates of survival when they receive a cisplatin-containing chemotherapy regimen plus radiation therapy.

Breast Cancer

Less Extensive Surgery, Same Survival Rate

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

For many years, there was no clear option for women seeking to reduce their risk of breast cancer. A large study was designed to see if the drug tamoxifen could reduce the risk of developing breast cancer in women who were already at high risk for developing the disease. The study found that those 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 who took a placebo.

Melanoma-Improved Survival Rates

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 (reappearance).

Apply what you've learned about clinical trials to respond to the following questions. You may wish to print these questions for a reference.

A. What happens to clinical trial results?

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B. Clinical trials answer research questions. How does this help people?

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C. Sometimes researchers decide not to continue studying an agent or to seek FDA approval. How do scientists decide when to move from one clinical trial phase to the next?

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D. How can public awareness about clinical trials influence the research process?

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Answers to Exercise 2