How Are Cancer Drugs Discovered and Approved?

The discovery and approval of cancer drugs take decades . On this challenging journey, the success stories of scientists and pharmaceutical companies are far outnumbered by their failures. So how is a new cancer drug discovered and approved? And why is the drug discovery process so difficult?

The institution whose decisions on the approval of new drugs are followed by countries worldwide is the United States Food and Drug Administration(FDA). The FDA regulates a range of consumer products, including drugs, medical devices, vaccines, blood products, biological agents, animal and veterinary products, cosmetics, tobacco products, radiation-emitting products, and food.

FDA approvals in 2018 for oncology included 47 new drugs, and 20 new approvals have been granted so far in 2019.

The Drug Development Journey

Although different product types follow different regulatory pathways, most oncology drugs follow a similar overall development pathway. Traditional drug development can take approximately 15 years , but the pharmaceutical industry and the FDA are working to shorten this period.

In general, drug development is a lengthy process because a potential new drug must first be identified and then evaluated in preclinical and clinical studies. A potential new drug can be discovered in several different ways. Researchers may identify a new drug by testing countless compounds in the laboratory for beneficial effects, such as stopping cancer cell growth or killing cancer cells.

The 3 Different Branches of Cancer Drug Development:

• Sometimes, a new discovery in cancer biology leads to the development of a compound targeting cancer growth pathways , an approach known as rational drug design.
• Sometimes, existing drugs are found to have a beneficial effect against different types of cancer.
• Finally, new technologies and/or formulation designs can change how drugs reach cancer cells within the body. As a result, an anticancer agent that previously did not have a sufficient effect in the body may become more effective in a new formulation (for example, through nanotechnology solutions).

After initial testing, any promising compound—a potential anticancer agent—is studied further in the laboratory. Cancer cells and animals are used to compare the best way to administer the compound and at what dose, its mechanisms of action, how the body absorbs and metabolizes it, how it interacts with other drugs, and its effectiveness. These investigations are preclinical (before clinical testing) studies. Animal studies are often used to obtain detailed information on dosing and toxicity (side effects).

Study Phases

If the results of preclinical studies are promising, human studies begin and the lead compound enters clinical testing. This process involves several phases of clinical studies: phase 1, phase 2, phase 3 and sometimes phase 4 (also called the post-approval phase). Clinical studies are carefully designed to answer specific research questions about the compound for a particular disease.

• Phase 1 studies are small and typically include approximately 20 to 100 healthy volunteers or patients with the target cancer of interest. The aim of phase 1 is to establish a safe dosage; sometimes the compound’s effectiveness may also be assessed. Approximately 60% of drugs entering phase 1 clinical trials move on to phase 2.
• Phase 2 trials test hundreds of patients with specific cancer types to evaluate any anticancer activity and side effects of the compound. Phase 2 studies may last from a few months to 2 years and generally have no control or placebo group. Approximately one third of drugs entering phase 2 will proceed to phase 3.
• Phase 3 clinical studies may take longer and include several hundred to several thousand patients with a particular cancer type. The aim of phase 3 trials is to assess the drug’s safety and effectiveness in a larger group of people, and these trials are typically used in the FDA application process.

As shown in the figure above, an agent that has passed preclinical testing (laboratory and animal studies) and is considered promising has less than a 10% chance of becoming available for use in humans. Today, almost all supplements marketed as phytotherapy (herbal treatment) products, such as curcumin (turmeric), high-dose vitamin C, cannabis oil, mistletoe , have only shown activity in preclinical studies, have stalled at the human clinical research stages, and have not been found effective enough to be used as drugs.

Phase 3 trials have historically been understood to be pivotal trials because they provide evidence for obtaining FDA approval for use; these are efficacy trials used as evidence to support a drug’s approval for a particular disease.

If approved by the FDA, some drugs continue into phase 4 testing. At this stage, the long-term effects of a product are monitored after it enters use.

FDA Approval Process

When the results of preclinical and clinical studies indicate that a potential new drug is safe and effective, the pharmaceutical company submits an NDA (new drug application) to the FDA. This application includes all preclinical and clinical data for the new drug, along with its proposed prescribing information (label), instructions for use, patent information, safety updates, and potential for abuse. After receiving the application, the FDA determines whether it is complete. Incomplete applications are not filed or reviewed. Complete applications must be reviewed, and the FDA must issue a decision within 6 to 10 months.

During the NDA review, members of the FDA review team examine sections of the application covering different areas. The team evaluates the application in terms of data quality, as well as manufacturing, handling, and data storage. After interpreting the data, the FDA review team recommends whether the potential new drug should be approved, and a senior FDA official makes the final decision.

If the NDA does not contain sufficient information or further questions arise, the FDA may convene an advisory committee. This committee consists of outside experts who review the application and make recommendations to the FDA. The FDA may take the advisory panel’s recommendations into account when making its final decision.

Efforts to Accelerate the Drug Approval Process

Because the drug development process can be lengthy and there is a great need for new, safe, and effective drugs , the FDA offers several options that can accelerate a drug’s approval process.

These include:

• Fast-track designation (an expedited development route),
• Breakthrough therapy designation (designation as a breakthrough therapy),
• Accelerated approval pathway (an expedited approval route), and
• Priority review designation (priority assessment).

All of these expedited approval options are designed to reduce development and/or FDA review time and are typically reserved for compounds considered highly promising in preclinical and/or early clinical testing. These additional options are especially common in oncology because cancer is a life-threatening disease and there is a major unmet need for new treatments, particularly in metastatic disease.

When drugs are approved through the accelerated approval pathway, the FDA requires a subsequent clinical study to establish effectiveness and safety.

The Concept of Off-Label Use

Once a drug is approved, the pharmaceutical company is permitted to market it for the approved indication/disease. When the company is ready to manufacture and distribute the drug, physicians can prescribe it. Drug advertisements are regulated by the FDA, and all advertising must be limited to the approved indication and must accurately describe the drug’s effectiveness and potential side effects.

Drugs prescribed for the indications/diseases listed on their label are considered “on-label” use. Sometimes, however, drugs are prescribed for diseases other than those listed on their label, a practice known as “off-label” use . A drug is approved for a particular indication because the FDA has reviewed scientific data specific to that indication. There are generally insufficient data to use a drug outside the scope of its label. However, some information about the drug, such as its mechanism of action, suggests that it may offer an effective treatment approach for off-label use. In some cases, international clinical practice guidelines may recommend a drug’s off-label use even without FDA approval because published preliminary studies suggest a possible benefit.

How Common Is Off-Label Use in Oncology?

It is estimated that chemotherapy is used off-label in 13% to 71% of patients and that targeted drugs are used off-label in 62% of cases. Although off-label drugs are used throughout oncology, they are most commonly used among patients with metastatic disease, those receiving palliative care , and patients with breast, pancreatic, head and neck, or ovarian cancer.

Patients can also receive treatment with drugs not yet approved by the FDA by participating in clinical trials . In addition, the FDA has a new program that allows patients access to investigational drugs. In May 2018, the United States government passed the “right-to-try” (RTT) law. This law allows patients who cannot participate in clinical trials to use investigational drugs outside a clinical trial after trying all other treatment options. Patients have the right to ask their physicians about investigational drugs, but physicians are not required to help patients access them. Nor is there any guarantee that pharmaceutical companies will approve a drug request or that insurers will cover the costs of investigational treatment. In our country , many clinical studies are now also being conducted. As of July 2019, there are 649 clinical studies actively ongoing in cancer in our country. Worldwide, there are 60,681 clinical studies in cancer.

Clinical research is one of the most valuable investments a country can make in its health and future. It is no coincidence that developed countries attach great importance to this field and allocate substantial funding to it. The best way to address the relative youth of our country’s clinical research culture or difficulty accessing clinical trials is to educate the public to overcome the prejudice that “people are being experimented on,” refer patients to clinical trials according to their eligibility, or make use of compassionate early access programs. In this way, we take one of the most important steps toward giving our patients access to the right treatment options at the same time as the rest of the world.