Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics

Name of Guidance
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics

Status of Guidance
Final

When was the Guidance released?
May 2007

Which organization released the Guidance?
Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER)

Link to the Guidance
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf

Target Audience
Sponsors submitting clinical trial data in support of a new drug application (NDA) or biologics license application (BLA), or supplemental application for cancer treatments.

Laws and Regulations Referenced

21 CFR part 314, subpart H: Accelerated Approval of New Drugs for Serious of Life-Threatening Illnesses - New drug products intended to treat serious or life-threatening illnesses may be considered for fast-track approval if there is sufficient data showing that the drug is safe and treatment will be more effective than existing treatments. Postmarketing safety reporting requirements still apply and the sponsor may not distribute promotional materials about the drug until at least 120 days after the FDA approves the treatment.

21 CFR part 601, subpart E: Accelerated Approval of Biological Products for Serious or Life-Threatening Illnesses - New biologic products intended to treat serious or life-threatening illnesses may be considered for fast-track approval if there is sufficient data showing that the drug is safe and treatment will be more effective than existing treatments. As with the corresponding regulation for drugs (21 CFR part 314, subpart H), postmarketing safety reporting requirements still apply and the sponsor may not distribute promotional materials about the biologic product until at least 120 days after the FDA approves the treatment.

21 CFR 314.126: Adequate and well-controlled studies - Sponsors of new pharmaceutical or biologic drug products must conduct adequate, well-controlled clinical studies to demonstrate safety and efficacy. This includes valid comparison to a control product, minimization of bias in how participants are assigned to treatment and control groups, use of appropriate analytic and statistical methods to assess data from clinical trials, and other requirements.


Definitions

• Biological marker (biomarker): A physical characteristic that can be measured objectively to indicate the progression of a disease or normal biological process, or the response to a therapeutic intervention. Examples include elevated blood glucose concentration (used to diagnose diabetes mellitus), blood cholesterol concentrations (used to determine risk of heart disease), and tumor size (used to assess efficacy of treatment in certain cancers).
• Clinical endpoint: A measure of what a patient experiences directly as a result of a treatment including how the patient feels (eg, reduction in pain or other symptoms), functions (eg, regaining mobility or normal organ function), or survives (eg, outliving expected lifespan). In clinical trials, clinical endpoints are the most reliable indicators of whether the new treatment is effective and safe. For serious or life-threatening diseases such as cancer, the clinical endpoints usually include survival (how long the patient lives) or progression-free survival (how long the patient lives without the disease getting worse).
• Complete response: Regression of a tumor to the point where there is no clinical evidence of the tumor. However, does not imply that the patient is “cured.”
• Disease-free survival: The time from the patient enters the clinical trial until recurrence of the tumor or death from any cause.
• Objective rate response: The proportion of patients whose tumors are reduced by a predetermined amount for a minimum time period.
• Overall survival: The time from the patient enters the clinical trial until death from any cause.
• Progression-free survival: The time from the patient enters the clinical trial until there is objective evidence that the tumor has progressed or death.
• Surrogate endpoint: A biomarker that is used as a substitute for a clinical endpoint in a clinical trial. Surrogate endpoints predict clinical benefit based on existing scientific evidence but are not as reliable as clinical endpoints and may not always predict clinical benefit accurately. Surrogate endpoints are used when a sponsor is seeking accelerated marketing approval for a drug or biologic product.
• Time to progression: The time from the patient enters the clinical trial until there is objective evidence that the tumor has progressed.
• Time to treatment failure: The time from the patient enters the clinical trial to discontinuation of treatment for any reason (eg, disease progression, toxicity from the treatment, death).

Background
Clinical and surrogate endpoints are used to demonstrate the safety and efficacy of drugs and biologic products. Clinical endpoints are considered to be the most reliable, but surrogate endpoints were permitted so long as their usefulness in predicting clinical outcomes was well established.

In 1992, FDA started permitting the use of less established surrogate endpoints in clinical trials for drugs and biologic products meant to treat serious or life-threatening diseases (21 CFR part 314, subpart H and 21 CFR part 601, subpart E). These additional surrogates had to be reasonably likely to predict clinical benefit. The goal was to shorten drug development time and accelerate the marketing approval process. (Patients reach surrogate endpoints (eg, tumor shrinkage) much faster than clinical endpoints (eg, symptom improvement or survival), so clinical trials can be completed in less time.)

Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (“the Guidance”) is the first in a series of guidances that will help pharmaceutical and biotechnology sponsors choose meaningful endpoints for clinical trials for new cancer treatments. Subsequent guidances focus on endpoints for specific cancers.


Summary
The Guidance provides an overview of commonly used clinical and surrogate endpoints along with the advantages and disadvantages of each. Also discussed is the appropriateness of different study designs for each type of endpoint.

Of the clinical endpoints listed in the Guidance, FDA considers overall survival to be the most reliable for cancer treatment because it is precise and easy to document and measure. Symptom endpoints reported by patients are somewhat less reliable because data is frequently incomplete and blinding can be difficult, but they are appropriate.

The surrogate endpoints listed in the Guidance can all be used for accelerated or regular approval, but are less statistically valid and are often not direct measures of benefit. Disease-free survival, for example, is not statistically validated and may even be defined differently among studies. Objective response rate and complete response are not considered direct measures of benefit and progression-free survival is subject to assessment bias.

Biomarkers taken from blood or body fluids have not been validated as surrogate endpoints and are rarely used as primary endpoints in cancer drug trials.

The Guidance is nonbinding and sponsors are urged, but not required, to follow the recommendations provided.


Rationale
The Guidance and subsequent publications in the series were put together based on input from oncologists, hematologists, statisticians, patient advocates, and industry representatives through public workshops and discussions before the FDA’s Oncologic Drugs Advisory Committee (ODAC).


Resulting Recommendations

The following are considered to be clinical endpoints:

• Overall survival - this is the most reliable cancer endpoint
• Symptom endpoints (patient-reported outcomes)

The following are considered to be surrogate endpoints:

• Disease-free survival
• Objective response rate
• Complete response
• Progression-free survival
• Time to progression

The following are not recommended for use as endpoints:

• Time-to-treatment failure
• Biomarkers assayed from blood or body fluids

It is recommended that sponsors consult with FDA to select appropriate endpoints for cancer drugs and biologics before submitting clinical trial protocols.


Impact
The Guidance will improve the quality of clinical trials for cancer treatments and facilitate accelerated marketing approval for promising drugs and biologics. Patients suffering from serious and life-threatening cancers will benefit from getting access to treatments more quickly. Sponsors will save time and money by understanding the advantages and disadvantages of using various endpoints before initiating clinical trials. However, the Guidance is general and cancer-specific guidances should be consulted because each type of cancer is so different.