Regulatory Blog Post #4 - Laura Salomon

FDA GUIDANCE BLOG #4

Laura Salomon

Name of Guidance:
Guidance for Industry – IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer

Status of Guidance/Release Date:
The current, final version of this guidance is dated January, 2004; it replaces the original version that was published in September, 2003.

Link to the Guidance:
The guidance can be found at the following location:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071717.pdf

Target Audience:
This guidance is targeted to sponsors whose pharmaceutical portfolios include studies of marketed drugs or biological products for treatment of cancer.

Laws and Regulations Referenced:
52 FR 8634 Federal Register of March 19, 1987
21 CFR 312 Investigational New Drug Application (IND)

CBER Office of Communication, Training and Manufacturer Assistance - Reinventing the Regulation of Cancer Drugs – Accelerating Approval and Expanding Access

Background:
Generally, the FDA requires a sponsor to submit an IND before studying a drug or biological product in humans, but certain studies, such as those investigating drugs for cancer, can be exempt if specific criteria are met. An applicant can determine that a study may be exempt if 5 criteria are met:

1. The study is not intended to support approval of a new indication or major labeling change.
2. The study is not intended to support a significant change in the product’s advertising.
3. The study does not involve any factor (dosage, route of administration, etc.) that greatly increases risk associated with product use.
4. The study complies with IRB and informed consent regulations (21 CFR parts 56 and 60).
5. The study complies with accepted regulations for investigational drug promotion and charging.

The FDA has attempted to clarify its policy on IND exemptions since 1996, when it launched the Reinventing the Regulation of Cancer Drugs initiative. At that time, sponsors were often submitting INDs for off-label indications, which were unnecessary. Sponsors and manufacturers incorrectly thought that if they provided study drug at no cost, the Agency would view this as promotional activity. As a result, the policy was further clarified, and the FDA stated that it was the investigator’s duty, rather than the IRB’s or manufacturer’s, to determine if an IND was necessary for a certain study. However, the Agency has since found that many cancer drug INDs were still being submitted when not required.

The staff at the FDA performs an initial brief review of an application it receives to determine whether or not it is exempt by focusing on parts of the protocol describing dose, schedule, route of administration, and patient population. If the Agency determines that the protocol is exempt from the requirement for an IND, a letter is sent to notify the sponsor, and there is no further review.

In cancer studies, changes in dosing recommendations are common, and oncologists need to carefully consider the probability of a major increase in risk (criterion 3 for IND exemption). The FDA recognizes that oncology drugs are associated with significant risk from known toxicity and that off-label therapy is common; these characteristics make oncology studies a specific class of investigations that may be exempt from IND submission.

Rationale:
The original version of this guidance was designed to clarify types of studies that could be exempt from the Agency’s IND requirements because many sponsors were submitting applications unnecessarily. To correct this issue, the guidance listed criteria that could allow for exemption as well as examples of oncology protocols that generally are and are not exempt. The Agency believes that explicit examples and criteria will help prevent sponsors from submitting studies that would be considered exempt under its regulations.

The guidance has since been updated. In the original version, the Agency stated that most randomized studies large enough to support a labeling supplement would probably not be exempt from IND regulation. Because this wording was often been misinterpreted to mean that the size of a study alone could lead to its exemption, the guidance was revised and the statement removed.

Resulting Recommendations:
The Agency stresses that it is the investigator’s role to determine whether or not a study is exempt from IND regulations. The investigator should be particularly aware of details of study design and purpose in oncology trials, because drugs for cancer are often used off-label and dosed differently than other drug classes. As a result, a thorough risk/benefit analysis is recommended.

Impact:
One major impact of this guidance is clear: fewer studies that qualify for exemption are submitted to the Agency erroneously, since it defines criteria and lists examples. This guidance also ensures that most of the responsibility for determining IND exemption lies with the sponsors and not with the IRBs or drug manufacturers. The sponsors should therefore be aware of these recommendations so that they are more able to make a correct determination. Sponsors who limit the number of unnecessary IND submissions would be able to promptly begin the investigations that are so important to the drug development and marketing process.