New rules proposed for IND exemptions

HHS guidance issued in April

The rules soon may change for investigational new drug (IND) studies that involve lawfully marketed cancer drugs or biological products. "It will have a significant impact," says Francis LeVeque, DDS, chairman of the Human Investigation Committee at Wayne State University in Detroit.

Under regulations 21 CFR 312, sponsors who plan to study a drug or biological product in humans must submit an IND application to the Food and Drug Administration (FDA). The regulations provide for some exemptions under certain criteria. Now in a draft report, the FDA offers further explanations for how those exemptions might apply.

"Guidance for Industry: IND Exemptions for Studies of Lawfully Marketed Cancer Drugs or Biological Products" was issued in April 2002 by the Department of Health and Human Services (HHS). It was prepared by the Division of Oncology Drug Products in the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research at the FDA.

"I believe that the general understanding of use of INDs is not good among investigators in this country," LeVeque says. While most investigators generally know that if they are using an investigational drug or device that needs an IND, most fail to realize that there are many other situations that require INDs, LeVeque explains.

"The problem is with the lack of knowledge or overall misunderstanding that approved drugs, if they are going to be used in other applications in different dosing ranges and conjointly with other drugs, etc., may also require an IND," LeVeque says. "They’ll need either a reference IND or manufacturer’s IND for each drug that is approved."

The guidance may clarify some of the misunderstandings, but it also may put more responsibility on the shoulders of IRBs to decide whether an investigator has correctly interpreted the FDA exemptions, LeVeque says. Previously, the policy at some IRBs, includ- ing the committee LeVeque chairs, has been to require investigators to obtain IND numbers for all investigational drugs and products. And if they are unable to obtain such a number, they will need to provide documentation and justification for not having it.

Now IRBs will need to have a clear understanding of the FDA exemptions for INDs. "The FDA is clever and uses the phrase, It may be exempt,’" LeVeque says. "But there is an old saw in research that nobody can exempt themselves." So while there may be exempt research at Wayne State, those exemptions need to be granted by some authority, LeVeque says. "Once they’re granted there is no further interface with the IRB except for changes, chart reviews, etc.," he adds.

Five criteria for exemption

The FDA regulations state that some studies may be exempted from IND regulations if they meet the following five criteria, as stated verbatim:

1. The study is not intended to support FDA approval of a new indication or a significant change in the product labeling.

2. The study is not intended to support a significant change in advertising for the product.

3. The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.

4. The study is conducted in compliance with IRB and informed consent regulations set forth in 21 CFR parts 56 and 50.

5. The study is conducted in compliance with 21 CFR 312.7 (promotion and charging for investigational drugs).

In the new FDA guidance, the FDA acknowledges that these rules require a considerable amount of professional judgment in determining whether the condition significantly increases the risk associated with using the drug. This is where oncology drugs and biological products are different from other types. Unlike other uses for drugs/biological products, it is a common practice to modify labeled dosing recommendations, and cancer drug treatment typically is associated with significant risk from known toxicity. Also, off-label therapy with cancer drugs is common practice, according to the FDA guidance.

Although the FDA does not require submissions to determine an exempt status, the agency will perform an initial limited review of such applications to determine whether the study is exempt. Then if the review determines that the study protocol is exempt, the FDA will send a letter to the study’s sponsor. However, the FDA’s new guidance makes it clear that it’s preferable for the study sponsor to determine that a protocol is exempt and therefore reduce the number of unnecessary IND applications to the FDA. 

"If the drugs have been used and published, then there probably is a good chance for an exemption," LeVeque notes. "I think IRBs need to get some guidance as to how to manage these exemptions, particularly in investigator new use studies," LeVeque says. "Industry often doesn’t do these studies — why would they want to do studies with approved drugs?"

So the primary researchers doing studies of this nature will be oncology cooperative groups that are either investigator-initiated studies or that are sponsored by the National Cancer Institute, LeVeque says. This still leaves open the question of who should have the final say over whether a study is exempt from an IND application, if that final say is not going to be from the FDA.

Since the FDA says the decision about exemptions should be based on a risk-benefit ratio, then it would appear that IRBs need to be involved in the decision-making process. "If you have a situation where there is a significant risk to using a drug combination and the benefit is marginal, then that weighs into the decision," LeVeque explains. "And as far as IRBs are concerned, they do look at that combination of risk vs. benefit."

The FDA notes that planned studies may be considered exempt from the requirements of an IND if the studies involve a new use, dosage, schedule, route of administration, or new combination of marketed cancer products in a patient population with cancer when the five criteria apply.

Some examples of studies that generally are exempt, according to the FDA, are as follows:

"Single-arm, phase 2 trials using marketed drugs to treat a cancer different from that indicated in the approved labeling and using doses and schedules similar to those in the marketed drug labeling are usually exempt. An exception may exist when standard therapy in the population to be studied is very effective (e.g., is associated with a survival benefit); in that case, use of another regimen may expose patients to the risk of receiving an ineffective therapy."

"The study of new combinations of drugs would not ordinarily constitute a significant risk if these combinations have been described in the literature. Even when the regimen described in the literature does not use exactly the doses planned for study, incremental differences in doses from those described in the literature would not normally pose a significant risk and would not require an IND.

"Because of the danger of synergistic toxicity occurring with a new drug combination, if there are no data from the literature on its safety, the initial study of a new drug combination should ordinarily be performed under an IND. Synergistic toxicity may be anticipated when one agent interferes with the metabolism or elimination of the other agent; when both agents target the same metabolic pathway or cellular function; or when one agent targets signaling pathways that are reasonably expected to modulate sensitivity to the other agent. If it is determined that synergistic toxicity is likely, animal studies should be considered for determining a safe starting dose for the drug combination in humans."

"Many studies of high-dose therapy in patients with cancer are exempt. Studies involving adequately evaluated regimens that appear to have an acceptable therapeutic ratio for the population being studied may be considered exempt. Similarly, phase 1 studies involving incremental changes from such well-described regimens are generally exempt."