How the IND 30-day Hold Impacts Clinical Trial Activities
The Food and Drug Administration (FDA) is the federal entity in the U.S. charged with (among other things) “ensur[ing] that safe and effective drugs are available to improve the health of the people in the United States.”
Before the FDA permits a pharmaceutical drug product to be lawfully marketed, sponsors are required to submit information about the product’s safety and efficacy so the FDA can determine:
- “Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.
- Whether the drug’s proposed labeling (package insert) is appropriate, and what it should contain.
- Whether the methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity.”
The FDA requires the data for these assessments to generally come from animal studies and clinical investigations1 of the investigational product(s)2.
In addition to granting new drug approvals, the FDA is also the gatekeeper for whether a sponsor can conduct the clinical investigations necessary to gather the data required for drug approval. In other words, the FDA also regulates whether investigational products may be manufactured, shipped, and administered to human subjects who participate in clinical investigations.
This blog focuses specifically on the investigational new drug application (IND)3 and when investigational drugs may be manufactured, shipped, and administered in clinical investigations.
When Does an IND go into Effect?
An IND may only be used in a clinical investigation after the following steps are completed:
- The sponsor of the investigation submits an IND to the FDA;
- The IND goes into effect; and
- The sponsor has received institutional review board (IRB) review and approval of a clinical investigation in accordance with FDA regulations at 21 CFR parts 50, 56, and 312. (21 CFR 312.40(a))
The FDA will send the sponsor an “IND Acknowledgement” letter or email after the sponsor submits an IND. This letter will include the date the FDA received the application. This is the date the sponsor should use to calculate when the IND goes into effect.
The IND goes into effect:
- 30 days after the FDA receives the application, unless the FDA notifies the sponsor the investigations described in the IND are subject to a clinical hold under 21 CFR 312.42; or
- On earlier notification by FDA indicating the clinical investigations in the IND may begin (21 CFR 312.40(b))
The period between when the FDA receives the IND and when it goes into effect is often referred to as the “30-day hold.” It’s at the end of that period, unless one of the above criteria is met, when an IND automatically goes into effect.
When can a Sponsor Submit to the IRB?
Sponsors may submit research to be conducted under an IND to an IRB at any time before or after the IND is in effect. However, the research itself (including study-specific recruitment) may not begin until after the IND is in effect, even if the IRB has approved the research. (At Advarra, the IRB approval notice notes this requirement.)
When can a Sponsor Ship an Investigational New Drug?
Once an IND is in effect, a sponsor may ship the investigational product to the investigator(s) named in the IND application. The regulations at 21 CFR parts 50, 56, and 312 do not require IRB approval (in addition to the IND being in effect) before shipping the investigational product.
When can an Investigational New Drug be Administered?
A clinical investigation involving an investigational product may not begin until after both IRB review and approval have been obtained and the IND is in effect. This means in general, an IND can only be administered after both the IND is in effect and an IRB has reviewed and approved the research.
What About Amendments?
Sponsors are required under the IND regulations (21 CFR 312) to amend the IND as needed “to ensure the clinical investigations are conducted in accordance with protocols included in the application.” There are three types of amendments specified in these regulations:
- New protocols
- Change in protocol
- New investigator
According to the regulations, sponsors must submit an IND Change in Protocol Amendments for “any change in a Phase I protocol that significantly affects the safety of subjects or any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study.” (21 CFR 312.30(b)(1))
Examples of protocol changes requiring an IND amendment include, but are not limited to:
- Any increase in drug dosage or duration of exposure of individual subjects to the drug beyond the current protocol
- Any significant increase in the number of subjects under study
- Any significant change in the design of a protocol (such as the addition or dropping of a control group)
- The addition of a new test or procedure intended to improve monitoring for, or reduce the risk of, a side effect or adverse event (AE)
- The dropping of a test intended to monitor safety
Any of the categories of IND amendments may be implemented:
- After FDA submission
- After the IRB of record reviews and approves the IND amendment (i.e., new protocol, change in protocol, and/or new investigator)
Note a protocol change intended to eliminate an apparent immediate hazard to human subjects may be implemented immediately, provided the sponsor promptly:
- Submits an IND Change in Protocol Amendment to the FDA after the change is implemented
- Notifies the IRB of record of the change in accordance with the IRB’s policies and procedures
Can Recruitment Activities Begin During the 30-day IND Hold?
In general, no study-specific activities may begin before the IND is in effect and an IRB has reviewed and approved the research. This means study-specific activities such as advertising, eligibility screening, and seeking informed consent are prohibited during the 30-day IND hold.
The IND waiting period can be particularly challenging in Phase I research, where timelines are especially tight. When appropriate, consider speaking with your IRB to understand what recruitment-related activities might be permitted (or precluded) during the 30-day IND hold period.
It’s important to bear in mind: the 30-day IND hold is an FDA requirement. IRBs do not have the authority to change these legal requirements. It may be helpful to contact FDA for specific information regarding its IND review.
1Clinical Investigation means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice. (21 CFR 312.3(b))
2 Investigational new drug means a new drug or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes. The terms “investigational drug” and “investigational new drug” are deemed to be synonymous for purposes of this part. (21 CFR 312.3(b))
3 IND means an investigational new drug application. For purposes of this part, “IND” is synonymous with “Notice of Claimed Investigational Exemption for a New Drug.” (21 CFR 312.3(b))