Research · 6 min read
What Investigational Means, and What May Not Be Said About It
A drug under study occupies a defined legal category with its own labeling sentence, its own waiting period, and an explicit rule against promoting it. The rule against promotion is the part most often ignored in marketing copy.
Key takeaways
- The statute bars introducing an unapproved new drug into interstate commerce; investigational use is an exemption from that bar, not a lesser form of approval.
- An IND goes into effect thirty days after FDA receives it unless a clinical hold is imposed, and no human subject may be given the drug before it is in effect.
- A clinical hold is an order that stops dosing in a proposed study and stops new enrollment in an ongoing one, with existing patients ordinarily taken off the investigational therapy.
- Section 312.7 prohibits representing in a promotional context that an investigational drug is safe or effective for the use under study, and prohibits commercial distribution or test marketing, while expressly protecting the exchange of scientific information.
- An investigational drug's immediate package must bear the caution limiting it to investigational use, and its labeling may not represent it as safe or effective for the use being investigated.
- Material shipped for in vitro or laboratory-animal testing carries a different required caution stating that it is not for use in humans, plus due-diligence and record duties on the shipper.
Answer first: investigational is an exemption, not a status upgrade
The statute starts from a prohibition. Under 21 U.S.C. 355(a), "No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application filed pursuant to subsection (b) or (j) is effective with respect to such drug." Everything about investigational drugs is a carve-out from that sentence.
The carve-out is in subsection (i), which directs that regulations be written "for exempting from the operation of the foregoing subsections of this section drugs intended solely for investigational use by experts qualified by scientific training and experience to investigate the safety and effectiveness of drugs." The regulations written under it are 21 CFR part 312, which is why the part's own definition says the term IND "is synonymous with 'Notice of Claimed Investigational Exemption for a New Drug.'"
That phrase is the whole idea in six words. An investigational new drug is not a drug that has cleared a lower bar. It is an unapproved drug that may lawfully be shipped and administered only because a claimed exemption is in effect and its conditions are being met. The regulation defines the term plainly: an investigational new drug "means a new drug or biological drug that is used in a clinical investigation."
The exemption starts on a clock, and can be stopped by an order
A sponsor must submit an IND before conducting a clinical investigation subject to the part, and "shall not begin a clinical investigation... until the investigation is subject to an IND which is in effect." The regulation then says exactly when that happens: an IND goes into effect "Thirty days after FDA receives the IND, unless FDA notifies the sponsor that the investigations described in the IND are subject to a clinical hold," or on earlier notification by FDA that the investigations may begin.
Shipment follows the same clock. A sponsor may ship an investigational drug to investigators named in the IND thirty days after FDA receives it, or on earlier authorization. And an investigator "may not administer an investigational new drug to human subjects until the IND goes into effect."
The brake is the clinical hold, which the regulation defines as "an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation." Its consequences are written out: when a proposed study is held, subjects may not be given the drug; when an ongoing study is held, no new subjects may be recruited and placed on the drug, and patients already enrolled "should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the interest of patient safety."
The listed grounds for holding a phase 1 study include that human subjects "are or would be exposed to an unreasonable and significant risk of illness or injury," that the named investigators are not qualified by scientific training and experience, that the investigator brochure "is misleading, erroneous, or materially incomplete," or that the IND lacks sufficient information to assess the risks. For phase 2 and 3 studies, those grounds apply plus one more: that the plan or protocol "is clearly deficient in design to meet its stated objectives."
The rule against promotion, quoted in full
This is the provision that matters most for anyone reading marketing copy, and it is short enough to read whole. Section 312.7(a) states: "A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug."
The same paragraph then draws its own boundary, which is worth quoting because it is often misdescribed as a gag rule: "This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution."
Two more restrictions follow. "A sponsor or investigator shall not commercially distribute or test market an investigational new drug." And "A sponsor shall not unduly prolong an investigation after finding that the results of the investigation appear to establish sufficient data to support a marketing application."
So the line the regulation draws is between reporting a finding and making a claim. Publishing results, including in lay media, is expressly protected. Representing in a promotional context that the drug is safe or effective for the use under study, or otherwise promoting it, is not.
The label of an investigational drug says what it is
An investigational drug carries a required sentence. Section 312.6(a) provides that "The immediate package of an investigational new drug intended for human use shall bear a label with the statement 'Caution: New Drug—Limited by Federal (or United States) law to investigational use.'"
Paragraph (b) adds the labeling counterpart of the promotion rule: the label or labeling "shall not bear any statement that is false or misleading in any particular and shall not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated."
A parallel sentence exists for material that is not meant for people at all. Under section 312.160, a person may ship a drug "intended solely for tests in vitro or in animals used only for laboratory research purposes" if it is labeled: "CAUTION: Contains a new drug for investigational use only in laboratory research animals, or for tests in vitro. Not for use in humans." The shipper must "use due diligence to assure that the consignee is regularly engaged in conducting such tests," keep records of each shipment for two years, and permit FDA to inspect them. FDA may terminate the authorization to ship if the conditions are not met or if "the drug is used for purposes other than bona fide scientific investigation."
Those are two different sentences for two different situations, and neither of them is an endorsement. Both are warnings that the article is outside the approved supply.
What the part does not reach
Part 312 is narrower than the phrase clinical research suggests, and the exclusions are explicit. The definition of clinical investigation says that "an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice." And section 312.2(d) states that the part "does not apply to the use in the practice of medicine for an unlabeled indication of a new drug product approved under part 314 or of a licensed biological product."
A study of a drug that is already lawfully marketed can also be exempt from the part, but only if all five listed conditions hold: the investigation is not intended to be reported to FDA as a well-controlled study supporting a new indication or any other significant labeling change; if the drug is marketed as a prescription drug, the investigation is not intended to support a significant change in advertising; the investigation does not involve a route of administration, dosage level, patient population or other factor that significantly increases the risks; it complies with the institutional review requirements in part 56 and the informed consent requirements in part 50; and it complies with section 312.7 — the promotion rule, which follows the drug even out of the part.
For a reader comparing sellers, the useful consequence is this. Words like study, trial, protocol and research carry no regulatory weight on their own. The questions that carry weight are whether an IND is in effect, whether an institutional review board and informed consent process are involved, and whether what is being said about the product is a scientific finding or a promotional claim about safety or effectiveness. The regulation treats those last two as different things and permits only one of them.
Sources
- 21 CFR Part 312 — Investigational New Drug Application (sections 312.2, 312.3, 312.6, 312.7, 312.20, 312.40, 312.42 and 312.160)The definitions of investigational new drug, clinical investigation and IND, including the synonym Notice of Claimed Investigational Exemption for a New Drug; the requirement to submit an IND and the thirty-day effective date, shipment timing and bar on administration before the IND is in effect; the definition of a clinical hold and its consequences, and the listed grounds for holding phase 1 and phase 2 or 3 studies; the full text of the promotion, commercial distribution and prolonged-investigation rules in 312.7; the required caution statement and the labeling restriction in 312.6; the shipping caution, due-diligence, record and termination provisions in 312.160; and the exclusions in 312.2, including the five conditions for exempting a study of a lawfully marketed drug and the statement that the part does not apply to unlabeled use in the practice of medicine.
- 21 U.S.C. 355 — New drugs (subsections (a) and (i))The prohibition in subsection (a) on introducing or delivering an unapproved new drug into interstate commerce, and the direction in subsection (i)(1) to promulgate regulations exempting drugs intended solely for investigational use by qualified experts, along with the conditions Congress permitted to be attached to that exemption.
Frequently asked questions
What is an investigational new drug?
The regulation defines it as a new drug or biological drug that is used in a clinical investigation. The application that permits its use is described in the same definitions section as synonymous with a Notice of Claimed Investigational Exemption for a New Drug, which is what it is: an exemption from the statutory bar on shipping an unapproved new drug.
When may a study actually start?
An IND goes into effect thirty days after FDA receives it, unless FDA notifies the sponsor of a clinical hold, or earlier if FDA notifies the sponsor that the investigations may begin. An investigator may not administer the drug to human subjects until the IND is in effect, and shipment to named investigators follows the same timing.
Can a company advertise a drug that is still in trials?
The regulation says a sponsor or investigator, or anyone acting on their behalf, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes under investigation, or otherwise promote it. The same provision states that it is not meant to restrict the full exchange of scientific information, including dissemination of findings in scientific or lay media.
What does a clinical hold do?
It is an order to delay a proposed investigation or suspend an ongoing one. Under a hold, subjects in a proposed study may not be given the drug; in an ongoing study, no new subjects may be recruited and placed on it, and enrolled patients should be taken off therapy involving it unless FDA specifically permits otherwise in the interest of patient safety.
What does a research-only label on a substance mean?
Section 312.160 permits shipment of a drug intended solely for tests in vitro or in laboratory research animals if it bears a caution stating that it contains a new drug for investigational use only in laboratory research animals or for tests in vitro, and is not for use in humans. The shipper must use due diligence about the recipient and keep shipment records, and FDA may end the authorization if the drug is used for purposes other than bona fide scientific investigation.
Does a doctor prescribing an approved drug for an unapproved use need an IND?
Part 312 states that it does not apply to the use in the practice of medicine for an unlabeled indication of a new drug product approved under part 314 or of a licensed biological product, and its definition of a clinical investigation excludes the use of a marketed drug in the course of medical practice. Whether any particular use is appropriate is a clinical judgment, and this article makes no recommendation about one.