Investigational Applications and the Clinical Hold
An investigational application is never approved. It becomes effective when nobody objects within a fixed period, which makes the agency's silence the operative event and a clinical hold the only thing that can interrupt it.
The rule in short
Under 21 U.S.C. 355(i) and 21 CFR Part 312, a sponsor intending to administer an investigational drug to human subjects submits an application containing manufacturing, pharmacology, toxicology and prior human experience information plus protocols. Section 312.40 permits the study to begin thirty days after receipt unless a clinical hold is imposed. Section 312.42 states the grounds for a hold and how one is lifted.
Federal law bars shipping an unapproved new drug in interstate commerce. Clinical research would be impossible under that rule, so the statute creates an exemption for drugs intended solely for investigational use, and the regulations set the conditions. The result is an application that is never granted. It simply becomes effective if the agency does not stop it.
When an application is required
Section 312.20 of Title 21 requires a sponsor to submit an investigational new drug application before conducting a clinical investigation with an investigational drug. The sponsor is whoever takes responsibility for and initiates the investigation, which may be a company, an institution or an individual physician. A physician who both sponsors and conducts a study carries both sets of obligations.
Not every study of a marketed drug needs one. The regulations exempt certain investigations of a lawfully marketed drug where the study is not intended to support a new indication or a labeling change, is not intended to support a significant change in advertising, does not involve a route, dose, population or other factor that significantly increases risk, and complies with review board and consent requirements. Sponsors who assume the exemption applies without walking through each condition are the ones who discover afterward that it did not.
What the application must contain
Section 312.23 lists the content. There is a cover sheet identifying the sponsor and the drug, a general investigational plan describing what the sponsor intends over the coming year, and an investigator's brochure summarizing what is known about the drug's chemistry, pharmacology, toxicology and any prior human experience. Protocols for each planned study follow.
The application is also a living file rather than a fixed submission. Protocol amendments are filed when a protocol changes or a new one is added, information amendments carry new chemistry or toxicology data, and new investigators are reported as they join. A sponsor that treats the original filing as complete and adds nothing generates the most common deficiency in this area, which is an agency reviewing a program on information that no longer describes it.
The technical sections carry the weight. Chemistry, manufacturing and control information must establish the identity, quality, purity and strength of the material to be administered, and must show that the manufacturing process is adequately controlled. Pharmacology and toxicology information must be sufficient to conclude that the drug is reasonably safe to administer at the proposed doses and durations. Where the drug has been used in humans anywhere, that experience must be summarized, including any withdrawal from marketing in another country and the reasons for it.
The waiting period is thirty days from the agency's receipt of the application, not thirty days from the sponsor's mailing and not thirty business days. If the agency does not act, the sponsor may proceed. Sponsors sometimes read a lack of comment as a lack of engagement, which is a mistake: the agency reviewed the file and chose not to intervene. Nothing about that constitutes an endorsement of the design, and it does not prevent a hold later.
The clinical hold
Section 312.42 defines a clinical hold as an order to delay a proposed investigation or to suspend one already in progress. It may be complete, stopping all work under the application, or partial, stopping a protocol, a dose level, a population or further enrollment. The order may issue before the waiting period expires or at any point afterward.
Two features of the hold power are worth separating. It is not a penalty and it does not require any misconduct; it is a safety instrument used when the agency cannot satisfy itself on the information available. And it does not require the study to have started. A hold imposed during the waiting period simply prevents the application from becoming effective, which is why sponsors that have planned a site initiation for the day after the period expires are exposed to a schedule they do not control.
The grounds differ by stage. For a phase 1 study, a hold may be imposed where human subjects would be exposed to an unreasonable and significant risk of illness or injury, where the clinical investigators are not qualified by training and experience, where the investigator's brochure is misleading, erroneous or materially incomplete, or where the application does not contain sufficient information to assess the risks. For phase 2 and phase 3 studies, those grounds remain available and one more is added: a plan or protocol clearly deficient in design to meet its stated objectives.
| Route | What is filed | Who must act before enrollment | Waiting period | How work is stopped |
|---|---|---|---|---|
| Investigational new drug application | Full application under 21 CFR 312.23 | Review board approval; agency may object | Thirty days from receipt | Clinical hold under 312.42 |
| Significant risk device study | Investigational device exemption application | Agency approval and review board approval | Until the agency approves or the period runs | Withdrawal of approval of the exemption |
| Nonsignificant risk device study | No application to the agency; abbreviated records | Review board approval only | None | Review board suspension, or agency action |
| Exempt study of a marketed drug | Nothing, if every exemption condition is met | Review board approval | None | Review board suspension |
| Expanded access for treatment use | Protocol or separate application | Agency authorization and review board approval | As specified for the access type | Clinical hold on the access protocol |
Responding to a hold and living under the application
A hold is communicated first by telephone or other rapid means and then confirmed in writing with the reasons. The sponsor prepares a complete response addressing each stated ground, and the agency evaluates it and either lifts the hold or explains what remains outstanding. The hold ends only by written notification, so a sponsor that believes it has answered everything may not resume on that belief.
Once studies are running, the application becomes a continuing reporting relationship rather than a filed document. Serious and unexpected suspected adverse reactions must be reported on an expedited basis, with the shortest deadline reserved for reactions that are fatal or life-threatening, an obligation that parallels the postmarket duties described in adverse event and malfunction reporting. Protocol amendments, new investigators and annual updates are submitted as the program develops.
Two constraints bracket the whole period. Study conduct depends on oversight and consent obtained under the rules set out in review board approval and the elements of a consent document. And commercialization is barred: a sponsor may not represent an investigational drug as safe or effective for the use under investigation, a limit closely related to the promotional rules discussed in what may be said outside approved labeling. What the accumulated data eventually supports is filed in the application described in the new drug application and its review cycle.
Points to carry away
- The application becomes effective by the passage of thirty days rather than by approval.
- A clinical hold may be imposed before a study starts or on a study already underway.
- Unreasonable and significant risk of illness or injury is the core ground for a hold.
- Later-phase studies can be held for a design clearly deficient to meet stated objectives.
- A hold is lifted in writing after the agency evaluates a complete response.
- Commercial promotion and commercial distribution of an investigational drug are prohibited.
Questions readers ask
Can a sponsor charge subjects for an investigational drug?
Only with authorization, and the default is that a sponsor may not commercialize an investigational drug. The regulations permit charging in defined circumstances, principally to recover certain costs in a clinical trial or in expanded access, and the sponsor must obtain the agency's authorization and justify the amount by reference to permitted cost categories. Charging without authorization is treated as commercialization of an unapproved drug. Sponsors also may not represent an investigational drug as safe or effective for the purpose under investigation, which limits what may be said to potential participants and to investors alike.
What is a partial clinical hold?
It is a hold that stops part of the investigational work rather than all of it. The agency may hold a single protocol while others continue, hold enrollment of a particular population such as pediatric subjects, hold a dose level above a stated threshold, or hold escalation while permitting subjects already dosed to continue. Partial holds are common in dose-finding programs where a specific safety signal appeared at one level. The procedural consequences are the same as for a complete hold: the sponsor responds, the agency evaluates, and the hold is lifted only in writing.
Does an investigational application ever expire?
It does not expire on a clock, but it can be placed on inactive status where no subjects are enrolled and no studies are ongoing for a sustained period, and it can be withdrawn by the sponsor at any time. The agency can also propose to terminate an application on stated grounds, with an opportunity for the sponsor to respond. Sponsors that let an application go quiet should understand that reactivating it means demonstrating the manufacturing, safety and protocol information is current, not simply announcing an intention to resume.
Sources
- Cornell Legal Information Institute — 21 U.S.C. 355, New DrugsSubsection (i) authorizes the exemption for drugs intended solely for investigational use.
- eCFR — 21 CFR 312.20, Requirement for an INDWhen a sponsor must submit an investigational new drug application.
- eCFR — 21 CFR 312.23, IND Content and FormatThe required sections, from the investigational plan to chemistry and toxicology information.
- eCFR — 21 CFR 312.40, General Requirements for Use of an Investigational New DrugThe thirty-day waiting period and the conditions for beginning a study.
- eCFR — 21 CFR 312.42, Clinical Holds and Requests for ModificationThe grounds for a hold by phase and the procedure for imposing and lifting one.
- eCFR — 21 CFR 312.32, IND Safety ReportingExpedited reporting of serious and unexpected suspected adverse reactions.
- eCFR — 21 CFR Part 812, Investigational Device ExemptionsThe parallel route for investigational devices and the significant risk determination.
Liberty Law Library is a publication, not a law firm. This article states general rules and cites its sources; it is not advice about any particular case, and the law differs by state and changes over time.
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