FDA rules for clinical studies of drugs and biologics

Studies of drugs and biological products in people are governed by 21 CFR Part 312 and 21 CFR Part 50. Part 312 applies to all clinical investigations of products subject to section 505 of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions of the Public Health Service Act.¹ A sponsor must submit an investigational new drug application to FDA before beginning such an investigation and may not begin until the IND is in effect.¹ Part 50 applies more broadly, to all clinical investigations regulated by FDA and to investigations whose results are intended to support an application for a research or marketing permit.²

When an IND is required

A sponsor must submit an IND if it intends to conduct a clinical investigation with an investigational new drug subject to § 312.2(a), and it may not begin that investigation until an IND is in effect under § 312.40.¹ Part 312 defines a clinical investigation as any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. Use of a marketed drug in the course of medical practice falls outside that definition.¹ An investigational new drug means a new drug or biological drug used in a clinical investigation, and the term also covers a biological product used in vitro for diagnostic purposes.¹

An IND goes into effect 30 days after FDA receives it, unless FDA notifies the sponsor that the investigations are subject to a clinical hold.¹ It goes into effect earlier if FDA notifies the sponsor that the investigations may begin. FDA notifies the sponsor in writing of the date it received the IND.¹ An investigator may not administer an investigational new drug to human subjects until the IND is in effect.¹

A clinical investigation involving an exception from informed consent for emergency research under § 50.24 must be performed under a separate IND that clearly identifies protocols which may include subjects unable to consent.² That IND goes into effect 30 days after FDA receives it, unless FDA notifies the sponsor of a clinical hold, or on earlier notification that the investigations may begin.¹ FDA provides a written determination 30 days after receiving that IND or earlier.¹ The separate application is required even where an IND for the same drug product already exists.²

Investigations exempt from Part 312

A clinical investigation of a drug product lawfully marketed in the United States is exempt from Part 312 if all five conditions in § 312.2(b)(1) are met. The investigation must not be intended for report to FDA as a well-controlled study supporting a new indication or any other significant labeling change. For a lawfully marketed prescription drug, it must not be intended to support a significant change in advertising. It must not involve a route of administration, dosage level, patient population or other factor that significantly increases the risks associated with use of the drug. It must comply with the institutional review requirements of part 56, the informed consent requirements of part 50 and the promotion restrictions of § 312.7.¹

Three further exemptions appear in § 312.2(b). A clinical investigation of blood grouping serum, reagent red blood cells or anti-human globulin is exempt where the product is intended to confirm a diagnosis made by another medically established product or procedure and is shipped in compliance with § 312.160. A drug intended solely for tests in vitro or in laboratory research animals is exempt if shipped under § 312.160. An investigation involving a placebo is exempt where the investigation does not otherwise require an IND.¹ FDA will not accept an application for an investigation exempt under § 312.2(b)(1).¹ Part 312 does not apply to use in the practice of medicine for an unlabeled indication of an approved drug product or a licensed biological product.¹ On request, FDA will advise on the applicability of the part to a planned clinical investigation.¹

Phases of an investigation

An IND may be submitted for one or more phases, and the investigation of a previously untested drug is generally divided into three.¹ Phase 1 covers the initial introduction into humans, is designed to determine metabolism, pharmacologic actions and side effects at increasing doses, and generally involves 20 to 80 subjects.¹ Phase 2 covers controlled studies evaluating effectiveness for a particular indication and common short-term risks, usually in no more than several hundred subjects.¹ Phase 3 studies are expanded controlled and uncontrolled trials that support the overall benefit-risk evaluation and physician labeling, usually with several hundred to several thousand subjects.¹ The phases may overlap.¹

FDA reviews Phase 1 submissions with a focus on the safety of the investigation. For Phases 2 and 3 the review also assesses scientific quality and the likelihood that the studies will yield data capable of meeting the statutory standards for marketing approval.¹

Content of the IND

Section 312.23 requires the application to be submitted in a set order, beginning with a cover sheet on Form FDA 1571. That cover sheet contains:

• the sponsor’s name, address and telephone number, the date of the application and the name of the drug
• identification of the phase or phases of the clinical investigation to be conducted
• a commitment not to begin clinical investigations until an IND covering them is in effect
• a commitment that an IRB complying with part 56 will be responsible for initial and continuing review and approval of each study
• a commitment to conduct the investigation in accordance with all other applicable regulatory requirements
• the name and title of the person responsible for monitoring the conduct and progress of the investigations
• the names and titles of the persons responsible under § 312.32 for review of safety information
• a statement identifying any contract research organization and the obligations transferred to it
• the signature of the sponsor or the sponsor’s authorized representative

Where the person signing does not reside or have a place of business in the United States, the IND must contain the name and address of a United States attorney, agent or other authorized official and be countersigned by that person.¹ A table of contents follows the cover sheet. The introductory statement gives the following.¹

• the drug name and active ingredients
• pharmacological class
• structural formula
• dosage form
• route of administration
• objectives
• a summary of previous human experience
• any withdrawal from investigation or marketing in another country for reasons of safety or effectiveness

A sponsor may request a waiver of a requirement of Part 312, either in the IND or in an information amendment.¹ FDA may grant the waiver where noncompliance would not pose a significant and unreasonable risk to human subjects and one of the grounds in § 312.10(b) is met.¹

Clinical holds

A clinical hold is an order issued by FDA to the sponsor to delay a proposed investigation or suspend an ongoing one, and it may apply to one or more investigations under an IND.¹ Subjects may not be given the drug under a proposed study on hold. In an ongoing study on hold, no new subjects may be recruited and placed on the drug, and patients already enrolled should be taken off therapy unless FDA specifically permits otherwise in the interest of patient safety.¹

The grounds for holding a Phase 1 study are unreasonable and significant risk of illness or injury to subjects, investigators unqualified by scientific training and experience, an investigator brochure that is misleading, erroneous or materially incomplete, and insufficient information under § 312.23 to assess risk.¹ A further ground applies where a drug for a life-threatening condition excludes men or women of reproductive potential because of reproductive or developmental toxicity risk.¹ For Phase 2 and 3 studies, those grounds apply and FDA may also hold a study whose plan or protocol is clearly deficient in design to meet its stated objectives.¹

Sponsor responsibilities

Sponsors are responsible for selecting qualified investigators, giving them the information needed to conduct the investigation properly, ensuring proper monitoring and maintaining an effective IND.¹ Before permitting an investigator to begin, the sponsor must obtain a signed investigator statement on Form FDA 1572, a curriculum vitae showing the investigator’s qualifications and the clinical protocol.¹ The sponsor ships investigational drugs only to investigators participating in the investigation.¹ A sponsor other than a sponsor-investigator must give each participating investigator an investigator brochure before the investigation begins and must keep investigators informed of new observations as the investigation proceeds.¹

A sponsor who discovers that an investigator is not complying with the signed agreement or the regulations must promptly secure compliance or discontinue shipments and end that investigator’s participation, and must notify FDA if participation ends.¹ A sponsor who determines that its drug presents an unreasonable and significant risk to subjects must discontinue the investigations presenting that risk and notify FDA, all IRBs and all investigators who have participated. Discontinuation must occur as soon as possible and no later than five working days after the determination.¹ Sponsor records must be retained for two years after approval of a marketing application, or for two years after shipment for investigational use is discontinued and FDA is notified.¹

Promotion of an investigational new drug as safe or effective for the use under investigation is prohibited, as is commercial distribution or test marketing.¹ A sponsor may not unduly prolong an investigation after finding that the results appear to establish sufficient data to support a marketing application.¹

Investigator responsibilities

An investigator is responsible for conducting the investigation according to the signed investigator statement, the investigational plan and the applicable regulations, for protecting the rights, safety and welfare of subjects, and for control of the drug.¹ The investigator must obtain informed consent from each subject in accordance with part 50 and must assure that an IRB complying with part 56 carries out initial and continuing review.¹ The drug may be administered only under the investigator’s personal supervision or that of a responsible subinvestigator.¹

Investigator records include the disposition of the drug and case histories recording all observations and data for each individual. Case histories include case report forms, signed and dated consent forms and medical records, and each must document that consent was obtained before participation.¹ These records are retained for two years after a marketing application is approved for the indication under investigation, or for two years after the investigation is discontinued and FDA is notified.¹ An investigator must immediately report to the sponsor any serious adverse event, with an assessment of whether there is a reasonable possibility that the drug caused it.¹

Protocol amendments, safety reporting and annual reports

A new protocol is submitted to FDA as a protocol amendment, and the study may begin once the sponsor has submitted it to FDA and the IRB has approved it. The two conditions may be met in either order.¹ The same two conditions apply to a protocol change that significantly affects subject safety in Phase 1. They also apply to a change affecting safety, scope or scientific quality in Phase 2 or 3.¹ A change intended to eliminate an apparent immediate hazard may be implemented immediately, with subsequent notification to FDA by protocol amendment and to the IRB under § 56.104(c).¹ A new investigator is reported to FDA within 30 days of being added.¹

Section 312.32 defines the terms that drive safety reporting. An adverse event is any untoward medical occurrence associated with drug use, whether or not considered drug related. A suspected adverse reaction is an adverse event for which there is evidence suggesting a causal relationship with the drug. An event is serious where it results in death, a life-threatening event, inpatient hospitalization or its prolongation, persistent or significant incapacity, or a congenital anomaly. An event is unexpected where it is absent from the investigator brochure or appears there at lesser specificity or severity.¹

The sponsor submits an annual report within 60 days of the anniversary of the date the IND went into effect. It covers the status of each study, enrolment tabulated by age group, gender and race, a summary of adverse experiences and IND safety reports, subjects who died or dropped out in association with an adverse experience, preclinical studies completed or in progress, significant manufacturing or microbiological changes, the investigational plan for the coming year, investigator brochure revisions, significant Phase 1 protocol modifications and foreign marketing developments.¹

Informed consent under Part 50

No investigator may involve a human being as a subject unless legally effective informed consent has been obtained from the subject or the subject’s legally authorized representative.² Consent must be sought under circumstances that give sufficient opportunity to consider participation and that minimize coercion or undue influence. The information must be in language understandable to the subject or representative, and exculpatory language waiving legal rights is prohibited.²

The basic elements required by § 50.25(a) are:

• a statement that the study involves research, its purpose, the expected duration and a description of the procedures
• a description of reasonably foreseeable risks or discomforts
• a description of benefits reasonably expected for the subject or others
• disclosure of appropriate alternative procedures or courses of treatment
• a statement on confidentiality of records and the possibility of FDA inspection
• for research involving more than minimal risk, an explanation of compensation and medical treatment available if injury occurs
• whom to contact about the research, subject rights and research-related injury
• a statement that participation is voluntary and may be discontinued without penalty

Additional elements in § 50.25(b) apply when appropriate, including unforeseeable risks, circumstances of termination by the investigator, additional costs and the approximate number of subjects.² For applicable clinical trials under 42 U.S.C. 282(j)(1)(A), consent documents and processes must carry the prescribed ClinicalTrials.gov statement.² Consent is documented by a written form approved by the IRB and signed and dated by the subject or representative, with a copy given to the person signing. A short form written document with a witness and an IRB-approved written summary is the alternative.²

Exceptions to the consent requirement

Section 50.22 allows an IRB to alter or waive consent for a minimal risk investigation where it finds and documents the following.²

• the study involves no more than minimal risk
• the study could not practicably be carried out without the waiver
• the study could not practicably be carried out without identifiable information or biospecimens where these are used
• the waiver will not adversely affect subject rights and welfare
• where appropriate, subjects or their representatives receive additional pertinent information after participation

Section 50.23 covers life-threatening situations where the investigator and a non-participating physician certify in writing that consent cannot be obtained, that time is insufficient to reach the subject’s legal representative and that no alternative therapy offers an equal or greater likelihood of saving the subject’s life.² Where immediate use is required, the independent review is made within five working days and the documentation goes to the IRB within five working days of use.²

Section 50.24 governs emergency research. The IRB must find that subjects are in a life-threatening situation, that available treatments are unproven or unsatisfactory and that consent is not feasible. A licensed physician who is not participating must concur in those findings. Additional protections include community consultation, public disclosure before and after the investigation and an independent data monitoring committee.²

Children as subjects

Subpart D of Part 50 sets the conditions for enrolling children. An IRB may approve an investigation presenting no greater than minimal risk, or one presenting more than minimal risk with the prospect of direct benefit where the risk is justified by the anticipated benefit.² Where more than minimal risk is presented with no prospect of direct benefit, the risk must represent a minor increase over minimal risk and the study must be likely to yield generalizable knowledge of vital importance about the subjects’ condition.² Investigations outside these categories proceed only after the Commissioner of Food and Drugs consults a panel of experts and makes the determinations in § 50.54(b).² Permission of one parent may suffice under §§ 50.51 and 50.52, and both parents must give permission under §§ 50.53 and 50.54 unless one is deceased, unknown, incompetent, not reasonably available or without legal responsibility for the child.²

Foreign studies conducted without an IND

FDA will accept a well-designed and well-conducted foreign clinical study not conducted under an IND in support of an IND or a marketing application, where the study was conducted in accordance with good clinical practice and FDA is able to validate the data through an onsite inspection if it deems that necessary.¹ Good clinical practice for this purpose includes review and approval by an independent ethics committee before the study begins, continuing IEC review and documented freely given informed consent.¹ The sponsor or applicant must describe the actions taken to ensure conformity with GCP, including the investigator’s qualifications, the research facilities, a detailed summary of the protocol and results, and a description of the drug substance and drug product used.¹

Questions people also ask

Does a study of an already approved drug need an IND?

Not in every case. A clinical investigation of a drug product lawfully marketed in the United States is exempt where all five conditions of § 312.2(b)(1) are satisfied. Those conditions concern the intended use of the results in labeling and advertising, the level of added risk from the route, dose or population, and compliance with parts 50 and 56 and with § 312.7. FDA will not accept an application for an investigation that is exempt on this basis.¹

How long after submitting an IND can dosing begin?

An IND goes into effect 30 days after FDA receives it, unless FDA notifies the sponsor of a clinical hold under § 312.42. It may go into effect earlier if FDA notifies the sponsor that the investigations may begin. A sponsor may ship the drug to named investigators 30 days after receipt of the IND or on earlier FDA authorization.¹

What is Form FDA 1572 and who signs it?

Form FDA 1572 is the signed investigator statement that a sponsor must obtain before permitting an investigator to begin participation. It records the following.

• the investigator’s name and address
• the protocols to be conducted
• the research facility
• clinical laboratory facilities
• the responsible IRB
• the subinvestigators

It carries the investigator’s commitments to follow the protocol, to supervise the investigation personally, to obtain informed consent and to report adverse experiences to the sponsor under § 312.64.¹

Can a trial proceed without informed consent from subjects?

Three provisions allow it in defined circumstances. Section 50.22 permits an IRB to waive or alter consent for minimal risk investigations on documented findings. Section 50.23 covers use of a test article in a life-threatening situation certified by the investigator and an independent physician. Section 50.24 covers emergency research, which requires IRB findings, community consultation and public disclosure, and must be conducted under a separate IND.²

Who counts as a sponsor-investigator?

A sponsor-investigator is an individual who both initiates and conducts an investigation and under whose immediate direction the drug is administered or dispensed. The requirements applicable to that person include both the sponsor requirements and the investigator requirements of Part 312. An organization that uses its own employees to conduct an investigation it initiated is a sponsor, and those employees are investigators.¹

Footnotes

1. 21 CFR Part 312, Investigational New Drug Application. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³ ↩¹⁴ ↩¹⁵ ↩¹⁶ ↩¹⁷ ↩¹⁸ ↩¹⁹ ↩²⁰ ↩²¹ ↩²² ↩²³ ↩²⁴ ↩²⁵ ↩²⁶ ↩²⁷ ↩²⁸ ↩²⁹ ↩³⁰ ↩³¹ ↩³² ↩³³ ↩³⁴ ↩³⁵ ↩³⁶ ↩³⁷ ↩³⁸ ↩³⁹ ↩⁴⁰ ↩⁴¹ ↩⁴² ↩⁴³ ↩⁴⁴ ↩⁴⁵ ↩⁴⁶ ↩⁴⁷ ↩⁴⁸ ↩⁴⁹ ↩⁵⁰ ↩⁵¹ ↩⁵² ↩⁵³ ↩⁵⁴ ↩⁵⁵ ↩⁵⁶ ↩⁵⁷ ↩⁵⁸

2. 21 CFR Part 50, Protection of Human Subjects. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-50 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³ ↩¹⁴ ↩¹⁵ ↩¹⁶ ↩¹⁷