2. General Questions

2.1 Name of Regulatory Authority

U.S. Food and Drug Administration: the FDA is the regulatory authority that regulates clinical investigations of medical products in the U.S.

Within the FDA there are several centers. The ones responsible for the review of medicinal products are:

• Center for Drug Evaluation and Research (CDER)
• Center for Biologics Evaluation and Research (CBER)

The FDA regulations governing human subject protection and the conduct of clinical trials are found in the following links:

• Electronic Records; Electronic Signatures (21 CFR Part 11)
• Regulatory Hearing Before the Food and Drug Administration (21 CFR Part 16)
• Protection of Human Subjects (Informed Consent) (21 CFR Part 50)
• Financial Disclosure by Clinical Investigators (21 CFR Part 54)
• Institutional Review Boards (21 CFR Part 56)
• Investigational New Drug Application (21 CFR Part 312)

2.2 Name of Ethics Committee

IRBs can be independent (Central IRB) or affiliated with an institution (Local IRB).

In its DRAFT Guidance “Decentralized Clinical Trials for Drugs, Biological Products, and Devices”, the FDA has recommended the use of a central IRB in DCTs to facilitate efficient review of the protocol, the informed consent documents, and other relevant trial-related information.

In March 2006, the FDA published the guidance “Using a Centralized IRB Review Process in Multicenter Clinical Trials”. This guidance is intended to assist sponsors, institutions, IRBs, and clinical investigators involved in multicenter clinical research in meeting the requirements of 21 CFR 56 by facilitating the use of a centralized IRB review process (using a single central IRB), especially in situations where centralized review could improve efficiency or IRB review. 

2.3 Clinical Trial Application Language

English.

“(c) Material in a foreign language. The sponsor shall submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor shall also submit a copy of each original literature publication for which an English translation is submitted.” 

(Please refer to Section 4.1 of this guidebook and to 21CFR312.)

2.4 Is regulatory approval required from both regulatory authorities and/or EC?

Yes.

When submitting an Investigational New Drug (IND) application to the FDA, the sponsor is required to make “[a] commitment that an Institutional Review Board (IRB) that complies with the requirements set forth in 21CFR56 – will be responsible for the initial and continuing review and approval of each of the studies in the proposed clinical investigation and that the investigator will report to the IRB proposed changes in the research activity in accordance with the requirements of [21CFR56]." 

2.5 Can regulatory authority and EC submission be done in parallel?

Yes.

IND and IRB/s submissions can be made in parallel, but it is normally considered as a “submission at risk”, meaning that if the FDA has any additional comment and requests changes to the protocol submitted, the submission to the IRB will need to be amended. Sponsors must ensure that the IRB/s involved approved the latest protocol approved as per the IND. 

2.6 Requirement of any import permit/license before investigational product/study product is shipped from point of origin

See 21CFR312- § 312.110 Import and export requirements - once the investigational new drug application (IND) is in effect, import of the investigational product is permitted into the U.S:

“Imports. An investigational new drug offered for import into the United States complies with the requirements of this part if it is subject to an IND that is in effect for it…. and: 

1. The consignee in the United States is the sponsor of the IND; 
2. The consignee is a qualified investigator named in the IND; or 
3. The consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the investigational drug, and the IND identifies the consignee and describes what actions, if any, the consignee will take with respect to the investigational drug.”

See also Section 4.2 of this guidebook.

2.7 Biological Specimen Export Requirements

Please refer to Section 6 of this guidebook.

2.8 Are studies of GMOs permitted (e.g., GMOs used in vaccines/vaccine manufacture and other modified products)?

Yes.

Gene therapy products are biological products regulated by the FDA’s Center for Biologics Evaluation and Research (CBER). Clinical studies in humans require the submission of an investigational new drug application (IND) prior to initiating clinical studies in the United States. Marketing a gene therapy product requires submission and approval of a biologics license application (BLA).

The FDA has published various guidance on cellular and gene therapy. The most recent and draft guidance published includes:

• DRAFT Guidance: Safety Testing of Human Allogeneic Cells Expanded for Use in Cell-Based Medical Products (Open for public comment on April 2024)- this guidance supplements the following final guidance:
  • Guidance for Industry-Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy 29 Investigational New Drug Applications (INDs) (January 2020).
  • Guidance for Human Somatic Cell Therapy and Gene Therapy Guidance for Industry (March 1998), which provides that: “IND applications for somatic cell and gene therapies should follow the same format and contain the same sections as IND's for any investigational biological product, as described in 21 CFR 312.23 which sets out the Investigational New Drug Application (IND) content and format that a sponsor must submit to the FDA before commencing clinical trials and which does not explicitly mention either GMOs, somatic cell, or gene therapies).”

(Somatic cell therapy is the administration to humans of autologous, allogeneic, or xenogeneic living, non-germline, cells, other than transfusable blood products, which have been manipulated or processed ex vivo. For therapeutic, diagnostic, or preventive purposes. Gene therapy is a medical intervention based on the modification of the genetic material of living cells. Cells may be modified ex vivo for subsequent administration to humans or may be altered in vivo by gene therapy given directly to the subject. When the genetic manipulation is performed ex vivo on cells which are then administered to the patient, this is also a form of somatic cell therapy. The genetic manipulation may be intended to have a therapeutic or prophylactic effect or may provide a way of marking cells for later identification. Recombinant DNA materials used to transfer genetic material for such therapy are considered components of gene therapy and as such are subject to regulatory oversight).

The FDA requires that exploratory phase I trials for somatic cell and gene therapy products should be based on data that assure reasonable safety and rationale. Fewer data may be submitted to support beginning exploratory trials that may be submitted at later stages of product development, especially in the case of severe or life-threatening diseases. The review of data to support the initiation of phase I trials focuses on safety, although some demonstration of rationale should also be provided by sponsors.

Further reading:

• Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products Guidance for Industry (June 2015); and
• FDA Guidance: Cellular & Gene Therapy Products.

2.9 Is in-country sponsor presence/representation required?

Yes.

As per 21CFR312 - § 312.23 IND content and format - 1 (ix)…” if the sponsor is not based in the U.S., then the IND is required to contain the name and address of, and be countersigned by, an attorney, agent, or other authorized official who resides or maintains a place of business within the United States.”

“(viii) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, a statement containing the name and address of the contract research organization, identification of the clinical study, and a listing of the obligations transferred. If all obligations governing the conduct of the study have been transferred, a general statement of this transfer - in lieu of a listing of the specific obligations transferred - may be submitted.”

2.10 Is there any mandatory requirement to identify a local PI or can a PI be based in a foreign country? 

Yes.

21CFR312, § 312.53 Selecting investigators and monitors, sets forth the requirements for selecting investigators.

Investigators conducting clinical trials in the U.S. must be licensed physicians and hold license/s for the state/s in which they intend to practice medicine. 

2.11 Is there any mandatory requirement to identify a local chief or coordinating investigator? 

No.

21CFR312 - § 312.3 Definitions and interpretations: “Investigator” means an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. “Subinvestigator” includes any other individual member of that team.”

2.12 If the applicant is CRO or a third party, does regulatory authority need any authorization or transfer of obligations from the sponsor? Does the authorization letter need to be notarized and/or apostilled? 

Yes.

Any trial-related responsibilities transferred to and assumed by a CRO should be specified in writing, and those obligations not covered by the written description shall be deemed not to have been transferred. Further, a CRO that assumes any sponsor obligations must comply with the specific regulations delineated in 21CFR312.23 and shall be subject to the same regulatory action as the sponsor for failure to comply with any obligation assumed under these regulations.

If all obligations governing the conduct of the study have been transferred to the CRO, a general statement of this transfer - in lieu of a listing of the specific obligations transferred - may be submitted.

However, although a sponsor may transfer all of his/her trial-related duties and functions to a CRO, the sponsor is ultimately responsible for the study data’s quality and integrity.

We have not been able to determine any requirements to notarize/apply an apostille to such a letter of authority to the CRO submitted as part of the IND.

2.13 Is there a requirement to register clinical trials on a local registry or database?

Yes.

42CFR11.24 requires that the clinical trial be registered by the person responsible for it (either the sponsor, CRO, or principal investigator) on ClinicalTrials.gov no later than 21 days after the first clinical subject has been enrolled.

2.14 What is the local requirement for clinical study documents archival; minimum of years for the archival, specific format followed (electronic/paper and/or both)?

2 years after the grant of an MA/abandonment of the IND.

21CFR312.57 - Record Keeping & Retention - requires that records be kept for 2 years post the grant of a Marketing Authorization (or until 2 years after shipment and delivery of the drug for investigational use is discontinued and FDA has been so notified):

"(a) A sponsor shall maintain adequate records showing the receipt, shipment, or other disposition of the investigational drug. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment. 

(b) A sponsor shall maintain complete and accurate records showing any financial interest…. paid to clinical investigators by the sponsor of the covered study. A sponsor shall also maintain complete and accurate records concerning all other financial interests of investigators.

(c) A sponsor shall retain the records and reports required by this part for 2 years after a marketing application is approved for the drug; or, if an application is not approved for the drug, until 2 years after shipment and delivery of the drug for investigational use is discontinued and FDA has been so notified. 

(d) A sponsor shall retain reserve samples of any test article and reference standard identified in, and used in any of the bioequivalence or bioavailability studies described…. and release the reserve samples to FDA upon request [for at least 5 years – see 21CFR320.28]."

2.15 Requirements around periodic safety reporting and timelines on SAEs/AEs/ADRs/SUSARs/DSURs.

21CFR312.32 - IND Safety Reporting - provides detailed requirements and definitions for safety reporting.

(c) (1) “[t]he sponsor must notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potentially serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies for reporting….. In each IND safety report, the sponsor must identify all IND safety reports previously submitted to FDA concerning a similar suspected adverse reaction, and must analyze the significance of the suspected adverse reaction in light of previous, similar reports or any other relevant information.”

As further detailed in 21CFR312, the notification requirement covers:

• Serious and unexpected suspected adverse reactions
• Findings from other studies
• Findings from animal or in vitro testing
• Increased rate of occurrence of serious suspected adverse reactions
• Submission of IND safety reports
• Unexpected fatal or life-threatening suspected adverse reaction reports - the sponsor must also notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the information.
• Reporting study endpoints

Additionally, the FDA page “IND Application Reporting: Safety Reports” provides a summary of requirements and supporting available guidance, such as:

• Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies
• Final Rule: Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans
• Sponsor Responsibilities—Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies Guidance for Industry (Draft 2021)
• Investigator Responsibilities – Safety Reporting for Investigational Drugs and Devices (Draft 2021)

2.16 Requirement on any periodic clinical study update, specific template, and its frequency (e.g., interim or annual progress report and final report, etc.)? 

According to 21CFR312.33, the sponsor is required to submit annual reports, as follows:

“A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief report of the progress of the investigation that includes:

(a) Individual study information. A brief summary of the status of each study in progress and each study completed during the previous year. The summary is required to include the following information for each study:

1. The title of the study (with any appropriate study identifiers such as protocol number), its purpose, a brief statement identifying the patient population, and a statement as to whether the study is completed.
2. The total number of subjects initially planned for inclusion in the study; the number entered into the study to date, tabulated by age group, gender, and race; the number whose participation in the study was completed as planned; and the number who dropped out of the study for any reason. 
3. If the study has been completed, or if interim results are known, a brief description of any available study results. 

(b) Summary information. Information obtained during the previous year's clinical and nonclinical investigations, including:

1. A narrative or tabular summary showing the most frequent and most serious adverse experiences by the body system. 
2. A summary of all IND safety reports submitted during the past year. 
3. A list of subjects who died during participation in the investigation, with the cause of death for each subject. 
4. A list of subjects who dropped out during the course of the investigation in association with any adverse experience, whether or not thought to be drug-related. 
5. A brief description of what, if anything, was obtained that is pertinent to an understanding of the drug's actions, including, for example, information about dose-response, information from controlled trials, and information about bioavailability. 
6. A list of the preclinical studies (including animal studies) completed or in progress during the past year and a summary of the major preclinical findings. 
7. A summary of any significant manufacturing or microbiological changes made during the past year. 

(c) A description of the general investigational plan for the coming year to replace that submitted 1 year earlier.

(d) If the investigator brochure has been revised, a description of the revision and a copy of the new brochure. 

(e) A description of any significant Phase 1 protocol modifications made during the previous year and not previously reported to the IND in a protocol amendment. 

(f) A brief summary of significant foreign marketing developments with the drug during the past year, such as approval of marketing in any country or withdrawal or suspension from marketing in any country. 

(g) If desired by the sponsor, a log of any outstanding business with respect to the IND for which the sponsor requests or expects a reply, comment, or meeting.” 

2.17 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol? 

Yes, in certain circumstances.

21CFR56.113 - Suspension or termination of IRB approval of research - covers the circumstances in which notification is required: “[a]n IRB shall have authority to suspend or terminate approval of research that is not being conducted in accordance with the IRB's requirements or that has been associated with unexpected serious harm to subjects. Any suspension or termination of approval shall include a statement of the reasons for the IRB's action and shall be reported promptly to the investigator, appropriate institutional officials, and the Food and Drug Administration.”)

21CFR312.56 - Review of ongoing investigations - is also relevant: “a sponsor who discovers that an investigator is not complying with the signed agreement (Form FDA-1572), the general investigational plan, or the requirements of this part or other applicable parts shall promptly either secure compliance or discontinue shipments of the investigational new drug to the investigator and end the investigator's participation in the investigation”. In those circumstances, the sponsor should also notify the FDA.

2.18 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?

U.S. regulations do not require insurance.

There is no federal requirement for clinical trial liability insurance or indemnity coverage. However, it is standard business practice for sponsors/representatives to carry liability insurance coverage on clinical trials and for sponsors/representatives and investigators/sites to enter into indemnity agreements. Some IRBs may require evidence of liability insurance coverage and indemnity agreement in order to approve the study protocol.