Medicinal Products

Use of FDA 1572 form for clinical trials in Rebublic Serbia (RS)

FDA  –  Food and Drug Administration

CFR  –  Code of Federal Regulations

GCP  –  Good Clinical Practice

IND  –  Investigational New Drugs

RBI  –  Institutional Review Board

CT  –  Clinical Trial

Do investigators in CTs have to sign a 1572 form and is it consistent with RS local regulations to conduct a clinical trial in RS under United States (US) Investigational New Drug (IND) regulations?

No, the investigators in the RS cannot fulfill the requirements stated in the form 1572. The clinical trial conducted at the sites in the RS cannot be conducted under any law of a foreign country. CT must be carried out in accordance with the national legislation specified in the Law and subsequent by-laws:

  • Law on Medicines and Medical Devices (“Official Gazette of the RS”, no. 30/2010 and 107/2012, 105/17-dr.zakon, 113/2017 – dr.zakon)
  • Rulebook on clinical trials of drugs in human medicine (“Official Gazette of RS”, no. 51/2022, 65/2023, 86/2023)

A common finding during surveillance of multinational clinical trials by US sponsors or sponsors conducting a clinical trial under US regulations are FDA 1572 forms signed by investigators. FDA Form 1572 is rooted in US law Title 21 Code of Federal Regulations (CRF) 312.53 (c) “Responsibilities of Sponsors and Investigators: Selecting Investigators and monitors” and the form should be signed by the investigator if the CT is being conducted as a so-called IND study .

In section 9 of FDA Form 1572, entitled “Obligations“, by signing the form the investigator agrees to comply with the following conditions, but not limited to:

  • Title 21 CFR Part 50 (obtaining informed consent)
  • Title 21 CFR Part 56 (ensuring that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for review and approval)
  • Title 21 Part 312 (compliance with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements)
  • Title 21 CFR 312.62 (maintaining adequate and accurate records, making these records available for inspections in accordance with 21 CFR 312.68)
  • Title 21 CFR 312.64 (reporting of adverse experiences that occur in the course of the investigation)

The above regulations are US regulations that are not valid in the RS.

In accordance with FDA guidance 21 CFR 312.120 – the sponsor has the option to include sites that are not covered by the regulatory scope for IND studies as so-called non-IND sites. Thus, US requirements regarding the conduct of CTs will be met when the CT is conducted in accordance with international ethical standards and quality standards that are implemented in binding local requirements. In this case, the signing of FDA Form 1572 is not required.

The question now is how to proceed when a signed FDA Form 1572 is found and/or how to answer relevant legality questions.

Clinical trials submitted to the US FDA for marketing approval must comply with the IND regulations found in Title 21 CFR 312. Compliance with it can be achieved by:

  • conducting trials as IND or
  • as a non-IND (“non-IND foreign clinical study“) or
  • as a combination of investigational sites in the US as INDs and sites outside the US that are not under IND application (non-IND sites), whichever is most appropriate.

If a sponsor chooses to submit a single protocol for an IND study and conduct a trial for all IND-designated study sites, then the sponsor and all investigators must meet all IND study requirements.

If non-US local laws or regulations prohibit the signing of the FDA Form 1572, FDA should expect such sites to operate as non-IND sites or the trial conducted as a non-IND trial.

If the sponsor decides to conduct a clinical trial without an IND and outside the USA, then the trial must be conducted in accordance with the regulation 21 CFR 312.120 – Foreign clinical studies not conducted under an IND (Guidance for Industry and FDA Staff FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND, Frequently Asked Questions).

If the sponsor chooses to conduct a multinational CT, with some sites outside the US, then the sponsor can choose not to have sites outside the US under the IND application.

A sponsor may submit a single protocol to the FDA that clearly defines and describes both IND and non-IND sites. Investigators at these non-IND sites are not required to sign FDA Form 1572. However, the sponsor must ensure that the non-IND sites are in compliance with 21 CFR 312.120, “Foreign clinical studies not conducted under an IND,” ​​which requires that the trial be conducted in in accordance with Good Clinical Practice (GCP) and that the FDA is able to validate data from on-site inspections, if deemed necessary by the FDA.

A sponsor may submit one protocol for sites as IND (US sites and some foreign sites) and a separate protocol for foreign sites not under the IND definition. FDA Form 1572 does not apply to non-IND sites. If the intention is to pool data from US and foreign sites for marketing authorization, then the protocols would usually be very similar or identical. However, the FDA recommends that the sponsor discuss plans for pooling data from different sites with the appropriate FDA review division before starting the trial.

The signing of the FDA 1572 form by investigators in RS is unacceptable from the point of view of local regulations, because it gives assurance to the sponsor that the study will be conducted in accordance with the legal provisions of the USA, which is opposite with the requirements of the national regulations and even the EU regulations, because Serbia belongs to the countries of the European continent and harmonizes its work with EU guidelines.

Therefore, it is desirable that sponsors include sites in RS as non-IND sites. If the sponsor, however, has decided to include sites in the RS as IND sites then the CT agreement with the investigator/health institution should contain an explicit provision that national laws generally take precedence over US laws.

In that case, the sponsor is expected to perform a comparative analysis that identifies discrepancies between local and US requirements and to demonstrate how compliance with applicable national regulations can be ensured.

If FDA has granted a waiver at the sponsor’s request, it must be verified that the waiver covers all CFR requirements that are inconsistent with local requirements, such as IRB requirements, safety data reporting, data protection, retention periods, etc. The sponsor should explain CFR requirements to sites, particularly those requirements that conflict with or complementary to local legal requirements.

The sponsor’s comparative analysis and the relevant FDA-approved waiver must be permanently attached to the FDA Form 1572 and stored in the Trial Master File (TMF) and the Investigator Site File (ISF) together with documents related to sponsor clarifications. If the waiver is approved, the sponsor should ask the investigator to file a copy of the letter approving the waiver at the ISF center. These documents must be submitted to the Agency upon request.

A finding of a signed FDA Form 1572 without the above documents constitutes a Major finding for which the sponsor is responsible. The classification of the findings for which the investigator is responsible is based on the circumstances that arose during the supervision.

Special note:

  • recommendation to CRO companies and other sponsor representatives in Serbia to forward this Notice to their investigators
  • this notice applies from the day it was published on the Agency’s website – it is not valid for cases that occurred before April 2025.