The Spanish Competent Authority (AEMPS) has joined the position of the other European Agencies (Denmark, Germany, Norway, Sweden and Switzerland) by releasing a statement on the 24th April 2019, announcing that the FDA1572 forms should not be signed by Spanish investigators. Main reason is that 21 CFR 312 is not the regulation in force in EU/Spain and that signing off the FDA1572 by a Spanish investigator requires the Ethics Committees in Spain to adhere to 21 CFR 312.
“The investigators in Spain cannot commit to comply with the established requirements by FDA 1572 form. A clinical trial carried out in Spain, the rest of EU, and EEE must not follow any third-country’s legislation. The clinical trial must be carried out in accordance with Spanish legislation that transposes EU directives 2001/20/EC, 2001/83/EC and 2005/28/EC, and EU regulation no. 536/2014 (once this will be in force)… It should be noted that The inspectors of clinical trials in Spain will consider the signature of FDA 1572 form as a serious finding applicable to the Sponsor of the clinical trial and to the Principal Investigator too as s/he will be the signatories of this form.”
Informal Translation of Spanish Competent Authority’s communication on the use of 1572 forms in Spain (24-Apr-2019)
“The investigators in Spain cannot commit to comply with the established requirements by FDA 1572 form. A clinical trial carried out in Spain, the rest of EU, and EEE must not follow any third-country’s legislation. The clinical trial must be carried out in accordance with Spanish legislation that transposes EU directives 2001/20/EC, 2001/83/EC and 2005/28/EC, and EU regulation no. 536/2014 (once this will be in force).
The clinical trials submitted to the FDA of USA for marketing approval must comply with IND legislation, established in the Title 21 of Code of Federal Regulations (CFR) Part 312. This would be met by:
- Performing the clinical trial under IND or,
- Under non-IND (foreign clinical trials non-IND) or,
- As a combination: USA sites as IND and foreign sites as non-IND, as required.
If the Sponsor decides to submit an IND protocol and carry this out with all sites under IND, then both the Sponsor and the investigators must comply with the established requirements for IND clinical trials.
However, it is possible to request an FDA exemption for those requirements related to Institutional Review Board (equivalent to a Drug Research Ethics Committee). The Sponsor should request an IND exemption before the beginning of the study. If the exemption is authorized, then the Sponsor should attach a copy of the letter authorizing the exemption to the FDA 1572 form. If the exemption letter does not specify what has been exempted, the exemption request must be attached too.
If the local legislation outside of the USA forbids the signature of FDA 1572 form, then FDA would accept that sites operate as non-IND sites and that the study is carried out as non-IND.
If the Sponsor decides to carry out the clinical trial under non-IND and outside of the USA, the clinical trial must then be carried out in accordance to 21 CFR 312.120 “Foreign clinical studies not conducted under an IND”. The requirements of 21 CFR 312.120 can be met if a clinical trial is carried out in compliance with the ethical and data quality standards described in Directives 2001/20/EC, 2001/83/EC and 2005/28/EC (and the EU regulation No 536/2014, once this is in force). The FDA 1572 form would not be applicable then.
21 CFR, part 56 “IRB functions and operations”, establishes some requirements that are not in line with Spanish legislation: Royal Decree 1090/2015, from 4th December, that regulates the clinical trials with drugs, the Drug Research Ethics Committees and the Spanish Register for Clinical Studies, therefore the investigator cannot commit to sign the FDA 1572 form accepting that the Drug Research Ethics Committees (DREC) would comply with a foreign legislation that establishes different requirements in terms of its composition and functions.
If the Sponsor decides to carry out a multinational clinical trial with sites outside of the USA, then the Sponsor can opt for not having the sites outside of the USA under the IND procedure.
The Sponsor can submit a protocol to FDA clearly defining and describing which sites are under IND and which are not. The investigators in those non-IND sites should not sign the FDA 1572 form. However, the
Sponsor must ensure that non-IND sites are compliant with what is established for non-IND clinical trials (that is, carrying out the clinical trial in compliance with GCP’s).
The Sponsor can submit a protocol for IND sites (basically sites from USA and some foreign sites which accept this) and a separate protocol for the non-IND sites. If the intention is to handle the data from USA sites together with the data of foreign sites for the marketing authorization application, then the protocols should be similar or identical. For non-IND sites outside of the USA, it is not required to submit the protocol under IND procedure. However, the FDA recommends that the Sponsor discusses their plans of adding data for the different sites with the appropriate review division (evaluation) before starting a clinical trial.
The inspectors of clinical trials in Spain will consider the signature of FDA 1572 form as a serious finding applicable to the Sponsor of the clinical trial and to the Principal Investigator too as s/he will be the signatory of this form. “