Natalia Buchneva

An ever-changing regulatory framework is the biggest challenge for multinational clinical trials today. Back in 2009, the clinical research world welcomed the launch of the European Medicines Agency (EMA) and FDA good clinical practice (GCP) initiative that set the goal “to increase globalization of clinical trials” and improve cooperation with the non-EU regulatory bodies to standardize GCP interpretation globally.

	Clinical Trial Regulation No 536/2014 was developed in 2014 to consolidate the intent to “harmonize the assessment and supervision processes for clinical trials throughout the EU” and to streamline the application and approval processes for market authorization when the clinical study is conducted in several EU countries.

	In the meantime, some European countries considered whether to reinforce the local expectations for the conduct and reporting of clinical trials on their territory, while awaiting the implementation of the Clinical Trial Regulation No 536/2014.

	In January 2018, the German Federal Authority for Health Protection in relation to Medicinal Products and Medical Devices (Zentralstelle der Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten, further referred to as “ZLG”) published Vote summary V05005 “Handling of FDA 1572 form in Germany.”

 This local guidance attracted major reaction in the clinical research professional media, as it is being interpreted in conjunction with the recommendations from the Danish Medicinal Agency (Laekemiddelstyrelsen, further referred to as “DMA”) on the use of the FDA 1572 form released in October 2017 in Denmark (see Table 2).

	There have been prior occasions when non-U.S. clinical investigators refused to sign the FDA 1572 form. However, these cases were individual investigators’ decisions, rather than representing the point of view of the country or region. There has previously been no alternative non-U.S. regulator´s statement available; therefore, the instructions on the FDA 1572 form itself and the recommendation from the 

FDA Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions: (Form 1572)

 of May 2010 were, in general, followed by sponsors of clinical trials and the involved investigators.

	The FDA 1572 form is one of the key documents within the investigational new drug (IND) submission to the agency in support of marketing approval. It is treated by FDA as “an agreement signed by the investigator to provide certain information to the sponsor and assure that he/she will comply with the FDA regulations related to the conduct of clinical investigations.”

	By signing this “statement,” the investigator indeed pledges to adhere to the following regulations under Title 21 “Foods and Drugs” of the U.S. Code of Federal Regulations (CFR) related to the conduct of a clinical trial:

		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 clinical trial)

	As the standard for the conduct of clinical trials in the U.S. and EU is similar, sponsors of clinical studies were submitting the non-U.S. investigators as IND sites and were collecting FDA 1572 form as part of the application.

	The legally binding nature of the signed FDA 1572 form is underlined on the form itself stating that “willfully false information is considered criminal offense U.S.C. Title 18, Sec. 1001.” However, this is being questioned by the Danish and German regulators, and they promote the introduction of standpoints of non-U.S. regulators to address compliance with local laws, Clinical Trial Regulation No 536/2014, and CFR Part 21.

	The following scenarios are mapped out for sponsors carrying out multinational clinical trials with U.S. and non-U.S. sites, or solely non-U.S. sites as per 

Following 21 CFR 312.120, FDA commits to review any foreign study or data that are submitted within marketing authorization application in the U.S.; however, only the GCP-conformant clinical trials where the non-U.S. investigators will agree to allow FDA inspections, if necessary, will be accepted.

	The statistics about the FDA acceptance rate of the data submitted under 21 CFR 312.120 is limited, the FDA guidance (question 14) recommends that “if the sponsor intends to submit the data in an application for marketing approval, we recommend that the sponsor identify the foreign sites that will not be conducted under the IND and discuss plans to pool the data from U.S. and foreign sites with the appropriate FDA review division.”

	The DMA and ZLG advocate for triggering the option is mentioned in question 10 of the FDA guidance: “If local laws or regulation prohibit the signing of a 1572, FDA would expect the sites to operate as non-IND sites and the study conducted as a non-IND study.”

	In DMA´s opinion, the Danish investigators must not sign FDA 1572 form, as “a clinical trial conducted at a site in the EU and European Economic Area (EEA) cannot be conducted under any foreign country legislation.”4

	Vote summary V05005 recommends that the German investigators should preferably be involved as the non-IND sites in the relevant studies. Additionally, the sponsors have the possibility to maintain the German sites as IND sites and collect FDA 1572 forms, provided that certain criteria are met. The details of the DMA´s and ZLG´s recommendations are presented in Table 2.

	Time will tell whether Denmark and Germany become trendsetters for other EU countries or if their decision will remain isolated in their view of the FDA 1572 form. The countries outside of the EU tend to accept FDA requirements to keep the investigators that agree to sign FDA 1572 as the IND sites, though, there is no known official position and isolated refusals from the non-EU investigators cannot be excluded. Of note, the number of other individual EU investigators who are refusing to complete the FDA 1572 form is growing. The investment 

will most probably be justified proportionately with the amount of data that will be produced by the German and Danish sites in support of the IND application. Sponsors and global CROs are striving to take the burden off of investigators´ shoulders and tend to abandon completion of FDA 1572 forms in the countries where they are explicitly forbidden and for those investigators who are not comfortable with signing off the forms.

	In absence of EMA´s official standpoint, clinical research sponsors operating in Europe are hesitant to revise their overall approach to handling the non-U.S. sites as non-IND sites and abolish collection of FDA 1572 forms in all EU countries.

	As part of an associated risk mitigation program, the internal regulatory groups at sponsors and CROs were alerted to monitor the release of other EU and non-EU inspectorates’ opinions about the use of the 1572; statistics on acceptance of the foreign data by the FDA are being collected and the EU and non-EU clinical investigators who deny their sites to be maintained under IND are being tracked.

	The clinical research world anticipates that revisions and clarification of the local laws in certain EU countries are associated with major regulatory changes in Europe, such as addressing Brexit in 2019 and the recent application of the General Data Privacy Regulation (GDPR) (EU) 2016/679 in May. It is essential, therefore, for the clinical trials market in Europe that Clinical Trial Regulation (EU) No 536/2014 is adopted and the balanced and EMA and FDA mutually recognized improvements are considered.

		European Medical Agency website, EMEA-FDA GCP Initiative, Doc. Ref. General-EMEA/INS/GCP/541006/2008 of 31 July 2009. Retrieved on April 10, 2018 from 

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2009/12/WC500016820.pdf

		European Commission website, Clinical Trial Regulation (EU) No 536/2014 of the European Parliament and of the Council of April 16, 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC.  Retrieved on April 10, 2018 from 

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf

“Handling of FDA 1572 form in Germany”

 of 27 September 2017 (officially published on ZLG website on 29 Jan 2018).  Retrieved on April 10, 2018 from 

https://www.zlg.de/index.php?eID=tx_nawsecuredl&u=0&file=fileadmin/downloads/AM/QS/V05005.pdf&hash=a4aa55d4542a4b641237886a8586ca9d42474aee

“Clinical trials under US legislation” 

Questions & Answers published Oct. 2, 2017.  Retrieved April 10, 2018 from 

https://laegemiddelstyrelsen.dk/en/licensing/clinical-trials/gcp-inspection/clinical-trials-under-us-legislation/

“FDA Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions: (Form 1572)”

 of May 2010.  Retrieved on April 10, 2018 from 

https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm214282.pdf

 (OMB No. 0910-0014, expiration date Feb. 28, 2019). Retrieved on April 10, 2018 from 

https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM074728.pdf

“Foreign clinical studies not conducted under an IND”

https://www.law.cornell.edu/cfr/text/21/312.120

		General Data Privacy Regulation (GDPR) website, General Data Privacy Regulation (EU) 2016/679) of May 24, 2016. Retrieved on April 10, 2018 from 

https://ec.europa.eu/info/law/law-topic/data-protection/data-protection-eu_en

 is Manager, Clinical Quality Assurance, UCB Biosciences GmbH

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