Top 5 Global Clinical Trial Disclosure Changes in 2020 Amidst Pandemic

Thomas Wicks

This year has been a busy one in the clinical trial disclosure and transparency space. The coronavirus pandemic has encouraged the rapid sharing of clinical data at a speed and scope that well exceeds regulatory requirements. It is unclear whether this broader and earlier data availability will eventually impact disclosure regulations, but it is no doubt shaping expectations and redefining what is possible.

On the regulatory front, 2020 has seen five significant developments:

• In the US, a federal district court expanded the results disclosure requirements following a lawsuit brought against the National Institutes of Health (NIH).
• The US Federal Drug Administration (FDA) published guidance on civil monetary penalties related to trial disclosure.
• The European Medicines Agency (EMA) updated its plans for implementing its Clinical Trial Information System (CTIS), the EudraCT replacement system, by the end of 2021, bringing the Clinical TrialRegulation EU No 536/2014 into effect.
• Brexit will change how clinical data are made public for trials conducted in the UK and require substantial organizational and process changes for UK and EU organizations.
• Japan made the disclosure of protocol and trial results information mandatory on the JRCT registry.

Expansion of trial results disclosure requirements in the US

On Feb. 24, the US District Court for the Southern District of New York ruled that results for all trials applicable to the FDA Amendments Act section 801 of 2007 (FDAAA 801) must be disclosed on ClinicalTrials.gov. The disclosure deadline is no later than 30 days after the studied product is approved, licensed, or cleared (approval), even if that approval occurred after trial completion.

Issued in 2016, the Final Rule clarifying and expanding FDAAA 801 had revised the requirements for disclosing results of applicable clinical trials completed before the rule’s enactment on Jan. 18, 2017. Under the Final Rule, results for applicable trials were only required if the product was approved (or the device cleared) for any use before the trial’s completion date. Previously, FDAAA 801 required disclosure of results for applicable clinical trials within 12 months of the completion date or 30 days after the product approval, whichever came later, irrespective of whether the product was approved or cleared before or after the trial completion date. The ruling by the Southern District of New York invalidated the Final Rule results reporting exception for trials of products approved after the completion date.

On July 28, the NIH accepted the ruling, requiring results disclosure of applicable clinical trials studying a drug, biological, or device product approved by FDA within 30 days of the approval. If the disclosure deadline has already passed for trials affected by the ruling, results are due as soon as possible.

FDA final guidance on civil money penalties relating to trial disclosure

The FDA has issued the final guidance related to financial penalties for noncompliance with US trial registration and results disclosure regulations. Following is a summary of the steps the FDA will take in issuing financial penalties for noncompliance with 402(j) of the Public Health Service Act (PHS Act) and 42 CFR part 11:

1. The centers¹ identify a violation through the FDA’s Bioresearch Monitoring Program (BIMO) or based on complaints received by the agency.
2. The centers will send the responsible party a Preliminary Notice of Noncompliance (Pre-Notice) Letter, which describes the potential violation and requests that the responsible party take any necessary actions to address the possible violation within 30 calendar days of receiving the letter. Failure to comply with the requirements relating to applicable clinical trials may result in further regulatory action by the centers, including the issuance of a Notice of Noncompliance, civil money penalties, injunction and/or criminal.
3. 30 days after issuing a Pre-Notice letter, the centers will follow up on the violation if the submitter fails to submit the required certification to the FDA or knowingly submits a false certification. In that case, the agency intends to issue a Notice of Noncompliance to the submitter, giving the sponsor another 30 days to remediate. The Notification of Noncompliance will be made publicly available on the agency’s website and ClinicalTrials.gov.
4. Failure to remediate the issues identified in the Notification of Noncompliance within 30 days means the centers intend to seek civil money penalties, taking into account the type of noncompliance and the circumstances associated with the lack of remediation.

Considerations and next steps

Disclosure practices are under considerable scrutiny by transparency advocates and patient groups. Noncompliant organizations are identified publicly, with their trials listed with the potential fines that the FDA could be collecting. While the final guidance on civil money penalties describes a fairly lenient process where the FDA provides organizations with time to address noncompliance, the public naming and shaming can have serious reputational impacts. Industry sponsors with large portfolios of trials tend to be highly compliant with the disclosure regulations. However, more than 60 % of trials conducted by smaller sponsors are noncompliant, creating significant regulatory risks that may affect valuations and create challenges during a future acquisition.

Organizations should conduct an internal disclosure audit of all trials posted to ClinicalTrials.gov to identify potential issues, including trials of acquired products or companies. At a minimum, these trials should be reviewed on the FDAAA TrialsTracker to confirm compliance with the Final Rule, though this will not help assess compliance with the original FDAAA 801.

EU CTIS

The EMA has shared its plans for implementing the new CTIS, replacing the current EudraCT system used to submit and manage Clinical Trial Applications (CTAs) and trial results in the EU. The CTIS will support a centralized procedure for submitting CTAs and is now expected to go live in December 2021, provided the independent audit scheduled to start in November 2020 does not uncover significant issues. Six months after the European Commission publishes a notice confirming the full functionality of CTIS following the independent audit, the EU Clinical Trial Regulation (Regulation EU No 536/2014) will go into effect.

Considerations and next steps

For the first 12 months after the CTIS go-live, sponsors and investigators may submit new CTAs to either the current EudraCT system or the new CTIS. After the first year, new CTAs must be submitted to the CTIS, and 36 months after go-live, all ongoing trials must be available in the CTIS, including those initially registered in the current EudraCT system.

Since the CTIS will change the processes and data layout for submitting CTAs, and the flow of communication with competent authorities, plans to adjust SOPs, work instructions and stakeholder communication should be in development. While the use of the CTIS is not mandatory for the first 12 months after go-live, it is recommended to identify at least one or two trials to submit through the new system in 2022 to prepare for the mandatory use in early 2023.

Brexit

Because the United Kingdom is part of the European Union, protocols and results for trials conducted in the UK were made public on the EMA’s EU CTR. Sponsors initiating trials after the UK exits the EU on Dec. 31, 2020, will be required to register trial protocols and results for interventional trials on alternate public trial registers such as the ISRCTN registry or ClinicalTrials.gov according to the Make it Public strategy published by the National Health Service (NHS). By the end of 2021, around the time that the EU CTIS system goes live, the UK expects to make a new clinical trial data hub available to support UK patients and researchers.

Considerations and next steps

The UK will recognize ethics and regulatory approvals for clinical trials that were granted through the current EU processes before Dec. 31, 2020, but any trial starting after 2020 will need local UK approval.

For trials that are ongoing after Brexit with locations in the EU where the Medicines & Healthcare Products Regulatory Agency (MHRA) is the Reference Member State (RMS), the sponsor will have to find a different Concerned Member State (CMS) to take over the role of the RMS. Also, while trials conducted in the UK after Brexit will be made public on registries other than EU CTR, any trial conducted in the UK that completes by Dec. 31, 2020, will require results posting on EU CTR, even if the disclosure deadline is after Brexit. Although sponsors have options where they chose to disclose UK trials statring Jan. 1, 2021, the recommendation is to use ClinicalTrials.gov as it is the most comprehensive global registry with currently around 360,000 trials publicly available. However, trials that also have locations in EU member states (other than Phase I trials without pediatric participants) will be publicly available on EU CTR.

Following Brexit, sponsors of clinical trials will have to ensure they have established appropriate local representatives in both the UK and the EU, including the Qualified Person for Pharmacovigilance (QPPV), the QP to certify compliant product manufacturing, and a local Market Authorization Holder (MAH). Unless the EU and the UK come to an agreement, sponsors will also need to establish batch control testing sites in both regions.

Japan Registry of Clinical Trials (jRCT)

Sponsors and investigators in Japan have had the option to publicly disclose clinical trial information on one of three registries, UMIN CTR, JMCATT CTR, and JapicCTI. Posting trial information on these registries was not mandated by Japanese regulations, though ethics committees, industry associations and organizational commitments may have required registration. However, Ministry of Health, Labor, and Welfare regulations now require the registration of all Phase I-IV² interventional clinical trials on the jRCT for studies that started on or after Sept. 1, 2020. The protocol registration is due before the start of enrollment and is submitted in Japanese and English. Sponsors must disclose the results of registered trials within 12 months of study completion. However, it may be possible to delay results disclosure until 12 months after product approval or sale in any country.

Considerations and next steps

Industry sponsors that have made their trial data public on JapicCTI in the past must now post their trial information on jRCT instead and recognize the need to register Phase I trials (other than bioequivalence studies) before enrollment starts. The mandatory registration and results disclosure may necessitate updating standard operating procedures (SOPs) as well as agreements with clinical research organizations (CROs) or investigators.

Summary

There are over 40 trial registries globally with an average of two new registries starting each year since 2000. These registries make data publicly available for trials run in well over 100 countries, based on a broad range of local regulatory requirements. With increasing public scrutiny and the inspections by national health authorities, organizations conducting multinational trials must have the regulatory intelligence and tracking capabilities to keep up with the evolving requirements. Sponsors may choose to dedicate internal resources to disclosure or outsource this function to vendors with a specialization in disclosure. In either case, 2021 is expected to bring significant additional changes that will require organizational resources and expanded investment in disclosure and transparency.

References

1. Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) and Center for Devices and Radiological Health (CDRH)
2. Disclosure of bioequivalence studies is not required

Thomas Wicks, Chief Strategy Officer, TrialScope