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:

 identify a violation through the FDA’s Bioresearch Monitoring Program (BIMO) or based on complaints received by the agency.

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.

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.

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.

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.

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.

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.

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.

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.

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-IV

 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.

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.

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.

Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) and Center for Devices and Radiological Health (CDRH)

Disclosure of bioequivalence studies is not required

Articles

Spotlight on clinical trials created by COVID-19 pandemic has forced regulatory officials around the world to expand disclosure requirements on results.

Top 5 Global Clinical Trial Disclosure Changes in 2020 Amidst Pandemic

	Clinical data transparency does not have to be difficult, but it does require attention.  Large biopharmaceutical companies are steadily expanding their transparency commitments, and most have achieved solid compliance with disclosure requirements. Unfortunately, smaller organizations are generally lagging in their commitments to clinical data sharing and all too often are non-compliant with regulations.   

	While some organizations are failing to comply with disclosure regulations, external pressures continue to build. Not only are health authorities now including trial disclosure in their inspections and watchdog organizations are publicly naming and shaming individual organizations of all sizes, but investors and potential acquirers are also assessing a company’s transparency practices as part of their due diligence processes.   

	Thankfully, the trend is shifting, and smaller organizations are starting to pay greater attention to clinical trial disclosure requirements, though they may face additional challenges than their larger peers. 

	Patient groups and trial participants are increasingly vocal in their demand that clinical trial information should be made available publicly in a language and in a format that is meaningful to patients. This includes providing easily searchable lists about trials that are enrolling and plain-language results summaries. Providing this information supports trial recruitment and patient engagement efforts, which are important to companies of all sizes.   

	Although the earliest trial disclosure regulations were enacted almost two decades ago, there has been virtually no enforcement in that time. However, inspections for compliance with these regulations have now started, with Qualified Persons for Pharmacovigilance (QPPV) of affiliates in the European Union reporting that they had to provide evidence of compliance during recent quality and pharmacovigilance inspections. The FDA has completed a pilot program and is expected to start including disclosure compliance in its inspections going forward. To be ready for these inspections means preparing the necessary process documents and developing the supporting evidence to show that the processes were followed in full compliance of the regulations.   

	Transparency advocates and industry watchdogs have periodically published assessment of clinical trial disclosure practices for years. Initially, these were broad analyses of disclosure based on limited data and aggregated across sponsors, without focusing the data of specific organizations. In recent years, these analyses have become much more rigorous and now name and rank every trial sponsor irrespective of size or industry segment. 

	In 2015 a group of 85 pension funds and asset managers representing more than $3.8 trillion joined the AllTrials campaign. These investors view great trial data transparency as one way to mitigate brand and valuation risks. Those organizations planning to seek funding or those that expect to be acquired in the future may find that poor disclosure practices can create issues during the vetting process. 

	In smaller organizations, trial information is often made public on registries across the world, without centralized oversight and relying on documents that were created without disclosure in mind. While there may be documented processes in place for the largest trial registries, such as ClinicalTrials.gov, these are often managed locally, with little or no coordination across affiliates or the local CROs. With no consolidated view into the data made public or a central tracking of global regulations, executives lack awareness of the disclosure landscape and the risks of inconsistent or non-compliant processes.   

Limited experience, resources, and automation

	With a more limited trial portfolio, smaller organizations disclose clinical data less frequently, and so often lack comprehensive guidelines for assessing trial disclosure requirements as well as consistent processes for ensuring efficient and compliant public sharing of clinical data. With fewer trials, smaller organizations typically have few, if any, dedicated disclosure specialists and often no local staff involved in disclosure outside the US and perhaps the EU.  

	These resource constraints are further compounded by a lack of automation that could alleviate some of these issues. Most smaller companies do not have a central clinical trial management system (CTMS) that could ease the effort of registering and periodically updating clinical protocol information. Instead of systems designed specifically to support trial disclosure, these companies often rely on a manual approach perhaps tracked through various spreadsheets. The difficulty of a manual approach is adapting quickly changing requirements and responding to tightening deadlines and increasingly frequent updates that are mandated by regulation. Spreadsheets and manual disclosure processes also make responding to inspections more difficult and rarely provide a global transparency perspective to company executives.  

Documents not authored with disclosure in mind

	Larger biopharmaceutical organizations are implementing guidelines and templates for authoring protocols, clinical study reports (CSRs), and SAS datasets that support the clinical data sharing and disclosure requirements. While the purpose of implementing these new authoring approaches goes beyond preparing for disclosure, well-structured sources of information that consider the downstream data sharing requirements greatly facilitate efficient trial transparency and help ensure global consistency of the data that is made public. 

Managing acquisitions, divestitures and name changes

	As organizations acquire products or entire companies, they also assume the responsibility for the data of the trials related to the acquisition. Life sciences companies of all sizes often struggle to identify all trials associated with the acquisition, especially if the acquired entity has previously grown through their own mergers and acquisitions. In the European Union, this requires documenting every trial initiated since May 2004 for all acquisitions and then disclosing results for these trials if the previous organization had failed to do so.   

	On the other hand, when a company divests a product or division, trial disclosure of divestiture becomes the responsibility of the new organization. However, the original company’s name will still be shown on the trial registry of the European Medicines Agency, which can mean a company might appear non-compliant, even if the responsibility has shifted to a new organization.  

	Identifying these older trials can be made even more difficult where companies have changed their name in the past fifteen years. In the US this is a little easier to manage, because the main registry, ClinicalTrials.gov, maintains a controlled list of organization names and allows updating the sponsor name of trials related to acquisitions or corporate name changes. In the EU, however, there is no controlled list of organization names and limited ability to change the sponsor name of acquired trials. 

	With the industry’s growing trend toward greater transparency and increasing pressure from health authorities, transparency advocates, investors, and patient groups, companies can no longer afford to consider trial disclosure just as a minor regulatory nuisance. Instead, trial disclosure deserves attention from the senior leadership at companies of any size, with agreement on an overall corporate transparency policy that clearly articulates the organization’s commitments.   

	More than 90 countries have some form of disclosure requirement to share trial data on one of 30-plus trial registries, so sponsors should have central visibility into these requirements and the ability to track disclosure globally, ensuring compliance and consistency. Companies with smaller trial portfolios that lack the experience developed over frequent disclosures and those that cannot afford to hire dedicated specialists should consider working with a solution provider that offers both automation and disclosure services.  

Transparency in clinical trials doesn't have to be difficult but requires attention writes Thomas Wicks, Chief Strategy Officer for TrialScope. Smaller organizations tend to lag in their commitments to clinical data sharing and be non-compliant with regulations, but the trend is shifting.

Why Midmarket Sponsors Struggle with Transparency and What They Can Do

	With 2018 not far behind us, we turn our attention to the coming year. On a daily basis, TrialScope’s collective fingers are on the pulse of clinical trial disclosure and transparency. Over the past decade and more, we have seen a heightened awareness of-and focus on-the compliance of clinical trial sponsors. And so we offer a laundry list of 2019 predictions for the pharmaceutical industry:

will be an ongoing theme in the clinical trials industry:

	1. Sponsors will make significant investments in patient-friendly clinical trial websites

to support active patient-engagement programs.

will be more vocal regarding their expectations of making clinical trial information more accessible and understandable.

	3. The healthcare community will develop initial metrics to measure the impact and value of various patient engagement initiatives.

	4. Sponsors that have waited to develop their plain (lay) language summary authoring capabilities will scramble to catch up to meet the pending regulatory requirements.

	Industry watchdogs will keep sponsors on their toes:             

	1. Sponsors will be forced to respond to new and expanded disclosure tracking sites ranking trial sponsors by compliance metrics. These were formed in 2018:
	

will aim for greater consistency and stricter enforcement:

	1. The Food and Drug Administration (FDA) is poised to assess civil monetary penalties and publish public notices

	2. Sponsors will be scrambling to test and prepare for the new EU portal, scheduled to launch in 2020, which will be the single entry point for submitting clinical trial information in the EU.

	3. Because International Committee of Medical Journal Editors (ICMJE) requirements to publish a data sharing plan cannot be fulfilled by all registries (EudraCT, for example), we will see more consolidation around CTGOV as the registry of choice.

	4. While big pharma will continue to be under the microscope, so to speak, greater attention will be placed on smaller biopharmaceutical and device organizations as well as academia

will be under greater pressure to monitor compliance.

	1. Device companies will need to pay attentionto the new Eudamed device regulations and database

	2. In the U.S., devices also are drawing more attention. This year, the FDA released its 

Medical Device Safety Action Plan: Protecting Patients, Promoting Public Health

	1. Sponsors will encounter challenges navigating the various 

in Europe, Canada, and the U.S. (FDA Pilot).

of clinical trials will continue to grow, as sponsors look for new ways to efficiently leverage existing data for the benefit of patient recruitment and retention, research transparency and innovation, and trial disclosure compliance.

	We’ll go out on a limb here and say that 2019 could be the “Year of Clinical Trial Transparency.” Patient centricity, patient experience and health literacy are buzzwords that are rapidly becoming the new reality. 

 is already gaining ground in Europe’s scientific community; it remains to be seen whether it will secure a strong foothold in the pharmaceutical industry as well.

, Vice President of Global Transparency and 

, Chief Strategy Officer, both at TrialScope

A Dozen Disclosure & Transparency Predictions for 2019

	A consistent and reliable approach to the increasing public availability of clinical trial data is dependent on a clear corporate policy and thoughtful coordination across the organization. To develop the necessary transparency policy and to ensure compliant and globally harmonized disclosure requires the active involvement from leaders across the organization collaborating through a cross-functional transparency committee.

	While it is common to think of clinical transparency in terms of disclosure regulations and trial registries, the truth is that clinical trial data is made available through many other outlets, including publications, corporate or health advocacy websites, and direct communications to patients or healthcare providers. The challenge is to coordinate the disclosure of data so that the publicly available information is globally consistent, timely, and accurate. However, the timing and detail of the disclosed data varies considerably based on legal obligations, commitments, and communication priorities making consistent disclosure difficult.

	Establish a disclosure stakeholder committee

	The key to consistent and efficient disclosure is to involve the right stakeholders throughout the data sharing lifecycle, from developing the corporate policies and processes, to coordinating disclosure requirements with the publication plan. We recommend including an executive from each of the following groups:

	· Chief Medical Officer (or representative)

	On occasion, the committee may seek advice from patient advocates and internal departments such as clinical development, investor relations, and IP attorneys, though these are typically not permanent members of the committee.

	The primary role of the transparency committee is to establish and promote the corporate transparency standards and facilitate cooperation across the organization. While the committee is not expected to manage the day to day disclosure operations, individual members will typically have direct involvement through their departments. The primary role of the clinical transparency committee is to:

	1) Shape disclosure commitments to provide value to patients beyond mere regulatory compliance.

	2) Develop a clear transparency policy that details the scope and timing of disclosure commitments.

	3) Promote a culture of transparency and resolve departmental or regional differences.

	4) Monitor compliance with regulatory requirements and policy commitments.

	5) Advocate for adequate and consistent investment in disclosure resources and systems.

	An engaged transparency committee helps connect an organization’s patient engagement goals and publications’ priorities, with disclosure regulations and transparency trends to help the organization adapt to the evolving requirements.

To manage the growing scope and complexity of global disclosure regulations and trial transparency initiatives, companies are advised to create a cross-functional clinical transparency committee.

Establishing a Clinical Transparency Committee is key to Managing Global Disclosure

	You may have heard that an amendment to Title VIII of the Food and Drug Administration Amendment Act has passed final review, and will be in effect on January 18, 2017. The legislation requires timely reporting by industry and academia of clinical trial results. Industry has not paid close attention because it’s taken so long to implement.
	
	But that’s about to change. Failure to comply will cost drug trial sponsors tens of thousands of dollars a day. It’s vital to know the full facts when it comes to clinical trial disclosure in order to avoid steep fines for failing to comply with new reporting requirements.
	
	

1) Myth: There’s no down side to the transparency that comes from reporting as much human clinical data as possible

 Drug industry innovation may be inhibited by requirements to share key finding if industry loses the ability to protect innovation based on findings that are sometimes unexpected and provide new clues for the manufacturer that it may not wish to share for competitive reasons.

 Another limit to transparency is the need to protect patient health information.
	
	

2) Myth: Now that regulations are in place requiring disclosure of clinical trial results, we should expect to see results published in a timely manner.

 Only 13.4% of trials reported summary results within 12 months after trial completion.

 That said, there are valid reasons to withhold data for more than 12 months and those reasons are included in the law. Most non-compliance analysis takes a strict definition of the law in to account – where a study must have EITHER results or a certificate of delay within 12 months. However, most companies understand that a certificate of delay is not necessary if there are legally acceptable reasons to delay results disclosure. Regardless, with just 13 percent of trials reporting results, it’s clear that there will be continued calls for trial sponsors to disclose results sooner.
	
	

3) Myth: Major medical journals have fixed the problem of inaccurate reporting of clinical trial results.

 Misleading transparency statements and inaccessible protocols continue to make possible publication of incomplete, misleading, and outcome switching data.

4) Myth: Clinical trial sponsors understand reporting requirements, and generally are in agreement on what should be published and when it’s expected.

 National health authorities and legislators in approximately 30 countries around the world have established trial transparency regulations, though the scope and timing of disclosure is generally not well harmonized across these requirements. Even established legislation such as the FDA Amendments Act of 2007 is still subject to differing interpretation by trial sponsors, which contributes to the reported non-compliance with legal and ethical standards in studies such at the Good Pharma Scorecard.

 For example, there is no general agreement whether it is mandatory to submit a certificate of delay or good cause extension when a sponsor postpones results disclosure for more than 12 months after the primary completion date.

	Another area in which those researching trial disclosure practices disagree with the policies of many sponsors, is the scope of transparency beyond strict compliance with country-specific regulations. For example, the FDA does not require the disclosure of protocol information or trial results related to Phase I trials, while many organizations including the World Health Organization (WHO) and the World Medical Association (WMA) expect the disclosure of information on all trials in humans, which includes Phase I studies. The WMA has enshrined these requirements in the Declaration of Helsinki since 2008 and while many trial sponsors align their ethical principles with the Declaration of Helsinki, this has not yet led to a consistent disclosure of data on Phase I studies by these sponsors.
	
	

5) Myth: When it comes to clinical trial data reporting, “best practices” for trial sponsors have been established.

 While trial sponsors commit to meeting their legal disclosure obligations, there are no industry best practices for meeting these obligations, in terms of the scope of disclosure, the preferred organizational roles and responsibilities and stakeholders, the standard operating processes or the disclosure technology. In 2015, TrialScope ran an initial Disclosure Maturity Assessment, establishing an initial set of industry transparency benchmarks, which confirmed that there is a broad range of approaches to trial disclosure. In comparing the 2015 assessment with earlier surveys certain trends are developing:

		Growing trend towards centralized disclosure management rather than relying on local affiliates, partners, or contract research organizations (CROs) to comply with local requirements.

		Increasing coordination with publications group to establish a common publication and disclosure calendar as well as ensuring a consistent public view of the trial data.

		Trend towards more expansive disclosure policies to include posting Phase I protocols and results as well as information on older trials.

		Trend towards greater automation among smaller industry sponsors and academia to ensure timely and consistent disclosure, especially in view of new disclosure deadlines for updating trial information within 15 – 30 days that are expected in 2017 and 2018.

 is Chief Operating Officer for TrialScope

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		“Compliance with results reporting at Clinicaltrials.gov,” NEJM, 2015 372;11, p 1031-1039	

		Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012,” BMJ Open, 2015; 5:e009758	

		“Failure to report: a STAT investigation,” STAT, December 13, 2015	

		“Another ethical breach at Annals? Misleading transparency statements, and inaccessible protocols,” 

		“Sharing clinical trial data: a proposal from the International Committee of Medical Journal Editors,” Annals of Internal Medicine, Editorial, January 26, 2016, p 1-2	

		“How pharma keeps a trove of drug trials out of public view,” 