Clinical Trial Disclosure and Data Transparency: Obligation or Opportunity?

The disclosure and transparency of clinical trials is both a legal and ethical principle now accepted by the majority of countries.* Based on this principle, commercial and non-commercial sponsors that carry out clinical studies (sponsors in the EU; responsible party in the United States (US) must register them on public databases equipped with specific uploading interfaces. The sponsors can access these databases after registering (EudraCT for the EU; ClinicalTrials.gov—Protocol Registration and Results System (PRS) for the US, to name the major ones) and publish the results according to defined criteria and times.

Globally, there are numerous regulations and requirements on the transparency of clinical trials, depending on the local laws and the type of studies. This paper considers the mandatory requirements of the European Union, the United Kingdom, and the US, while we refer to the mapping made by PhUSE for a broader overview.¹

In the case of the EU, it is interesting to note that the European Medicines Agency in its European Medicines Agency policy on publication of clinical data for medicinal products for human use (Policy 0070) stated : "A high degree of transparency will take regulatory decision-making one step closer to EU citizens, and promote the better-informed use of medicines. (…) The access to clinical data will benefit public health in the future."²

According to this policy, the sponsors should make an additional effort to combine the spirit of transparency with clinical research's complex activity. This effort involves investments of resources that, albeit in the different public and private sectors' perspectives, must produce benefits that go beyond compliance with a series of rules.

We suggest that implementing clinical trial disclosure and data transparency policies and procedures represents an opportunity for sponsors rather than viewing disclosure as an obligation.

Opportunities for sponsors

For commercial and non-commercial sponsors, clinical trial disclosure and transparency is an opportunity to describe how physicians and researchers investigate the efficacy and safety of new drugs and medical devices, and to make this information more accessible.**

In July 2013, the drug manufacturer associations EFPIA (Europe) and PhRMA (United States) adopted the joint document Principles for Responsible Clinical Trial Data Sharing, the objectives of which include the enhancement of public access to information on clinical trials. Many pharmaceutical companies have already established Clinical Trial Disclosure/Transparency policies and most (in some cases all) publicly posted results of their clinical trials. As early as 2015, companies such as GSK, Johnson & Johnson, and Bristol-Meyer Squibb took this path,³ followed in subsequent years by almost all major pharmaceutical companies.

By contrast, according to a recent study,⁴ the authors reported that trials with a commercial sponsor were substantially more likely to post results than those with a non-commercial sponsor (68.1% vs 11.0%). In particular, “compliance among pharmaceutical companies has been good; while universities have performed poorly."⁵

Also, the Clinical Trial Transparency at European Universities report⁶ indicates that academic sponsors' situation is much less mature noting that 83% of clinical studies (778 out of 940) conducted by the 30 European universities sponsoring the largest number of clinical studies do not comply with European transparency rules. The report was released in May 2019 by TranspariMED, BUKO Pharma-Kampagne, Test Aankoop and Health Action International. According to the results, only three universities (University of Oxford, University College London, and King's College of London) have published the results of more than 80% of their clinical studies while 13 universities published between two and 33% of the results obtained from their clinical studies. The remaining 14 universities in the sample, located in France, Italy, Norway and Sweden did not publish results.

The public databases Clinicaltrials.gov (US) and EU Clinical Trial Registry (EU) allow a user to freely consult tens of thousands of clinical studies, accessing information of considerable interest in terms of competitive intelligence. This result mainly depends on the commitment of commercial sponsors who, in turn, can draw valuable information from these sources. Since both platforms offer rather sophisticated search tools with multiple filters, the clinical research professionals can consult the data relating to studies carried out on pathologies and drugs of their interest, thus avoiding starting studies already carried out by others without success.

The EMA Clinical Data website is also a useful research tool. EMA publishes the registration dossiers, duly anonymized, of the products registered starting from September 2016. Accessing these documents requires registering in advance. Access to the documents is this database is intended for healthcare operators (in 2019, EMA Clinical Data counted 6,869 visitors ),⁷ and offers an essential tool for comparing and analyzing new therapeutic tools' most recent developments. By proactively publishing clinical data, EMA intends to help:

• avoid duplication of clinical trials, foster innovation and encourage development of new medicines;
• build public trust and confidence in EMA's scientific and decision-making processes;
• academics and researchers to re-assess clinical data.⁸

The timely registration of clinical trials on public databases can also facilitate patients’ recruitment in clinical trials: it also allows researchers to learn about clinical trials since their preliminary phase, providing information on the purpose of the trial, and potentially simplifying the enlistment process. Increased participation in clinical trials will not materialize in the absence of the public’s trust in research.⁹

In times of increasing demand for transparency, it seems strange that the investments made by sponsors to publish their clinical studies' results are not valued in terms of information to the public. Sponsors can improve their reputation with patients and public perception by communicating their commitment to making their clinical trial results public. Many pharmaceutical companies have already done this. Sponsors can highlight the quality of their research and development processes, demonstrating the efficacy, safety, and tolerability of their products and defuse one of the most potent mechanisms of dissuasion from the use of drugs: the lack of information that often generates distrust of public opinion.

Opportunities for patients

Article 25 of the Declaration of Helsinki on human experimentation (1964; last revision 2013) states that "The participation of individuals capable of providing their informed consent as subjects involved in medical research must be voluntary. While it may be appropriate to consult family members or community leaders, no individual capable of giving their consent can be placed in a clinical trial unless they are free to participate."¹⁰

Nevertheless, until the introduction of the US and European clinical trial public databases, patients who had agreed to take part in a clinical study encountered significant challenges in accessing the study results in which they had participated.

ClinicalTrials.gov and the EU Clinical Trial Register offered patients direct access to these results, responding to publicity claims highlighted by several observers. "Lack of transparency in clinical trials harms patients. The benefits and risks of drugs and medical devices cannot be fully understood and evaluated if the information generated about them through research is missing, conditioned, distorted, or incomplete. There are numerous and well-documented examples in which large groups of patients have suffered harm due to insufficient transparency of clinical trials".¹¹

As a result of the disclosure and transparency rules, patients can now access the results of studies. In the European Union, patient privacy is better protected, given the anonymization guarantees provided for by the current regulations and extended all healthcare personnel.

Opportunity for the community

As previously mentioned, the EMA Policy 0070² aims to bring citizens (note: not patients) closer to clinical trials. The EU Clinical Trial Regulation 536/2014¹² provides that, starting six months after the release of the new Clinical Trial Information System (CTIS) platform, expected by the end of 2021, sponsors will begin to publish the layperson summary for all clinical trials conducted under the new regulation.

This new regulation reaffirms the path that the European legislator and regulatory body have chosen to follow in terms of information to the public on clinical trials. Publication of lay summaries is not a requirement under the US legislation.

In terms of public costs associated with the lack of transparency of clinical trials, Bruckner¹¹ underlines the complexity for regulatory agencies in making informed decisions about drug or device candidates and the loss of public funds due to the difficulty in determining their effectiveness in the absence of precise information.

Compliance and sanctioning principles

Currently, clinical trial disclosure legislation varies according to the Member State. EU Regulation 536/2014 requires that Member States revise their local legislation to be consistent with the regulation. Many countries foresee penalties for non-compliance.

EU Clinical Trial Regulation 536/2014 provides in art. 94 that the regulatory sanctions for those who transgress the rules formalized therein, including clinical trial disclosure, are “effective, proportionate, and dissuasive”.

Recently, the attention to compliance with transparency regulations by governments and regulators has shown a multilateral acceleration. In January 2020, the Court of Justice issued two favorable rulings¹³ regarding making public some clinical studies and toxicological reports in the framework of the legislation on access to documentation. In particular, the Court of Justice confirmed that EMA's disclosure and transparency policies comply with this legislation.

EMA defined these rulings as "historical." They confirm the approach adopted since 2011, in defense of the transparency of its activities, in the interest of patients and public health.

On October 6, 2020 the Danish Medicine Agency (DMA) issued a statement¹⁴ reminding sponsors to publish all protocols and clinical trial results. Under Danish legislation, sponsors who fail to publish clinical trial results are liable to fines or imprisonment of up to four months (sic!). The Agency does not have the power to apply these rules in person but can contact a prosecutor.

On July 29, 2020 the UK Health Research Authority (HRA) unveiled how it intends to improve the clinical trials' transparency; this strategy¹⁵ envisages adopting measures that will introduce "proportionate consequences for those who do not take transparency seriously". On September 1, 2020 the UK Medicines and Healthcare products Regulatory Agency (MHRA) published guidance on “Registration of Clinical Trials for Investigational Medicinal Products and Publication of Summary Results from January 1, 2021”.¹⁶ It will be interesting to see how the HRA and MHRA will harmonize their requirements.

On August 14, 2020 the US Food and Drug Administration (FDA) issued a final guidance on “Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank”,¹⁷ which defines rather severe penalties for responsible parties that fail to register and publish results of applicable clinical trials including some studies completed between 2007 and 2017 on ClinicalTrials.gov. In particular, the FDA provides civil money penalties up to a maximum of $ 10,000 for the first 30 days of delay and up to a maximum of $ 10,000 per day for any further delay. The guidance also envisages the withdrawal of any public funds provided by the US National Institute of Health. FDA posted the availability of the final guidance in a Federal Register notice on August 17, 2020.

Overall, both in Europe and the US, the attention towards compliance with clinical trials' transparency appears to increase. This attention is further heightened by the large number of clinical trials initiated by the ongoing COVID-19 pandemic and by the wait for the availability of a safe and effective vaccine. In this regard, on September 16, 2020 the EMA clarified that "The suspension of clinical data publication does not apply to COVID-19 related products, in line with EMA's exceptional transparency measures for treatments and vaccines for COVID-19."¹⁸

As previously noted, the implementation of the EU Clinical Trial Regulation 536/2014 will become effective when the Clinical Trial Information System (CTIS) is launched, which is expected in late 2021. It is time for sponsors—especially non-commercial sponsors, i.e., universities, hospitals, and clinical research institutes until now less compliant in publishing their clinical studies' results—to verify their compliance level with the rules on transparency.

How to best prepare?

National legislators and regulatory bodies are increasingly demanding that the publication of the results obtained from clinical studies become a widespread and scrupulously applied practice. By implementing disclosure and transparency policies, sponsors will carry out, among other things, a service of public utility for patients and the community. In this way, they will enhance the impressive work that many of them have done to publish their results and prevent sanctions by regulatory authorities.

It remains to be defined which initiatives should be implemented (or harmonized) to face the regulatory push towards transparency. No recipe can apply in an undifferentiated way to any organizational reality. Having said that, we considered it useful to conclude these reflections by providing some suggestions for sponsors;

• Establish disclosure/transparency policy and SOPs.
• Incorporate disclosure strategy into clinical development plan and clinical trial activities.
• Ensure all applicable departments within the organization are in alignment with clinical trial disclosure policy.
• Coordinate the timing of publications, regulatory submissions and posting study results.
• Begin to plan for the implementation of the EU Clinical Trial Regulation and Clinical Trial Information System (CTIS).
• Establish a team responsible for Clinical Trial Disclosure and Data Transparency activities and provide it with adequate resources.
• Check for any completed or prematurely ended (terminated, according to ClinicalTrials.gov) clinical studies whose results are not yet published in the respective databases.
• Plan in advance the publication of the results of studies and prepare the related document production (e.g., CSR, Appendix, et al.) with disclosure in mind, taking into account the information necessary to populate the database loading requirements.
• Adapt the processes of the departments involved (e.g., Clinical Research, Medical Management) to the criteria of transparency.
• Include transparency in qualitative monitoring that already applies to clinical research processes.
• Make use of the commitment made for transparency to emphasize the sponsor's patient orientation.
• Include the transparency activities of clinical trials among the sponsor's communication topics to enhance the investments in reputation and increase its brand equity.

The application of these actions helps to create the organizational and operational conditions to address disclosure and data transparency activities and to ensure sponsors the maximum benefit of skills and reputation that derive from them.

Massimo Zaninelli is the CEO of Maxer Consulting and temporary lecturer CTD&DT at the University of Pavia. Robert Paarlberg is a principal at Paarlberg & Associates.

References:

* According to the PhUSE analysis poste on July 2020, 190 out of 253 countries have databases or a registry for the registration and publication of clinical studies

** While in the US the registration of clinical studies on medical devices and the publication of their results take place in the same database used for drugs (ClinicalTrial.gov), in the EU the release of the EudaMed database, reserved to medical devices, is scheduled for 2022.

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