As the COVID-19 pandemic severely impacts many facets of human activity around the world, the pharmaceutical industry is being presented with significant challenges related to the manufacturing and shipping of existing marketed products and to treatment development activities. Regulatory authorities have released guidance documents focusing on the impacts to study start-up activities, changes to ongoing study procedures, and items considered urgent safety matters during this pandemic. This blog considers the impacts of COVID-19 on clinical study disclosure and transparency, offering guidance from industry experts on what may require immediate action, as well as consideration of future implications.
REGULATORY BACKGROUND
In the current, constantly evolving atmosphere sponsors have been faced with urgent decisions regarding each individual clinical study in their portfolios, regardless of development stage. Challenging decisions based on mitigating the risks to study participants are being made on whether to delay initiation of new clinical studies, temporarily halt or terminate ongoing clinical studies, or update study protocols as necessary. These decisions must be based on the current regulatory guidance issued relevant to the COVID 19 pandemic, including those published by the US Food and Drug Administration (FDA) the European Medicines Agency (EMA) and many other countries (including individual member states within the EU). Given the scope and breadth of the guidance documents, as well as the multiple changes required to be considered for any given study, it is essential to collaborate with all relevant team members to ensure all disclosure and transparency updates are managed appropriately. Involvement in a COVID-19 task force will be helpful when communicating these types of challenges and developing decisions tailored to each study.
IMMEDIATE IMPACTS
Public Registries
There are many global requirements and recommendations for disclosing information and data publicly – see PHUSE Clinical Trials Data Transparency Toolkit: Clinical Trial Transparency and Disclosure: A Global View Note: An update to this white paper is expected to be published soon. Changes to study procedures and documents due to COVID-19 could affect the way in which information is updated now and for years to come. Registry portals were not designed to manage activities during a global pandemic, thus creating challenges for the disclosure and transparency community in keeping information consistent across global registries. This could mean enrollment and/or treatment being temporarily halted in specific locations, changes to the study timelines, or a lack of resources leading to the inability to meet compliance due date(s).
ClinicalTrials.gov is a prominent hub used to fulfill disclosure requirements, and the responsible party can do so manually within the Protocol Registration System (PRS). Under the Food and Drug Administration Act (FDAAA) Final Rule requirements, changes to certain data elements must be updated on ClinicalTrials.gov within 30 days. Such changes include the overall study recruitment status, individual site recruitment status, milestone dates, and any protocol amendment that affects the registration information (e.g., outcome measures, study description, and eligibility criteria). Pursuant to an FAQ document released by ClinicalTrials.gov on 02 April 2020, responsible parties should reference the data element definitions for overall and site recruitment status to best determine the appropriate recruitment status on a study by study basis. The current data element definitions should be reviewed and considered by each responsible party, focusing foremost on the safety of the current study participants, the severity of the condition, and whether alternative methods of continuing the study safely are viable. Additionally, expanded access programs may be developed to allow off-label use of an investigational treatment for COVID-19 which must be registered under the FDAAA Final Rule and then linked to the related studies, as applicable. Any COVID-19 risk mitigation plan being developed should also consider including the public registry status decision, based on the current definitions and guidance documents from the respective agencies.
Unlike ClinicalTrials.gov, which allows responsible parties to perform updates directly, there are several other global registries which are updated by a clinical trial application (CTA) or notification e.g., the EU Clinical Trials Register. These applications are not typically managed by the disclosure and transparency team but may include information that is disclosed publicly. Several countries have released guidance documents which describe when a CTA substantial amendment or protocol amendment may be required. Notably, guidance documents have indicated the importance of having as few CTA updates as possible, so it is essential to work closely with the appropriate teams to ensure all updates are included in the CTA, and that information is being disclosed consistently wherever possible.
Communicating with Study Participants
While study participants are concerned about the personal impacts of COVID-19, they may also be uneasy about how the pandemic will impact the study in which they are participating. Communication with study participants, or the lack thereof, has always been a point of contention from the public perspective. Increasing transparency by communicating to study participants about the effects of COVID-19 would not only help ease study participants’ certainties but could also support the successful completion of the study during this challenging time. These communications should be thorough, written in plain language, and updated as changes occur, including: (1) updates regarding recruitment status, (2) how suspension of enrollment or treatment at individual sites or for the overall study may directly affect enrolled participants, and/or (3) when the sponsor anticipates being able to resume enrollment and/or treatment.
It is important to note that many countries do not allow direct contact between sponsors and study participants, so it is useful to consider options such as publicly viewable announcements posted online or provision of guidance language for study investigators to use in communications with their participants. The sponsor should send these communications to the relevant IRB, competent authority, and/or ethics committee for reference.
Sharing of Personal Data
Through the myriad of study changes and communications required during COVID-19, there are still safeguards to the sharing of personal data and implications for doing so improperly. Many countries, including China and South Korea, are tracking COVID-19 infected individuals through mobile tracking apps to ensure the safety of others, where the design of such apps ensures ‘privacy-first’ (i.e. the personal data collected by the app is encrypted and remains secure on the phone until it is needed to ease medical intervention). These apps can also assist health authorities in finding and quarantining people who have encountered infected individuals.
The EU General Data Protection Regulation (GDPR) is a broad piece of legislation and provides for rules that also apply to the processing of personal data in the context of COVID-19. The GDPR allows competent public health authorities and employers to process certain personal data in the context of an epidemic, in accordance with national law and within the conditions set therein. Specifically, Articles 6 and 9 of the GDPR enable the processing of personal data, when it falls under the legal mandate of the public authority provided by national legislation and the conditions enshrined in the GDPR. Further related guidance has been adopted recently by the European Data Protection Board (EDPB).
LOOKING AHEAD
Summary Results Reporting
While all study deviations should be recorded and reported appropriately, it is yet unclear how these deviations will affect the reporting of study results on a public registry, specifically outcome measure results and adverse events. Some country-specific guidance requires additional reports to be submitted with the changes to study procedures that occur during the study, whereas others only require deviation descriptions in the clinical study report. With uncertainty as to whether these documents will be made public, it is best to prepare them with disclosure in mind.
With the need to urgently produce a vaccine or treatment for COVID-19, it is possible that priorities may shift toward the publication of results of these studies. Of course, it is in the public interest to disclose these results as soon as possible to further science and the development of needed treatments. Publication is dependent on the resources and capabilities of the study sponsors, who will need to plan resources accordingly.
Alternatively, resources being diverted to COVID-19 priorities may result in a delay in the reporting of results for other studies. Given this potential situation, ClinicalTrials.gov allows the responsible party to request an extension of the results submission deadline “for good cause” within the PRS system, which has been confirmed by the NIH to include delays due to COVID-19. The extension request must provide a rationale (in this case, an explanation due to COVID-19), which is to be approved by the NIH Director – https://prsinfo.clinicaltrials.gov/definitions.html.
Plain Language Summaries
Until the EU Clinical Trial Regulation ([EU CTR] No 536/2014) is in application, plain language (‘lay’) summaries are not yet mandatory. Some sponsors, though, are voluntarily releasing plain language summaries for their study participants and/or the public, in adherence to data transparency good practice and in preparation for the regulation. If the study has been delayed due to the pandemic, then it is likely that all results reporting will be delayed. If results are delayed and/or skewed due to COVID-19, then the plain language summary should explain this so study participants are aware of the impact on the study results.
Anonymization of Data from Collection Changes
Given the speed and volume of clinical research spurred by the COVID-19 outbreak, one of the likely major effects of this focused effort is a need to release data quickly to facilitate secondary analysis, inform vital policy decisions at local and federal levels, and promote public awareness. The EU Commission has even launched a new portal for the sharing of COVID-19 data. An early, focused effort to adopt and maintain best practices in data collection and coding will ensure that, both now and in the future, a robust and efficient pipeline exists between clinical researchers and those that use critically important data to drive policy and decision-making. The goal, as it has been heard before, to “think with the end in mind” is especially true when considering how to prepare for urgent scenarios such as this pandemic.
CONCLUSION
During this challenging time, it is essential to stay up to date with rapidly evolving requirements and recommendations posted by regulatory authorities. It is important to ensure that all national requirements are being followed based on the locations in which the study is being conducted and on any special considerations that may be allowed due to the pandemic. While some gaps exist in the definitive guidance for disclosure and transparency activities, the PHUSE Data Transparency team aims to share information related to these aspects of clinical study disclosure. Stay safe, stay healthy, and always stay transparent.