Globalization of Clinical Trial Registration in Light of COVID-19
As the novel coronavirus (COVID-19) circulates the globe, it has become the foremost topic of discussion—from social platforms to global news channels. For most, it has become a daily routine to check the most recent updates on this deadly crisis. The general public is now heavily engaged in the latest advancements in COVID-19 treatments and vaccinations. Public audiences are in search of news regarding vaccine development, treatment options, and precautionary measures to battle this disease. Should pharmaceutical companies be concerned with the implications of this sudden surge of interest in medical research?
Under growing public and legislative pressure, pharmaceutical companies are inclined to provide more information about their current drug development to restore public trust. The issue of transparency in the pharmaceutical industry is not new, and COVID-19 places the industry under further scrutiny in terms of clinical development and disclosure of trial results—the general public is more curious about drug development than ever. By being transparent, we decrease the likelihood of misinformation while simultaneously improving the public’s likelihood of volunteering for trials. In this case, individuals are more willing to volunteer for COVID-19 vaccine and treatment trials.
Clinical trial registration plays a key role in open knowledge sharing and the evaluation of clinical interventions. Registries can be used to generate annual reports, track epidemiological studies, and compare treatment performances, study combination therapies, and monitor physicians’ conduct. In particular, evidence-based prescription guidelines can be based on publicly disclosed clinical trial reviews. This might have particular implications for COVID-19 treatments.
What Is the Global Registry Landscape?
In 2000, the United States launched a national registry of federally and privately supported research studies. This registry serves as a public information resource for trials conducted under investigational new drug applications regulated by the Food and Drug Administration (FDA), carried out in the United States and beyond. Another expansion of federal law, the 2007 FDA Amendment Act (FDAAA), mandated a "responsible party (sponsor or designated Principal Investigator)" register to report results of "applicable clinical trials.” Separately, the International Committee of Medical Journal Editors (ICMJE) responded to reporting failures related to harm from antidepressants in 2004 by encouraging the registration of clinical trials. A clinical trial registration policy was issued by ICMJE requiring registration of clinical trials in a public registry with participant enrollment after September 2005 as a condition of consideration for journal publication. The ICMJE requires that registration adheres to the 20-item minimum dataset defined by the World Health Organization (WHO). The WHO International Clinical Trials Registry Platform (ICTRP) policy (2006) also specifies that "the registration of all interventional trials is a scientific, ethical, and moral responsibility." The WHO developed ICTRP to facilitate the harmonization of global registries. The WHO ICTRP provides a global forum for trial registries to share best practices and is a platform to link clinical trial registers, generating a more efficient strategy to search for global trials.
In October 2013, the European Medicines Agency (EMA) released a new version of the European Clinical Trials Database (EudraCT), enforcing all protocols and results information on interventional clinical trials to be publicly available through the EU Clinical Trials Register (EU CTR) from September 2011. The EU CTR is a common regional register of the 31 member countries of the European Economic Area (EEA). There are EEA countries that, in addition to the EU CTR, have additional public national registries/databases. Several countries have their own national registries as well, including Australia, Brazil, India, Iran, Peru, Republic of Korea, and Switzerland. Besides national databases, some databases are hosted by industries and academic institutions for disease-specific registrations and/or patient associations.
How Effective Is the Global Registry Network?
Regardless of a trial's publication status, registries assure the completeness of information for all initiated trials addressing a given research question. Despite the coordinated efforts of ICTRP to harmonize the trial information from multiple countries, accurate global trial registration status seems to lag. Currently, no common platform contains all ongoing trials worldwide that can be considered a repository of trial data. More than 100 countries currently do not have a national registry, although research investigators or sponsors may voluntarily partner with the WHO registry for disclosure if these countries do not possess regulations for information sharing. Many countries develop regional, national, or international registries in response to the evolving global registration framework but fail to keep them updated—leading to unregistered or retrospective registration with poor quality or incomplete information on trials.
With the introduction of the WHO minimum data set, a uniform approach was established towards trial registration. However, assessment of compliance with the WHO criteria shows a large variation in key clinical and methodological details, as different registries have different guidelines varying regionally in terms of minimum data sets. Several registry websites lack basic information related to posting, such as if prospective or retrospective reporting is permitted, the total number of registered trials, whether posting includes observational studies, study track changes and updates dates, multilingual options for non-English-speaking countries, and, most importantly, whether the registry has a section for result posting.
Even though ICTRP allows researchers from different regions to easily refer to the registered trials in the approved registries, the validation of data remains questionable due to a lack of quality assurance (QA) review of posted information in the majority of registries. Individual trials lack information such as study dates (recruitment dates, primary completion, or study completion dates); recruitment status (active, completed, or terminated); clear trial objectives, study endpoints; study design; publication details, and results posting. In general, even if the registries fulfill quality criteria, lack of a QA review of individual trial information leads to disclosure of incomplete information.
Consequences of Failing Trial Registration
The pharmaceutical industry’s persistent bias toward positive results leads to a lack of reporting, and thereby to unpublished trials that disappear without a trace. However, as research is a systematic process undertaken to accrue knowledge, every piece of information is crucial irrespective of its outcome. So, the lack of information sharing is a barrier to knowledge advancement. Clinical trial disclosure can save time and resources while also preventing duplication of research. Information sharing in clinical research becomes more imperative, as it deals directly with humans. Risks of exposing trial participants to threatening drug reactions can be avoided if the harmful effects were already disclosed from other studies on the same drug. Although the creation and maintenance of a clinical trial registry is a complex process, the outcomes surely outweigh the efforts.
Global Registries – An Evaluation Ground for COVID-19 Interventions?
Clinical trial research is emerging at an unprecedented rate to find safe and effective interventions for COVID-19. Given the evolving, fast-tracked rate of new COVID-19 clinical trial information and findings, an urgent need exists to track clinical data, prevent duplication of efforts, and understand what trials are being performed globally. Geographical mapping of these trials assessing variants such as the severity of conditions, patient groups, race, ethnicity, intervention characteristics, etc. is required to assist researchers and policymakers to make evidence-based decisions in hopes of minimizing COVID-19 morbidity. Although no specific antiviral drug has been shown to be effective thus far, researchers are currently testing several interventions to ascertain the best possible treatment.
Clinicians and researchers can benefit from registered COVID-19 clinical trials globally to make informed decisions. Many registries have proactively taken initiatives to highlight or provide information related to the ongoing and completed COVID-19 trials on their websites. For example, ClinicalTrials.gov provides not only a separate list of COVID-19 studies, but also a list of studies available on WHO ICTRP and therapeutic options currently under investigation. Similarly, the Chinese clinical trial registry (ChiCTR) and EU CTR are among other registries with lists of clinical studies on COVID-19. Moreover, the International Standard Randomized Controlled Trial Number (ISRCTN) registry is supporting global research on COVID-19 by giving priority to prompt registration and reporting of related studies.
The information from these registries is undoubtedly helpful; however, the trial information cannot be guaranteed to be up to date. Many registries still fail to report all clinical trials.
What Immediate Initiatives Can Sponsors Take?
As the global clinical trial registry framework holds huge possibilities for everyone in a research field—from researchers to patient advocacy groups to trial participants—the current urgency for this implementation would be time-consuming and complex. However, as trial registration is the “need of the hour,” it can still be attained with coordinated efforts of sponsors, governing bodies, and healthcare authorities. Until governing bodies and healthcare authorities work together to enforce transparency laws globally, the fate of transparency remains in sponsors' hands. Lack of quality review of posted information in the majority of registries allows trial sponsors to cherry-pick favorable results while holding back the unfavorable ones. ClinicalTrials.gov, being a hub of transparency and disclosure activities, is no exception to this as sponsors consistently find ways to escape reporting of unbiased and incomplete results.
However, with the COVID-19 crisis, the significance of transparency in the clinical research world is extremely important. We see this in the clinical development of remdesivir. Remdesivir has had a murky past, failing at treatment of viruses like hepatitis C in past studies. Gilead Sciences Inc. has continuously been transparent with the public regarding its study results, regardless of outcome. Remdesivir tops the list of several competing interventions in terms of clinical improvement by shortening the recovery time in some severe cases of COVID-19. Remdesivir has now been approved by the United States and Japan as a treatment for COVID-19. Past research suggests that remdesivir has potent effects against coronaviruses such as SARS and MERS. Therefore, past clinical trial information will be vital in determining the treatment ability of remdesivir.
Pharmaceutical organizations should recognize this and step up to responsibly provide valid results. Sponsors should perform a quality review of the records to check the credibility of data before posting. To maintain consistency, mandatory fields should be cross-checked for completeness so that minimum data sets are filled in accurately. It is necessary to align with the common standards of trial registration set by the WHO to ensure the validity of clinical trial data irrespective of where it takes place. Moreover, there is a need for standardization of previously posted trial information, enhanced usability and transparency, and routine checks for completeness and individual study-specific consistency. Additionally, if all journals follow and cooperate with the ICMJE initiative on trial registrations, consistency can be successfully achieved.
With no successful treatment for COVID-19, several expanded access programs are running globally. It is important that sponsors vigilantly report the outcomes of the associated investigational products to the public domain. Although expanded access programs fall under non-applicable clinical trials as per the US FDAAA Final Rule, the regulation also applies to the sponsor of an applicable clinical trial for an investigational product who is also the manufacturer of that product. In this case, an expanded access record is required by ClinicalTrials.gov to be submitted within 30 calendar days of expanded access availability. The sponsor should create a single record including all forms of expanded access for each investigational product. These records are linked to the applicable clinical trials studying that product. Moreover, for those countries where trial registrations are not mandatory, voluntary registrations can still be created by sponsors. In the absence of a country-specific registry, the sponsors or investigators can freely select a WHO primary registry for their trials. Prospective registration of trials will ensure that all trials undertaken are complete and up to date. Several pharmaceutical organizations recognizing the importance of trial registration have already stepped up to disclose trials on their company websites or commercial registries such as Thomson CenterWatch Clinical Trials Listing Service.
Existing information on clinical trial registries should be utilized and common standard guidance should be followed to fill in the gaps to implement an upcoming global registry framework. This is the right time to register your clinical trial so that we remain prepared for the future, as this COVID-19 pandemic will end one day, but the lessons we learn from it will go beyond.
At TransPerfect, we submit to both national and international registries on behalf of sponsors. Our translation teams can also ensure country-specific protocol and results postings. For more information on this topic, contact us at medicalwriting@transperfect.com.
