Clinical Researcher—September 2020 (Volume 34, Issue 8)

PEER REVIEWED

Dr. Kumari Priyanka, BDS, PGDCR; Tejas Thomas, MSc, PGDCR

 

Clinical trials lay the foundation for biomedical research to generate robust evidence on the safety and effectiveness of proposed treatments and/or preventive interventions for eventual use in routine clinical care. Clinical trials directly engage volunteer participants who trust the investigators to conduct their studies based on the best available scientific knowledge and ethical practices.

In this paper, we consider how data sharing and transparency are important practices of research for the drug and device development industry to follow in order to maintain the trust and confidence of the public. We also relate the history of how these practices have been developed in the U.S. to their current importance in the midst of the COVID-19 pandemic.

Background

Issues surrounding clinical trial data transparency came to light with the first requirements for trial registration from the U.S. Food and Drug Administration (FDA) Modernization Act of 1997. This act mandated the establishment of a database for clinical trials of experimental drugs being used to treat life-threatening conditions.

In 2000, ClinicalTrials.gov went live to allow public access to clinical trial data. Over the last decade, several other milestones were implemented worldwide for maintaining clinical trial transparency and compliance.{1,2} The World Health Organization (WHO) and the Declaration of Helsinki have also stressed the importance of clinical trial transparency.{3,4}

Transparency in clinical trials begins with registering a trial on a public database and continues with access to patient-level data for subsequent analyses and publication of the trial results, irrespective of the outcome.{5} Several large pharmaceutical companies have initiated transparency methods to ensure their research practices are compliant with a variety of laws, regulations, and guidelines.{6,7} Many of them have also collaborated with external medical and scientific researchers to advance their clinical research and thereby enhance public health.

Despite widespread efforts by regulators and sponsors to ensure compliance and clinical data transparency for all clinical trials conducted globally, results and outcomes from only about half of all trials are ever published.{8} Overall, lack of transparency leads to serious implications for patients, healthcare professionals, and health systems.

The New Challenge

On January 30, 2020, the WHO declared the novel acute respiratory infection caused by the SARS-CoV-2 virus, termed Coronavirus Disease-2019 (COVID-19), as a Public Health Emergency of International Concern.{9} As of July 20, 2020, more than 14 million people worldwide are confirmed to be infected, leading to increasing fatality rates.{10}

Numerous pharmaceutical companies and research institutions are conducting clinical trials to develop new or repurposed medicines and other therapies to combat COVID‑19. More articles are published each day on potential treatments or diagnostics for this pandemic, but evidence on the efficacy and safety parameters of interventions seems to have been overpassed along the way. Thereby, regulatory authorities and medical professionals are facing difficulty in decision-making on the best treatment options.

In the past, regulators and sponsors have had differences of opinions in publishing their confidential and proprietary information and certain patient-level data. This may be the time to pause and re-analyze whether clinical trial transparency would help the world overcome this pandemic with the best treatment option available.

There are many controversies and diverse questions related to the importance of transparency that are yet to be answered. It is always debatable whether the industry is following the right track by disclosing or withholding certain clinical trial data.

The Impact of COVID-19 on the Clinical Research Industry

The outbreak of COVID-19 has created a global health crisis and has deeply impacted almost everyone’s daily lives. Although COVID-19 has harmed the global economy, with many major businesses experiencing huge losses and countless small ones being forced to close, everyone is looking toward the clinical research industry as offering a ray of hope against a worst-case scenario for this outbreak.

Despite the many trials being conducted on COVID-19, due to a perceived lack of high-quality published trial data, some regulatory authorities and healthcare systems are expressing indecisiveness about the status quo of this worldwide effort. This could lead to a delay in availability of effective treatments, impacting public health and the global economy.

Across the industry, regulatory authorities, trial sponsors, healthcare professionals, and patients are facing serious challenges in fighting this pandemic (see Figure 1 for a summary). In the following sections of this paper, we will take a closer look at each of these sectors.

Figure 1: Challenges Across Multiple Sectors from COVID-19

Regulatory Authorities:                                                                 Sponsors:

Expedited review                                                                             Remote trial monitoring

Fast-track approvals                                                                        Virtual clinical trial conduct

Healthcare Professionals, Medical/Scientific Community:       Patients and General Public:

Telemedicines                                                                                  Insecurity and hope for cure

Maintain patient trust and confidence                                           Lack of routine treatment/care

Regulatory Authorities

A number of regulatory authorities (the FDA, European Medicines Agency, Medicines and Healthcare products Regulatory Agency, Health Products Regulatory Authority, and others) have released several guidance documents and dedicated the work of various ethics committees to expediting regulatory and ethical review processes to maintain high standards during this pandemic.{11–15} Most of the regulators have also implemented a fast-track approval system considering human safety as priority.

For instance, the European Commission published Recommendation (European Union) 2020/403, considering the shortage of necessities during the outbreak to supply non-CE marked devices in the interest of protection of health, as long as they comply with necessary specifications. However, documentation is the key that would be required for any future inspection purposes.{16}

Some of the key initiatives from regulators deal with such concerns as those listed below{17–20}:

• Prioritize, expedite review, and provide fast-track approval for clinical trials devoted to COVID-19
• Engage ethics committees to ensure patient safety concerns
• Support sponsors to amend any existing trial protocols or suspend trials, if possible
• Encourage sponsors on matters related to remote trial monitoring and providing investigational medicinal products to trial participants
• Report serious adverse events and submit annual safety reports and end-of-trial notifications
• Provide waivers as necessary in case of protocol deviations and serious breaches

Regulatory bodies are working closely with innovators/sponsors to foster the development of safe and effective medical countermeasures against the COVID-19 pandemic. They are under extreme pressure to ensure that the best treatment options are available at the earliest to protect public health and safeguard the public from the use of fraudulent products claiming to prevent, treat, or diagnose COVID-19.

Despite several initiatives from regulatory authorities, many ongoing clinical trials are unregistered, and their data continue to be unavailable to both the general public and the scientific community. In addition, some trial data are not even being shared with regulators appropriately, leaving them handicapped in terms of enforcing standard drug approval processes and, in turn, in protecting the public.

Corporate Sponsors and Other Researchers

Currently, there are no FDA-approved medical products for the prevention or treatment of COVID-19, and pharmaceutical company, academic, and government researchers are striving to find a potential drug candidate in record time. Globally, more than a hundred potential drug and vaccine candidates have been proposed to the WHO, but only a few are in the clinical evaluation stage.{21,22}

Certainly, technology and digital information could be the key to such rapid changes in the industry. Although there is room for flexibility, pragmatism, and speed, it is also important for sponsors and other researchers to adhere to well-established standards for quality, efficacy, and safety to promote the wellbeing of the public.

A whole new era of conducting virtual clinical trials is under way, and a great deal of responsibility rests on the shoulders of research teams to maintain patient safety and data integrity. Companies and institutions are evolving their capabilities and improving their methods for real-time data capture; moreover, many have deployed methods such as at-home care and remote monitoring to minimize the impact of pandemic conditions on ongoing clinical trials.{23–26}

FDA guidance issued in the context of COVID-19 also states that it is important to report any changes implemented during trials in the wake of the pandemic.{27} Henceforth, it is crucial for sponsors and other researchers to stay abreast of the concerns and guidelines of their local or regional regulatory agencies, and to document every action taken in their trials. Meanwhile, they should engage with sites, healthcare professionals, and patients to disclose study data appropriately.

Healthcare Professionals and the Medical and Scientific Community

During this COVID-19 outbreak, healthcare professionals and research scientists are in urgent search of a remedy to provide quality treatment to their patients and improve their quality of life. At the same time, they must ensure that preventive medicine options are in place to protect the general public’s safety.

There are several challenges that these professionals and the principal investigators of studies are currently encountering in terms of maintaining patients’ trust while prioritizing safety:

• Out-of-home travel restrictions due to government-enforced lockdowns in several countries
• Steps being taken to implement telemedicine and telehealth systems
• The need for frequent communication with patients{28–30}

It is therefore important to maintain transparency at all stages of research, as this helps healthcare professionals to choose the right medicine and provide high-quality care and treatment to their patients.

Patients and the General Public

The COVID-19 outbreak has left the general public clueless about many factors affecting its health and safety in pandemic conditions. Incomplete information about clinical trials and available treatment options are causing anxiety and confusion.

For example, many patients with chronic diseases who are trial subjects for non-COVID-19 conditions (and their caretakers) face dilemmas about their future care and treatment, as many ongoing clinical trials are being suspended or halted for safety concerns.{31,32} Patients may be required to self-isolate, causing more difficulties for trial investigators seeking to maintain medical oversight.

Meanwhile, we are seeing heightened urgency concerning who will have access and when to the results of COVID-19 trials as many companies and other research institutions race to cure this pandemic, which we will look at more closely in the next section. Any lack of clinical data transparency can cause patients to lose trust in their physicians and become extremely demotivated and insecure, leading to psychological and behavioral changes.

Importance of Clinical Trial Transparency During the COVID-19 Pandemic

In the midst of these difficult pandemic conditions, research scientists and pharmaceutical companies are prompted to dive deep to find a solution to the novel viral infection and patients are demanding clinical trial information. Most regulatory guidelines allow 12 months to elapse between study completion and posting of the trial results to public registries. Although some regulations do not mandate clinical trial disclosure for early-phase trials, it would be worthwhile publishing important trial observations in the public domain sooner rather than later, especially in situations such as the pandemic.{33}

Currently, WHO data present several potential COVID-19 drugs and vaccines that are being tested in various ongoing clinical trials.{34,35} Several sponsors have claimed their potential drug or vaccine candidates to be in advanced stages of clinical trials, but have revealed only incomplete data and preliminary trial observations, leaving the community in a dilemma about the safety and efficacy of the medicine.{36–38} In the urgency of the situation, it is of utmost importance for sponsors to comply with regulations while also considering patient safety in disclosing essential critical trial data.

In light of the ongoing health crisis, let’s consider the stakeholders and a few best practices each should follow that could benefit the clinical research industry and ultimately the whole world:

• Regulatory authorities: Availability and disclosure of full clinical trial data in a timely manner will help everyone to make the right decisions during the drug approval process. This will ensure that the best treatment option will be available as early as possible to overcome this global health crisis.
• Corporate sponsors and other researchers: Clinical data transparency could avoid duplication of research efforts and unnecessary financial losses while encouraging improvement in the design, conduct, and oversight of clinical trials, thereby providing appropriate diagnosis, treatment, and prevention of COVID-19.
• Healthcare professionals and others in the medical community: Appropriate disclosure of clinical trial data will help the medical community to make the right decisions in a timely manner by choosing the most effective therapies for the treatment and prevention of COVID-19. It could further help in explaining available experimental drugs or vaccines to COVID-19 patients. This will further enhance patients’ confidence and trust in the entire healthcare system.
• General public, including patients: Access to real-time data for members of the general public will build confidence in existing healthcare systems and in the security of their own health. This could motivate more people to take more effective steps toward “flattening the curve” of this outbreak and others to come.

Guidance for Transparency: Trial Registration, Data Disclosure, and Reporting Practices

As per the U.S. Final Rule (effective from January 18, 2017) for Clinical Trials Registration and Results Information Submission (42 CFR Part 11 in the Code of Federal Regulations) and Section 801 of the FDA Amendments Act (FDAAA 801) implemented in 2007, it is important for sponsors to register clinical trials on drugs, biological, and device products and submit their results to the ClinicalTrials.gov registry.{39,40} Similarly, the Clinical Trial Regulation (EU) No 536/2014 in the European Union implemented a portal to register EU-based trials on a database to ensure transparency in their conduct.{41}

According to the WHO best practices, results from every clinical trial should be uploaded in the respective local trial registry no later than 12 months after primary or study completion date.{3} The regulations are enforced for the benefit of the sponsors, regulatory authorities, healthcare professionals, and patients. This could further enhance public confidence in the clinical trial process, new medicines, and regulatory systems. It could also help healthcare professionals in deciding on treatment options.

These measures are fostered to accelerate further research by accumulating knowledge and technical ability. Therefore, duplication of trials, safety or efficacy failures, redundant data, and workforce investment in research may be avoided, and this could stimulate growth and development of commercial and academic research centers, medical facilities, and research expertise.

Meanwhile, FDA guidance first released in March 2020 and revised in July 2020 provides insights to sponsors and investigators on maintaining compliance with the tenets of Good Clinical Practice and minimizing risks to trial integrity in these pandemic conditions.{20}

Navigating a New Regulatory Landscape

The clinical research industry is adapting to rapid, pandemic-driven changes that have affected activities at all levels, starting from the regulatory authorities, sponsors, contract research organizations, and trial sites and reaching all the way to trial participants. There is more room for new technologies and start-up innovators to address the increasing demands of managing clinical trial data sources and remotely connecting with patients, to name just a few challenges.

Clinical trials are mostly patient-centered, and before long, the industry will be highly efficient in conducting clinical trials virtually with connected devices, medications delivered at home, and timely long-distance communication, therefore achieving accurate data capture and transparency and, at the same time, gaining and improving patient trust. Overall, the potential downside of increasing dependence on technology would be that it cannot replace human interaction and deliver the physical care provided by doctors in person.

Conclusion

COVID-19 is a severe and ongoing novel pandemic that has caused immense social and economic regression across the globe. Pharmaceutical companies worldwide are under public and competitive pressure to explore innovations in drug development and revamp their reputation.

During this time of increasing need for self-care and prevention, humankind is becoming even more dependent on technology and sponsors are implementing decentralized and stay-at-home clinical trials. Thereby, use of remote trial technologies could further overcome ethical and regulatory barriers to enhance patient safety and trial data integrity compared to traditional trial designs. However, lack of human connection in such conditions may have drawbacks that should be taken into consideration.

Pandemic situations definitely demand transparency in clinical trials. Lack of full, conclusive scientific evidence from the various ongoing COVID-19 trials could lead to ignorance of an effective treatment to curb the spread of the disease. Although there are various regulations and policies in place, sponsors and companies are still striving to understand the public scope of in-depth disclosure of trial plans and outcomes.

It is important for sponsor companies and others conducting studies to maintain high standards in research and to meet all regulatory and local requirements. Generally, bigger pharmaceutical companies are able to meet their compliance obligations with a dedicated team and all the requisite tools at hand, while smaller companies may fall short in disclosing data and/or meeting other expectations appropriately without significant external assistance. Nevertheless, smaller companies are gradually paving their way to gaining the necessary skills and resources.

Compliance also adds value to the credibility and reputation of these companies and researchers. Therefore, it is critical to report any observations and publish trial results appropriately to avoid any gaps in knowledge and deliver effective treatments for this global disaster. The future of clinical trials could be overwhelmingly positive if we consolidate the advances being made now and proceed toward greater data transparency.

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Dr. Kumari Priyanka, BDS, PGDCR, (kumari.priyanka@indegene.com) is Manager in Regulatory Solutions department at Indegene Pvt Ltd in Bangalore, India and lead author of this article. She leads Regulatory practice in Indegene with extensive experience in Regulatory Intelligence, Strategic Consultation, Regulatory Submission and Clinical Trial Disclosure services across geographies and product lines.

Tejas Thomas, MSc, PGDCR, (tejas.thomas@indegene.com) is a Senior Regulatory Associate with Indegene Pvt Ltd, Bangalore, India. She is proficient in disclosure planning, tracking workflow related to trial transparency, and ensuring timely and accurate disclosure of clinical data as required by international law/guidance policy.