Globally, researchers have long since been working on various aspects of medicine. Studi clinici are a core part of developing medicinal and health development products. They are systematic research procedures/studies carried out by pioneering companies to evaluate medical products/practices, mainly from a safety and security perspective.
Other clinical trials may focus on a different outcome, such as trying to gauge the efficiency of a new drug or device, garner feedback or study potential hazards and side effects. This is done prior to releasing the best drug candidates/ medical practices into the market. These procedures have been made thorough in terms of the impact of the drug on various body systems once consumed by patients- ultimately with an aim of leading to better safety of the patients. Therefore, it is understood that the trials and other associated studies take a long time, considering challenges related to patient outcome and their availability throughout the trial.
As medical products, diagnostics and methodologies evolve, so do clinical trials, in order to ensure they stay abreast of these technological advancements. Clinical research, in fact, took quite a long time to be refined into a humane and ethical process. The evolution of clinical trials makes for a fascinating read, with the earliest recorded clinical trials taking place in 500 BC, with the procedures described mostly concerning dietary solutions. The trials have evolved into more structural and statistical notes as we progress through the centuries, lending a glimpse into how clinical trials were streamlined over the years.
Clinical trials and studies have played a significant role in the evolution of modern-day medicine. However, there were too many challenges to face with the COVID-19 pandemic that devastated all the sectors globally. There was immense pressure on the regulatory authorities to take urgent informed decisions considering the high-risk situation. The first lockdown across countries was when the world came to a stop; there was a great need for researchers to develop COVID antibodies, such as therapeutics, vaccines, or any other medical products/devices with limited available resources. The autorità di regolamentazione had to step in to build crucial systems or protocols concerning clinical trial authorization, emergency use of certain drugs, and other related procedures.
Timeline of clinical trials
Clinical trials have four phases– Phase I, where safety is tested on healthy individuals, and Phase II, where different doses are tested among a small patient population. Phase III includes tests on large sets of patients and healthy individuals followed by regulatory approval submissions and lastly, Phase IV where long-term effects of the medical product/device.
The typical data life cycle of clinical trials is based on how and what data is to be shared. This includes trial design and registration, trial participant enrollment, study completion, publication, and regulatory application.
Trial design and conceptualization generally take six months to a year; later, it can take up to a few years to enroll patients in the trial and collect their data. Even though the trial design of protocols and the statistical data analyses are planned well before the recruitment of trial participants, it undergoes changes throughout the course of the trial. These amendments are to be explicitly recorded; these come in handy during publications in medical journals and trial registrations with the World Health Organization’s (WHO’s) International Clinical Trials Registry platform.
The trial data is continuously captured individually from both patients and healthy participants. Study completion includes a declaration of the last participant interaction and additional variables that measure data points without the interactions with the participants. Bio-statistical analyses are stored along with the raw data for probable future requirements. Specific portions of the data are then segregated and used to generate results for many publications from one trial. Some parts of the data generated from the trials are also used in regulatory applications.
Suppose a medical product’s intellectual property rights (IPR) are transferred to another sponsor. In that case, there will be an exclusive period where the new sponsor can pursue additional studies, apply for new patents, and prepare for regulatory submissions.
As per the Committee on Strategies for Responsible Sharing of Clinical Trial Data at the Institute of Medicine, Washington DC – “in case a sponsor abandons the product or indication and does not transfer the IPR to develop the product to another sponsor; sharing trial data may help other researchers and other sponsors develop similar products. Such data can benefit other researchers, clinicians, and the public, by increasing general knowledge of the product, including its efficacy and safety profile.”
As per the study conducted by Saito and Gill in 2014, they discovered the probability of high reporting bias. This was because they found that despite the trial completion, many studies (smaller studies in earlier stages) registered in the US-based ClinicalTrials.gov database had not achieved public disclosure of results (PDOR).
This makes one question the validity of the clinical literature available to draw conclusions. This would complicate the situation for the upper executives in the management teams to derive data-driven decisions. Leaders must align their business goals with the available data and analyses. With the knowledge of potentially skewed data, leaders will have to consider the contextual analysis of data with the help of regulatory scrittori medici while applying further for regulatory applications/certifications. In this era of data-driven leadership, data would enable foresight by understanding the deficiencies in the slow nature of trials when it comes to publishing their results, including the ones that failed to pass the tests.
Companies that hold trials or collaborate with those sponsors that carry out the trials should keep these deficiencies in mind and understand the importance of certified regulatory medical writers that would streamline the process through the regulatory approvals. Trial sponsors or pharmaceutical companies must submit detailed clinical study reports (CSRs) and individual participant data to regulatory bodies – the US Food and Administration (FDA) and the European Medicines Agency (EMA) while seeking regulatory approval for a product. Regulatory medical writers can prepare the CSRs. This process would enable better sales projections in terms of business development.
The Pandemic Obstacle
The COVID-19 pandemic had consequences on the global population and therefore also on clinical trials/studies. The pandemic highlighted the loopholes in conducting trials and the need for flexibility in the system. The pandemic came with tremendous uncertainty and created incredible pressure among the researchers, regulators, and policymakers to do their best to move quickly and safely. COVID-19 has placed researchers across the globe on a strict timeline that has never been experienced before.
The clinical research field faced major concerns regarding patient safety, recruiting new trial participants, and downstream data collection and management. The dire situation of the pandemic and redirected funding helped speed up the process of developing and discovering vaccines, therapies, and diagnostics specifically for COVID-19.
Clinical research was disrupted due to the first wave of the pandemic from March to May 2020. Participant enrolments crashed to a bare minimum for many trials as hospital trips became risky. The hospital staff was redirected to focus on COVID-19 patients, clinical trials of experimental vaccines or treatment for COVID-19. Many trials were discontinued/ suspended as they were deemed dangerous/highly risky during a pandemic. At the same time, the researchers tried their best to keep life-saving trials (such as cancer treatment studies) running despite the challenges. Regulatory bodies such as the USFDA issued guidance for trials that had to pause or change course.
Similarly, EMA and other National Competent Authorities’ (NCAs’) provided regulatory guidance and appropriate flexibility wherever possible to ensure trial continuity- this included digitalizing trial documents’ submission and review, releasing few restrictions on the supply of investigational medicinal products. At the peak of the pandemic, various ethics committees were immersed in helping researchers alter trial plans such that they could reduce the frequency of participants visiting the clinic.
Trials now: Overcoming Pandemic Stagnation
As of May 15, 2020, BioPharmaDive reported that nearly 100 companies and 240 trials had experienced disruptions. Major sponsors involved in the clinical trials, such as CROs and pharma companies, faced difficulties in patient recruitment and retention, safety, distribution/ supply of drugs, and scarcity of research staff at particular sites, which brought financial loss. The stagnation brought about delays in trial data submitted to the regulatory bodies, leading to delays in drug launches and in understanding which drug trials were to be dropped.
After the stagnation that disrupted clinical research globally, sharing and collaborating have become the main themes of operation during clinical trials/studies. Researchers have begun utilizing data-sharing cross-functional platforms such as Health Data Research UK e Vivli. The data in these platforms can be reviewed, analyzed and curated securely.
EMA and other NCAs improved the flexibility in how the trials operated by adopting measures such as centralized monitoring, telemedicine visits, and remote source data verification (rSDV) for various trials as per the EMA guidance on CT management during the pandemic (version 4; February 4, 2021). The guidelines also permit rSDV in regions outside the EU/EEA with the data protection rules applicable per EU norms.
The pandemic proved a great need for improving coordination and collaboration among the various stakeholders in clinical research. This could be achieved by funding bodies and global research organizations that hold the most amount of control over the trial designs. The UK RECOVERY trial and WHO SOLIDARITY trial are the two trials that showed great coordination among hospitals. They even took up an approach that involved multiple treatments against one condition while coordinating between multiple hospitals; this gave the trials sufficient numbers of patients to participate in the trials. This model that arose to tackle the problems of the pandemic, if widely applied to the ongoing or the upcoming trials, could pose a boon to provide a necessary number of participants and help prevent delays or slowing down of trials.
This collaborative approach would involve doctors and researchers to help them understand and experience running a well-designed trial.
Future that awaits…
The pandemic drove the operation of clinical trials as a catalyst in alternative and innovative approaches that were not implemented pre-COVID times. These include remote monitoring, phone and video visits, eConsent and electronic health records. As per the survey conducted by Informa Pharma Intelligence e Oracle, “82% of respondents feel that the new approaches adopted during the pandemic have had a positive impact on clinical trials overall, including 26% reporting a significantly positive impact.”
- The transition to decentralized trials: Historically, most clinical trials were conducted in a centralized/localized manner- an urban location or large institute. The pandemic gave the push to widen the net to recruit more patients and possibly do trials in a faster way as there are lesser chances of delay due to the lesser number of available patients. This occurred while balancing the rising concerns regarding data quality and conformità normativa. Major pharmaceutical players such as Pfizer-BioNTech, Johnson & Johnson, and Moderna successfully ran several trials for the COVID-19 vaccines, mainly decentralized. This has led to vaccine development, tests and release in record time despite limited resources with the coordination and efforts of the researchers, government, and community. These instances have shown the world that trials can be conducted faster, safer, and cheaper, breaking all barriers of bureaucracy to the betterment of humanity- a sure sign that virtual clinical trials are here to stay.
- Communication and coordination among various stakeholders: Research sites learned the importance of effective communication and coordination. Due to a staff shortage at sites, loads of those sites were shifted to another site. This load shifting was only possible through the investigator maintaining clear communication between the sites and sponsors. During such volatile situations where the regulations kept altering, the investigator and regulatory medical writers had to prevent confusion in deciphering it. This need to improve communication has encouraged better investment in communication technology and skills to bring about intra-site coordination to expedite future clinical trials through agility in working and quick problem-solving.
- Increasing virtual trials through mergers and acquisitions: FDA and other regulatory bodies across the globe have begun promoting the adoption of virtual clinical trials, providing flexibility to the investigators in framing appropriate protocols that would support remote care. The pandemic has also influenced an increase in partnerships and M&As. This change is occurring with the primary objective of providing support for the virtual trials in the new post-pandemic world. ERT, a clinical trial data management company, merged with Bioclinica to become a clinical trial endpoint technology leader. The virtual setup of trials has also promoted trial training to be conducted virtually and remotely.
- Improved patient/participant recruitment: Trial participant recruitment has become more distributed and decentralized across various regions and geographies to mitigate scarcity. This widespread participation has been enabled through methods that will soon become an industry norm, such as electronic consent (following the Good Clinical Practice (GCP) governed by ICH regulatory guidelines), virtual consultation, and remote monitoring. This pandemic led to increased consumer devices (phones- class II devices) to be used for test data collection securely and safely. With data as a universal equalizer, the post-pandemic era sees the ability to securely and safely collect upstream data from trial participants becoming a big highlight.
- Decrease in cost: The decentralized trials would cause a reduction in the costs involved in various aspects of running a trial. This cost reduction would be brought about by virtual meetings, remote clinical staff, and remote monitoring.
How Scrittori normativi Fit In
Taking up the prep work of detailed research and regulatory documents is usually an arduous task. Summarizing the complete procedure, methodologies and results of a drawn-out clinical trial in an objective manner requires a specific level of expertise that only qualified regulatory writers can provide.
In the aftermath of the pandemic, with the increasing adoption of virtual trials, the transition of academics to full-time freelancing and the growing integration of hybrid workforces, freelance regulatory writers can prove a cost-effective option for organizations.
Kolabtree's independent regulatory writers, for example, work on flexible on-demand projects helping organizations create and curate effective submission documents that ensure adherence to linee guida outlined by the relevant regulatory authorities.
A good regulatory writer not only guarantees compliance with existing rules but also designs protocols to maintain adherence going forward by eliminating potential scenarios that may lead to non-compliance in the future. Right from understanding the industry framework, to analyzing complex statistical data, a qualified regulatory writer does it all.
Più significativamente, freelance writers prove to be a good value for both money and time, as they can be consulted without the additional hassle of onboarding costs and procedures. Platforms like Kolabtree aim to make this process more efficient and streamlined by offering the clients several benefits, such as a secure workspace that ensures complete data confidentiality, custom NDA options to sign with the freelance consultant, and a global network of independent regulatory writers to vet and hire from.
Regulatory and technological evolution in trials
Il Oracle and Informa Pharma Intelligence survey also found that researchers using new methods in the trials found data more time efficient, higher quality and robust. About 81% of researchers using these modified approaches have high confidence in the data obtained. Here, 92% of the survey participating researchers stated that the new methods during the pandemic resulted in equal or more confidence in the data compared to the data collected employing pre-pandemic approaches. The survey also showed support for using hybrid (44%) and fit-for-purpose (42%) models after the pandemic. About 61% of researchers also believe a positive impact could be brought by allowing the patients freedom to choose the manner in which they would like to participate in the trials.
The survey results strongly suggest that the new methods are here to stay and give scope for more evolution of the methods in clinical trials.
Regulatory recommendations from OECD (The Organisation for Economic Co-operation and Development) suggest improving consistency through a standardized risk-based approach across national regulations and their interpretations while also protecting the participants of the trials. OECD also encourages international harmonization of multiple aspects of clinical trial regulations that can be achieved by working with the International Council for Harmonization (ICH) and public health professionals who are members of the Clinical Research Initiative for Global Health (CRIGH).
Fortunately, technological advancements in clinical research are evolving to help bridge such collaborations and carry the industry into the future.
Rai AK, Rice G. Use patents can be useful: the case of rescued drugs. Sci Transl Med. 2014;6(248):248fs30. Doi: https://doi.org/10.1126/scitranslmed.3009120
Saito H, Gill CJ. How frequently do the results from completed US clinical trials enter the public domain? — A statistical analysis of the ClinicalTrials.gov database. PLoS One. 2014;9(7):e101826. Published 2014 Jul 15. Doi: https://doi.org/10.1371/journal.pone.0101826
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