DRUG DEVELOPMENT FOR COVID – 19 : CHALLENGES AND KEY CONSIDERATION FOR CLINICAL TRIAL DESIGNS

Identification of the 2019 novel coronavirus (SARS-CoV-2) and the associated coronavirus disease (COVID- 19) global pandemic is the foremost human tragedy affecting our life today. This disease has reached nearly every country, causing significant morbidity and mortality as it continues to spread. The development of drugs and vaccines is critical to win the battle against the COVID-19 virus. At present, although different countries have employed different methods of controlling COVID-19 based on their national conditions and health-care systems, the general strategy is consistent: Flatten the growth curve of COVID-19 infections by public health measures while reducing their mortality by supportive care and accelerate the development of drugs and vaccines. We have to overview the challenges of conducting clinical trials under pandemic conditions; describes potential options to develop drugs for COVID-19 rapidly; discusses how to improve the likelihood of trial successes; and reviews currently registered clinical trials for the treatment and prevention of COVID-19 by analysing available initial data and assessing the potential success of upcoming trials.

Humans have experienced pandemics before, like the 1918 Spanish Influenza pandemic, but the present COVID-19 pandemic is perhaps unique due to modern trends of globalization and changing healthcare practices. However, we have a limited understanding of the SARS-CoV-2 pathogen and currently few ways to treat its victims. There is enormous pressure on our healthcare institutions to preserve the lives of the infected while finding effective treatments. We have long understood that the safety and efficacy of new medical treatments can only be evaluated through carefully and systematically designed clinical trials. How can we preserve this requirement while finding new treatments in the shortest possible time under conditions of intense crisis?

Conventional drug research and discovery can easily take a decade from target identification to pivotal phase III clinical trials. This approach cannot be used for COVID-19. There is simply not enough time. Instead, we must focus on identifying existing drugs or drug candidates intended for other indications that may have efficacy against COVID-19 and put them into accelerated clinical trials. By leveraging pre-existing drugs with known pharmacological data, we can reduce the need for dose-finding and toxicologic assessments. Further dose evaluations can be integrated into an expanded phase III trial using a combination of clinical, viral load reduction and immune response as endpoints. This kind of acceleration will place a substantial burden on regulatory agencies that only the pandemic itself can justify.

On current knowledge of the molecular and biochemical features of the SARS- CoV-2 virus suggest that drugs produced for related RNA viruses (e.g. Ebola) may also be effective for treating COVID-19.The clinical development pathway for an existing drug proposed for a new indication is well understood by regulatory agencies and is relatively brief. However, because SARS-CoV-2 is new, the repurposed drugs will not have undergone research and early development optimization for COVID-19.

Once a drug candidate is selected, the greatest unknowns are the dose, dosing regimen and treatment duration to be used. Conventionally these are determined in phase II trials with objectives of proof of concept (PoC) and dose ranging through studying a drug’s pharmacokinetics (PK) and pharmacodynamics (PD). This process may be compressed or even eliminated through the use of existing therapeutic dosing guidelines for established indications or acceptance of a near maximum tolerated dose. Alternatively, two or more dose levels may be tested in an expanded pivotal safety/efficacy trial. The absence of an optimal therapeutic dosing regimen for COVID-19 may lead to false negatives. In addition, the lack of knowledge about the viral dynamics of SARS-CoV-2 and disease progression means that the therapeutic dosing time window for treatment is not well defined, potentially leading to misleading conclusions.

Epidemiological shifts in disease burden across the global also complicate clinical trials. COVID-19 was first observed in the Chinese city of Wuhan. Many clinical trials of repurposed drugs were performed there. However, strict public health efforts reduced the number of new cases from hundreds each day to only a few in a matter of months. As a result, Wuhan is an unfavourable site for future clinical trials. Clinical trial design needs to take this dynamic into consideration. It is likely that future clinical trials will have to be designed as global trials for this reason. Clinical operations can also be an issue as routine evaluations requiring close patient observations can’t be conducted in settings of home quarantine. There are also ethical considerations and resource competition between clinical trials at play that will limit trial conduct or feasibility. Factors include immense pressure on clinical staff, equipment shortages, and patient desperation for effective treatment. At present most clinical staff are almost exclusively focused on the preservation of patient lives. Diversion of their efforts toward patient selection and treatment changes necessary for clinical trial conduct could meet serious resistance. Next, it will be difficult to define appropriate patient populations for trials. The availability of reverse transcription polymerase chain reaction (RT-PCR) testing to define SARS-CoV-2 infection is very limited and unequally distributed. A large fraction of patients with COVID-19 symptoms do not actually know if they are infected with SARS-CoV-2 virus and the time between symptom onset and confirmation of infection will vary widely. Furthermore, there is no well-established standard of care (SOC) on a global level. This will complicate construction of multinational control groups. Patient selection also needs to take into account the major differences in fatality between different age groups and patients with different co-morbidities. It is also important to consider patient concerns with respect to their likely enrolment into a clinical trial. In the context of potentially fatal disease, many patients may withdraw their participation in trials, especially if they are blinded to their treatment and they don’t know what the treatment they are receiving. Despite the need for expedited trials, all these issues must be taken into account for actionable results.

Clinical trials need to be reviewed on scientific and ethical grounds before they can take place. The requirements for review and approval are well established with relatively minor national differences. The Investigational New Drug(IND) review and approval process is the standard pathway for drugs entering the clinical phase. The review process usually takes a few months and involves national regulatory bodies. Due to time pressure and fast changing disease incidence, accelerated regulatory review and approval for IND are required. Some COVID-19 drugs qualify for so called “investigator- initiated trials” which only require local Institutional Review Board (IRB)/Enteric – Coated(EC) approval. This is a fast process for initiating clinical trials that will be critical in this crisis. In investigator-initiated trials, pre-existing drugs are repurposed for COVID-19 treatment. Because the drugs in these trials have already undergone review for other indications, less regulatory oversight is needed for their use in COVID-19.

We present three key ideas for trial design to emphasize high quality patient selection, study conduct, dose identification, and endpoint evaluation to produce meaningful results.

To design a robust clinical trial for an anti-infection drug, we usually need to know three sets of information: a) the disease symptomatology and progression; b) the underlying mechanism of disease periods, i.e., dynamics of viral load and immune response; and c) host-virus-drug interactions. We must have clear objective definitions of disease progression and improvement. Objectively, this may be reflected by viral load and host immune response. Viral load can be quantified through RT-PCR while immune response can be tracked through inflammatory markers and antibody production. By studying drug pharmacokinetics (PK) and pharmacodynamics (PD), maybe indirectly from previous programs, we can optimize the dosage regimen (dosage, dosing interval and treatment du- ration) to maximize the cure rate, reduce toxicity and avoid drug resistance. The information obtained is critical in understanding trial results, as drugs will have different effects depending on disease progression. For example, a drug may be falsely dismissed as ineffective if it is given too late in the disease course. We must go beyond standard clinical evaluations and leverage basic science measures to enrich trial outcomes.

Traditional Phase II studies on COVID-19 are largely missing due to the time pressure to produce clinically relevant results. Instead, many teams have progressed directly to exploratory, open-labelled studies, but these were often underpowered and led to inconclusive results. The few robust Phase III trials that exist lack COVID-19 applicable Phase II data and producing them may not be feasible under pandemic conditions. Instead, simultaneous combination of supportive care and RCTs (Randomized Clinical Trials) has been recommended as the way to find effective and safe treatments for COVID-19 and any other future outbreak. In addition, there are two types of trial designs, particularly useful in infectious diseases, that all parties involved in planning, designing and conducting COVID-19 like trials should be aware of through educational programs:

Adaptive platform (multi-arm, multi-stage) design approach studies multiple targeted therapies in the context of a single disease in a continuous manner utilizing a shared control arm. Individual investigational therapies are allowed to enter or leave the platform on the basis of a decision algorithm. The advantages to this approach include its flexible design, which allows for multiple drugs to be evaluated, reduced control population and potential for international deployment. However, international deployment would require a high degree of regulatory coordination and normalization of clinical operations across many different settings.

Prophylactic design studies focus on a less-studied population in the COVID-19 pandemic; the close contacts (household or healthcare workers) of COVID-19 patients. These individuals have a high likelihood of contracting disease and limiting spread of disease is critical for managing this crisis. Prospective, cluster- randomized, double-blind, placebo-controlled studies designed to investigate the efficacy of anti-viral drugs in prevention of the secondary spread of disease to close contacts have gained popularity through anti-influenza trials.

There is an urgent need for effective anti-viral drugs to combat the COVID-19 crisis. The identification and development of these drugs depend on effective clinical trials. However, there are tremendous challenges for the development of drug therapies under pandemic conditions, even for drugs repurposed from other indications. Current barriers that have limited previous trials include lack of pathophysiologic understanding of disease, unoptimized dose, operational and regulatory difficulties, poorly defined therapeutic timing windows, broad non-specific outcome measures, non-randomized and underpowered trial designs. As a result, though the knowledge previous trials have provided has been invaluable, conclusive results are lacking. Despite crisis conditions, we cannot forsake the need for well-designed clinical trials. We present three key ideas, namely, adhering to translational science principles, leveraging innovative trial design to increase likelihood of trial success and to produce high-quality data. Furthermore, we think it is particularly important to establish Global Clinical Trial models (e.g., adaptive platform trials) that can be implemented rapidly wherever a new pandemic breaks out. Conducting such trials is certainly a tremendous undertaking that will need significant resources and commitment. This will require international cooperation and a shift in the global pharmaceutics research landscape. Finally, we hope that this unprecedented pandemic will lead to development of more robust infectious disease research infrastructure and funding to help mitigate future pandemics.

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