Challenges in conducting clinical trials in a pandemic
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 ab nihilo . 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?
Time pressure : 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.
Repurposing drugs: Our 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-19.1,2 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.
Lack of information: 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 (lack of observed efficacy for an efficacious drug). 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.
Operational challenges : 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.3,4 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. After the Wuhan outbreak, COVID-19 cases spiked in Europe, especially Italy and Spain. At the time of this writing, the nation with the largest disease burden is the United States, which has the greatest number of total cases recorded. 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.
Regulation and approval : 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 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 IRB/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.