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.