Preparing to Face the Next Global Challenge: Studying Post-Acute COVID-19 Syndrome - NET
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Preparing to Face the Next
Global Challenge: Studying
Post-Acute COVID-19 Syndrome
Post-acute COVID-19 syndrome (PACS) could affect up Post-Acute COVID-19 Syndrome:
An Evolving Understanding
to 30% of patients who contract COVID-19. Symptoms are The initial response to the COVID-19
wide-ranging and can be debilitating, but the full clinical pandemic focused on the development
of treatments for acute infection and,
picture is still being revealed. The challenges to conducting in parallel, preventative vaccines. The
clinical trials for this as yet undefined disease are myriad. first clinical studies investigating ther-
apeutic treatments focused on assess-
PPD is well-positioned to help sponsors overcome these ment in severe hospitalized patients,
challenges and bring needed therapeutics to patients. and most studies limited recruitment to
patients requiring ventilatory support,
many of whom were more than 10–14
days post-infection or onset of symp-
toms. The focus for data collection was
Wesley Hicks, M.B.B.S., M.R.C.P., M.F.P.M. Vice President and Global Therapeutic Head, acute outcomes. Patients were typi-
Respiratory, Global Product Development, PPD cally evaluated at days 14 and 28 and
Sudhakar Sridharan, M.D., Executive Medical Director, Global Product Development, had either succumbed to the virus, re-
Immunology and Rheumatology, PPD mained in the hospital while recover-
Margaret Vernon, Ph.D., Senior Vice President, Patient Affairs, Evidera ing, or returned home.
Andrew Burr, Ph.D. M.I.C.R., C.Biol., F.R.S.B., Vice President, Infectious & Respiratory
Disease Therapeutic Unit Head, PPD As the pandemic progressed, therapeu-
Cristina Nieto, Vice President, General Medicine Therapeutic Unit Head, PPD tic development expanded, with a shift
Davide Garrisi, D.Ph.C., Executive Director, General Medicine, PPD toward the development of treatments
1 Decentralized Clinical Trials www.ppd.com
that could be administered earlier in can provide a great deal of information new disability and 19% experiencing a
the outpatient setting to prevent the about effects on long-term outcomes, health-related change of occupation.9
worsening of the disease and its po- while also helping build our under-
tential long-term effects. standing of post-COVID syndrome. It is still too early to know how long
these symptoms will persist, what per-
The indications of a more drawn-out As biopharma companies work to centage of patients will have symp-
disease process or syndrome associat- address the unmet medical needs of toms at one year, two years, and lon-
ed with COVID-19 infection were first patients with post-COVID syndrome, ger, and whether some patients who
seen in patients who were not able they will require clinical research or- appear to have recovered from a post-
to resume normal life functions after ganization (CRO) partners with broad COVID syndrome might subsequently
recovering from the initial infection. experience and innovative solutions. relapse. It is also unclear how patients
Eventually, as some of these patients We are encouraged by our early dis- who have experienced complications,
recovered, the profusion of those cussions with sponsors who are pur- such as cerebrovascular accidents, or
“long-haul” patients drew the atten- suing experimental treatments for show evidence of myositis or lung fi-
tion of clinicians. these complex and perplexing sequel- brosis will progress compared with pa-
ae. We are committed to applying the tients with these conditions from tradi-
The term post-acute COVID-19 syn- full range of knowledge and expertise tional etiologies.
drome (later abbreviated as post- that PPD offers — clinical therapeutic
COVID syndrome) was adopted to experience, data analysis capabilities, In addition to the physical damage
describe the broad constellation of and real-world evidence solutions — to caused by the virus, patients with
symptoms, including exercise intoler- advance therapeutic options for these COVID-19 also may experience psy-
ance, dyspnea, chest pain, palpitations, patients. chological complications and even
chemosensory impairment, lymphade- post-traumatic stress disorder (PTSD).
nopathy, appetite loss, fatigue, poor Uncertainty About Long-Term Effects The March U.K. study reported that
concentration, and pulmonary or cardi- An early study found that 87.4% of over 25% of discharged COVID-19 pa-
ac complications in patients who have patients who had recovered from tients had clinically significant symp-
recovered from the acute infection.1-5 COVID-19 reported persistence of at toms of anxiety and depression, with
least one symptom — particularly dys- 12% exhibiting symptoms of PTSD at
As time has progressed, more spon- pnea and fatigue — at a mean evalu- five-month follow-up.9 While this may
sors are including an extended ation time of 60.3 days after onset of be most evident for patients who have
post-treatment observation period the first COVID-19 symptoms, with been hospitalized and experienced
for trial participants at three-, six-, and 44.1% reporting a worsened quality of traumatic healthcare interventions, the
12-month timepoints or longer. Simple life.6 A later study found that 30% of anxiety associated with an unpredict-
questionnaires, which are relatively recovered COVID-19 patients reported able disease course or the fear of in-
inexpensive to develop and execute, persistence of at least one symptom fecting others means that even patients
(most commonly fatigue, loss of the with mild disease may be left with a de-
sense of smell or taste, or “brain fog”) gree of trauma disproportionate to the
We are encouraged by our as long as nine months after the acute acute illness they experienced.
early discussions with sponsors disease phase.7
Bringing Experience to Address a
who are pursuing experimental Many post-COVID syndrome patients Myriad of Challenges
treatments for these complex meet the clinical criteria for myalgic CROs involved in post-COVID syn-
and perplexing sequelae. We encephalomyelitis, commonly referred drome studies will need to have con-
to as chronic fatigue syndrome (CFS).8 siderable experience supporting
are committed to applying the Based on data available to date, it ap- COVID-19 therapeutic clinical trials,
full range of knowledge and pears that somewhere between 10% bringing the necessary understanding
expertise that PPD offers — and 30% of people who have had of who the potential participants are
COVID-19 — whether mild or severe and how to locate them. As one of the
clinical therapeutic experience, and whether they tested positive or first CROs to support COVID-19 trials,
data analysis capabilities, and not — will develop these long-term PPD is optimally positioned to support
real-world evidence solutions symptoms.7 A U.K. study published in post-COVID syndrome studies.
March 2021 found that 71% of COVID-19
— to advance therapeutic patients discharged from hospitals Our COVID-19–specific experience,
options for these patients. had not fully recovered five months which spans treatment to prophylaxis,
later, with 20% exhibiting persistent began early in 2020. We gained valu-
symptoms that met the threshold for a able experience encompassing a broad
2 Decentralized Clinical Trials www.ppd.com
range of patient populations, inpatient
and outpatient settings, study phases,
trial designs, global geographical loca-
tions, and types of drugs and drug for-
mulations. PPD has demonstrated the
ability to rapidly respond to changes
in direction dictated by the evolving
epidemiology of the pandemic and
has been recognized by clients for its
agility and speed.
Lack of a Standardized Definition
We may easily identify who has had
COVID-19, but we still do not know how
to definitively identify people suffering
from post-COVID syndrome. This is due
in part to the lack or a formal case defi-
nition, though the medical community
Establishing a Case Definition and academic researchers are actively
progressing this issue. However, any
proposed definitions likely will undergo
numerous revisions before a universally
To establish a case definition, a While this is a preliminary
accepted case definition is adopted.
large quantity of patient data is grouping, we expect this listing
needed, particularly in light of to evolve, perhaps with the A significant number of patients de-
the multiplicity of post-COVID addition of other subgroups or scribe disruptive neurologic symp-
syndrome manifestations. In new combinations of symptoms. toms, such as emotional detachment
and cognitive disorders, tremors, ex-
an early attempt to describe Cluster analysis of large data
treme fatigue, phantom smells, diz-
post-COVID syndrome, distinct sets may eventually identify
ziness, and bouts of profound confu-
subgroups of patients have been phenotypes within post-COVID sion — generally termed “brain fog.”
identified, including: syndrome sufferers or even Patients may experience one or more
predict which patients are at of these symptoms but may lack an
• Chronic fatigue syndrome identifiable physical cause. This is
greater risk of developing a
patients with brain fog; not unprecedented; the connection
particular pattern of symptoms.
between chronic neurologic condi-
• Post-ventilator syndrome tions and infectious viruses has been
Medical claims and patient
patients, whose symptoms known for almost a century. It may be
charts can be used to determine
may include physical helpful to differentiate these patients
new diagnoses that follow a with less well-understood symptoms,
weakness, cognitive COVID-19 diagnosis. However, for whom conventional imaging and
dysfunction, and as many of the symptoms of testing modalities appear normal,
posttraumatic stress from patients with lung fibrosis or ev-
post-COVID syndrome can only
syndrome; idence of cardiac damage and hence
be identified and reported by
a more obvious cause for their fatigue
• Patients with true neurologic patients themselves (fatigue,
and breathlessness.
symptoms, such as rigidity pain/discomfort, dyspnea),
and tremors, that likely additional research that directly Extended ICU stays are independently
reflect effects of the virus engages patients, either through associated with prolonged or incom-
qualitative (e.g., focus groups) plete recovery and may be associated
on the brain; and
or quantitative (e.g., web- with autonomic function disturbances
(e.g., fatigue, lung and nerve damage)
• Respiratory patients based surveys) methods, will
that also are recognized in patients with
with lung damage and be required to fully understand post-COVID syndrome. For patients
compromised lung function. the patient experience of post- who have had extended hospitalization
COVID syndrome. or who required prolonged intubation
3 Decentralized Clinical Trials www.ppd.com
and ventilation, it may be difficult or
even impossible to distinguish the im-
pacts of COVID-19 from those of the New Test for Past COVID Infections
interventions themselves. Can Potentially Increase the Prospective
PPD has worked with many different Patient Pool
viral infections and infectious diseases,
as well as indications related to other
viral and post-viral symptoms, includ- For a significant part of the pandemic, testing availability was
ing complications of HIV and post-HIV
limited and rationed. Many patients were unable to obtain testing,
development of AIDS, as well as CFS. In
addition, we have extensive experience
and others may have chosen not to be tested. This, coupled with a
in neurology, psychology, immunology, relatively high percentage of suspected false-negative tests, could
and respiratory and cardiovascular dis- reduce the pool of patients with confirmed post-COVID syndrome
eases, all of which may have relevant eligible for clinical trials.
application to post-COVID syndrome
clinical development programs. The FDA’s recent granting of emergency authorization for a new
T cell test could change this. The first-of-its-kind test uses T cells
PPD has extensive experience working to detect whether someone was previously infected with SARS-
with patients under these conditions to CoV-2, bringing clarity to these patients with suspected but not
enable understanding of their histories, confirmed infection.
current symptoms, and the range of
impacts on their lives.
Lack of Disease-Specific Validated
Outcomes Assessment PROs or other clinical outcome assess- For both orphan diseases and
Given the diversity of patients and ments (COAs) likely will be required COVID-19 itself, PPD has often had to
symptoms associated with post- as primary efficacy endpoints in some select and validate existing tools and
COVID syndrome, a wide range of clinical trials evaluating treatments rating scales/scoring methods for one
operational and medical scientif- for post-COVID syndrome, particu- sequela and apply it and make it more
ic experts will need to be involved larly when the syndrome manifests in relevant to the bigger picture. For in-
in clinical trials. Multiple endpoints symptoms that only patients them- stance, we have engaged with sponsors
will be needed within each patient selves can report (e.g., fatigue, dys- to adapt our FLUPRO patient-report-
subcategory based on the predom- pnea, loss of appetite). Evidence of ed outcomes instrument for evaluat-
inant symptoms. Initially, we expect validity and reliability, as well as clinical- ing the severity of flu symptoms. This
that established and accepted end- ly important differences of these tools tool was developed in collaboration
points, including patient-reported in post-COVID syndrome, will need to with the National Institutes of Health
outcomes (PROs), will be adopted be established in order to enable their for use in COVID-19 treatment and
from other conditions where we see use as registrational endpoints for ac- vaccine trials to evaluate treatment
clinical similarities. ceptance by regulatory authorities benefit in terms of reduction in dis-
(FDA 2009). ease severity.
Our extensive experience The complexity of trial designs and Defining Need and Value
implementation of post-COVID syn- Sponsors may recognize post-COVID
identifying the nuanced
drome studies will require the services syndrome as a legitimate disease with
information important to of CROs like PPD with extensive oper- a strong unmet medical need. Howev-
various groups and then ational and scientific expertise across er, work is still needed to understand
multiple therapeutic areas involved in the value associated with improved
developing evidence-
treating these patients. A broad array outcomes: this value proposition may
generation strategies to of resources will be needed for data be different for payers, regulators, cli-
support tailored value analysis, including both epidemiologi- nicians treating patients with post-
cal experts and data scientists. These COVID syndrome, and the patients
messages strongly positions
trials will also require experience in themselves. Mapping and understand-
PPD in accelerating this area. the determination of practical and pa- ing the often-conflicting priorities of
tient-focused endpoints/outcomes that various stakeholders is an important
provide reliable and valuable results. part of how development in this space
4 Decentralized Clinical Trials www.ppd.com
proceeds. Our extensive experience In addition to symptom or function dedicated post-COVID clinics. As a
identifying the nuanced information endpoints of interest to regulators, large CRO, PPD can supplement sites
important to various groups and then payers will look for measures that re- from our extensive network of investi-
developing evidence-generation strate- flect quality of life and economic im- gators across therapeutic areas, includ-
gies to support tailored value messages pacts, including utility measurements, ing specialists in neurology, rheumatol-
strongly positions PPD in accelerating work productivity, and activity impair- ogy, and respiratory diseases, who may
this area. ment determinations. Some payer bod- be investigating and managing patients
ies, such as the U.K.’s National Institute with post-COVID syndrome.
Through advisory panels with payers of Clinical Excellence (NICE), are inter-
across all key markets, our market ac- ested in ascertaining patient input on Finding and Recruiting Patients with
cess consultants gather clear insight protocol designs and clinical trial op- Post-COVID Syndrome
into what payers consider when as- erationalization to ensure that clinical While patients with post-COVID syn-
sessing products for reimbursement. trials are patient centered, meaning drome may be highly motivated, they
Our researchers focused on patient they maximize benefits and minimize may have difficulty remaining en-
involvement use a myriad of methods burden for patients. gaged with a clinical trial due to the
to elicit patient preferences and prior- debilitating nature of their symptoms
ities to help guide both development Finding Sites to Support Post-COVID (e.g., brain fog, severe fatigue, or per-
and uptake once on the market. By Syndrome Trials haps even grief and depression.) Pa-
understanding what is important to Selection of clinical personnel to treat tients may not want to or be able to
each stakeholder, the right evidence patients in a post-COVID syndrome make regular visits to clinical trial sites.
can be generated for the right audi- trial will present a new challenge. A CRO with strong experience and in-
ence to optimize product approval, Patients presenting with COVID-19 frastructure to support decentralized
access, and adoption. symptoms may have had minimal trials and drive patient-centric solu-
healthcare interaction at the time of tions can provide relevant strategies
Both regulators and payers will expect initial infection, and diagnosis may that will benefit study design and make
that PROs used as important efficacy have been via a walk-in test center participation more feasible for patients
endpoints will be reliable, valid, and not associated with delivery of care. and their caregivers.
responsive in post-COVID syndrome For patients requiring hospital care,
populations and to evaluate treat- this may have been supported by an With PPD’s experience in the develop-
ment benefits that are meaningful acute care team, pulmonologist, or ment of increasingly patient-centric tri-
to patients. Existing PROs and other infectious disease specialist. Patients als and running virtual and direct-to-pa-
outcome measures will be adapted for with unresolved symptoms or who tient studies, we are ideally positioned
use in post-COVID syndrome, but evi- have not returned to their baseline to support and encourage ongoing
dence still will need to be obtained to level of functioning are most likely patient participation in post-COVID
ensure that PROs included in clinical to present to primary care providers. syndrome trials. We know how to bring
trials are relevant, comprehensive, re- Any referral to secondary care will studies to patients using e-Consent,
liable, valid, and individualized to the depend on the symptoms the patient home-health nurses, video visits, and
symptom complex associated with has and whether dedicated post- electronic PROs, all within decentral-
the disease. COVID syndrome clinics are available. ized trial designs. Our experience with
Dedicated post-COVID clinics with long-term follow-up of gene therapy
access to a range of specialists may patients is also directly applicable to
become the optimal structure to eval- post-COVID syndrome patients. We
uate and manage these patients, giv- keep the patient experience in mind
The complexity of trial designs
en the potential for a broad range of and identify solutions that optimize
and implementation of post- clinical complications. Such dedicat- efficiency and effectiveness with the
COVID syndrome studies ed post-COVID syndrome clinics are goal of maintaining the necessary level
being established in many countries, of connection with the patient, the site,
will require the services of
but this is not universal. Many of these and the treating physician, while min-
CROs like PPD with extensive clinics are in their infancy, and, ow- imizing the burden across all of them.
operational and scientific ing to the lack of standardization of
assessments for these patients, the Other questions sponsors will need to
expertise across multiple
range of specialists and services may consider include:
therapeutic areas involved in vary from center to center. • How do we know when patients
treating these patients. are suitable for a trial?
Sponsors may not always have the • At what point do you assign pa-
luxury of being able to recruit from tients having reached a baseline
5 Decentralized Clinical Trials www.ppd.com
level for the study?
• If that point cannot be deter-
mined, how should the inclusion/ ABOUT THE AUTHORS
exclusion criteria be established?
• It is also important to identi-
fy not only the symptoms, but Wesley Hicks, M.B.B.S., M.R.C.P., M.F.P.M.
whether there is active disease Vice President and Global Therapeutic Head, Respiratory, Global
that is potentially amenable to an Product Development, PPD
intervention.
Email: Wesley.Hicks@ppd.com
Conclusions LinkedIn: www.linkedin.com/in/wesley-hicks-15841913
With our enterprise-wide approach,
PPD is able to develop bespoke solu-
tions for each client and trial that will
allow optimum connectivity with the Sudhakar Sridharan, M.D.
patient and continuous data collection Executive Medical Director, Global Product Development, Immunology
to meet regulatory and payer needs, and Rheumatology, PPD
both within and outside of standard
Email: Sudhakar.Sridharan@ppd.com
care. Our insights, together with our
proven and agile strategies, enable LinkedIn: www.linkedin.com/in/sudhakarsridharan
us to bring all of the necessary com-
ponents and functions together to
offer a comprehensive solution that
can be personalized depending on Margaret Vernon, Ph.D.
the needs of each sponsor, regulators, Senior Vice President, Patient Affairs, Evidera
and payers. We also bring a strong fo-
cus on prioritizing the needs of post- Email: Margaret.Vernon@evidera.com
COVID syndrome patients as we work LinkedIn: www.linkedin.com/in/margaret-vernon-16501541
together to help them find resolution
of their long-term sequalae and resto-
ration of health.
Andrew Burr, Ph.D. M.I.C.R., C.Biol., F.R.S.B.
Vice President, Infectious & Respiratory Disease
Therapeutic Unit Head, PPD
REFERENCES Email: Andrew.Burr@ppd.com
LinkedIn: www.linkedin.com/in/andy-burr-phd-cbiol-micr-frsb-5249384
1. Nalbandian, Ani et al. “Post-acute COVID-19 syndrome.”
Nature Medicine. 27: 601–615 (2021).
2. Perrin, Ray, Lisa Riste, and Mark Hann. “Into the looking
glass: Post-viral syndrome post COVID-19.” Med. Hypotheses. 144:
110055 (2020).
3. Walsh-Messinger, Julie et al. “The Kids Are Not Alright: A Cristina Nieto
Preliminary Report of Post-COVID Syndrome in University
Vice President, General Medicine Therapeutic Unit Head, PPD
Students.” medRxiv. doi: 10.1101/2020.11.24.20238261 (2020).
4. Demeco A. et al. “Rehabilitation of patients post-
COVID-19 infection: a literature review.” J. Int. Med. Res. Email: Cristina.Nieto@ppd.com
48:0300060520948382 (2020).
5. Oronsky, Bryan et al. “A Review of Persistent Post-COVID
LinkedIn: www.linkedin.com/in/cristina-nieto-9a7a717
Syndrome (PPCS).” Clin. Rev. Allerg. Immunol.
doi:10.1007/s12016-021-08848-3 (2021).
6. Carfi, Angelo, Roberto Bernabei, and Franceso Landi.
“Persistent Symptoms in Patients After Acute COVID-19.” JAMA.
325: 603–605 (2020). Davide Garrisi, D.Ph.C.
7. Logue, Jennifer K., Nicholas M. Franco, and Denise J. Executive Director, General Medicine, PPD
McCulloch. “Sequelae in adults at 6 months After COVID-19
Infection.” JAMA. 4: e210830 (2021).
8. Townsend, Liam et al. “Persistent fatigue following SARS- Email: Davide.Garrisi@ppd.com
CoV-2 infection is common and independent of severity of initial
LinkedIn: www.linkedin.com/in/davidegarrisi/
infection.” PLoS One. 15: e0240784 (2020).
9. PHOSP-COVID Collaborative Group. “Physical, cognitive and
mental health impacts of COVID-19 following hospitalisation – a
multi-centre prospective cohort study.” MedRxiv. 24 Mar. 2021.
6 Decentralized Clinical Trials www.ppd.com
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