Hot Topics in Medical Affairs – Check out the latest news in Medical Affairs in Medicines Development. IFAPP Academy provides an online, continuing professional development course, Medical Affairs in Medicines Development, resulting in the Professional Certification, Certified Medicines Development (CMD).
Under the umbrella of the IFAPP Academy’s Value Added Programs and Services, offering continuing professional development initiatives and avenues for networking for our expanding learning community, the Conversations with the Academy webinar programs have garnered enthusiastic engagement.
In the third event in the series Dr. Mark Lightowler, CEO, Phorix Limited, highlighted The Role of Digital Tools in Changing Health Behavior, exploring the evidence for behavioral change parameters – e.g., physical activity, medication adherence, smoking cessation — to be considered in health outcome programs, in tandem with patient engagement tools. While evaluating how innovative digital tools are unlocking our understanding of behavior and our ability to change, Dr. Lightowler shared insights and resources to promote behavioral change in the workplace.
Following on, Dr. Birka Lehmann, Senior Expert Drug Regulatory Affairs, reviewed theNew European Regulation for Clinical Trials, stressing the need for further legislative changes to drive a more harmonized approach by regulatory agencies granting clinical trials and Ethics Committees agreements. Dr. Lehmann outlined the transition with the regulations, which underscore the harmonization of conditions, emphasizing the new challenging interactions needed by regulatory agencies, Ethics Committees, and applicants. New timelines have to be respected by all involved partners. That e-handling of applications and approvals is imperative. Don’t miss the recording.
We express our sincere appreciation for the invaluable inputs and contributions from our expert faculty and hosts. We are encouraged by your active participation at these events and look forward to your continued support and engagement.
Yesterday, Pfizer and BioNTech announced that the first participants were dosed in the U.S. as part of the Global COVID-19 mRNA Vaccine Development Program
On May 5th, 2020 at 6:45 AM EDT, NEW YORK & MAINZ, Germany–(BUSINESS WIRE)–Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) announced that the first participants have been dosed in the U.S. in the Phase 1/2 clinical trial for the BNT162 vaccine program to prevent COVID-19. The trial is part of a global development program, and the dosing of the first cohort in Germany was completed last week.
The Phase 1/2 study is designed to determine the safety, immunogenicity and optimal dose level of four mRNA vaccine candidates evaluated in a single, continuous study. The dose level escalation portion (Stage 1) of the Phase 1/2 trial in the U.S. will enroll up to 360 healthy subjects into two age cohorts (18-55 and 65-85 years of age). The first subjects immunized in Stage 1 of the study will be healthy adults 18-55 years of age. Older adults will only be immunized with a given dose level of a vaccine candidate once testing of that candidate and dose level in younger adults has provided initial evidence of safety and immunogenicity. Sites currently dosing participants include NYU Grossman School of Medicine and the University of Maryland School of Medicine, with the University of Rochester Medical Center/Rochester Regional Health and Cincinnati Children’s Hospital Medical Center to begin enrollment shortly.
“With our unique and robust clinical study program underway, starting in Europe and now the U.S., we look forward to advancing quickly and collaboratively with our partners at BioNTech and regulatory authorities to bring a safe and efficacious vaccine to the patients who need it most. The short, less than four-month timeframe in which we’ve been able to move from pre-clinical studies to human testing is extraordinary and further demonstrates our commitment to dedicating our best-in-class resources, from the lab to manufacturing and beyond, in the battle against COVID-19,”
Albert Bourla, Chairman and CEO, Pfizer
Pfizer and BioNTech’s development program includes four vaccine candidates, each representing a different combination of mRNA format and target antigen. The novel design of the trial allows for the evaluation of the various mRNA candidates simultaneously in order to identify the safest and potentially most efficacious candidate in a greater number of volunteers, in a manner that will facilitate the sharing of data with regulatory authorities in real-time.
“It is encouraging that we have been able to leverage more than a decade of experience in developing our mRNA platforms to initiate a global clinical trial in multiple regions for our vaccine program in such a short period. We are optimistic that advancing multiple vaccine candidates into human trials will allow us to identify the safest, most effective vaccination options against COVID-19,”
CEO and Co-founder of BioNTech, Ugur Sahin.
During the clinical development stage, BioNTech will provide clinical supply of the vaccine from its GMP-certified mRNA manufacturing facilities in Europe.
In anticipation of a successful clinical development program, Pfizer and BioNTech are working to scale up production for global supply. Pfizer plans to activate its extensive manufacturing network and invest at risk in an effort to produce an approved COVID-19 vaccine as quickly as possible for those most in need around the world. The breadth of this program should allow production of millions of vaccine doses in 2020, increasing to hundreds of millions in 2021. Pfizer-owned sites in three U.S. states (Massachusetts, Michigan and Missouri) and Puurs, Belgium have been identified as manufacturing centers for COVID-19 vaccine production, with more sites to be selected. Through its existing mRNA production sites in Mainz and Idar-Oberstein, Germany, BioNTech plans to ramp up its production capacity to provide further capacities for a global supply of the potential vaccine.
BioNTech and Pfizer will work jointly to commercialize the vaccine worldwide upon regulatory approval (excluding China, where BioNTech has a collaboration with Fosun Pharma for BNT162 for both clinical development and commercialization).
This article has been prepared by Dr. Penny Ward FFPM, with input from Professor Tim Higenbottam PFPM, Dr. Flic Gabbay FFPM, Dr. Bob Holland FFPM, Dr. Sue Tansey FFPM, and Dr. Tahir Saleem MFPM.
It is provided for information and does not constitute advice or represent official FPM views or policy.
Summary
This review addresses current knowledge concerning SARS-CoV-2 and COVID-19 disease including:
Epidemiology of the outbreak
SARS-CoV-2 viral life cycle and clinical features of COVID-19 Disease
Current Treatment
An enormous effort is ongoing across the life science industry in the UK and beyond to address this pandemic. It is hoped that the insights provided in this article will excite interest and support for the challenge. Future articles will address work ongoing to develop a vaccine and effective antivirals for treatment/prophylaxis.
Introduction
At the end of the Great War, a conflict which convulsed most countries in the world over four years and killed an estimated 40 million soldiers and civilians among participating nations, the world was seized by a pandemic of Influenza, which, in the space of a year, spread to every country on earth, infected almost 500 million and killed 100 million people. Three months into the 101st anniversary year of that great pandemic, we are again witnessing a rapidly spreading, highly infectious serious acute respiratory syndrome (SARS) sweep across the world. Since first recognition in Wuhan, China in December 2019 to the time of this review, Corona Virus Disease -19 (COVID-19), caused by infection with a novel coronavirus, SARS-CoV-2, has spread to virtually all countries, infected over 900,000 individuals and caused more than 40,000 deaths. It is still increasing rapidly1. This bulletin reviews the state of understanding of the virus, the pattern of disease in infected individuals and discusses advances made and work ongoing to facilitate efficient diagnosis, prevention, and treatment of this significant health threat.
The Coronaviridae
Coronavirus disease was first recognized in humans in the 1930s, with the first virus (HCoV-229E) isolated in 19652. Subsequently, three further CoVs were identified in humans (HCoV-NL63, HCoVOC43, and HCoV-HKU1). These viruses are endemic in humans and, after rhinoviruses, are an important cause of the common cold, with outbreaks occurring throughout the year, but more frequently in winter and spring in temperate climates. While adults generally experience mild cold symptoms, among individuals with asthma/COPD exacerbations may occur. Infection may be more severe in infants and young children, causing tracheolaryngobronchitis (croup), bronchitis and pneumonia3. In November 2002 an outbreak of serious acute respiratory syndrome (SARS) was found to be due to a fourth, highly pathogenic, coronavirus the SARS coronavirus. The disease originated in China and subsequently spread to Vietnam, Hong Kong, Taiwan, Singapore, and Canada. Between its first and last appearance, 8096 cases were reported to the World Health Organisation (WHO) with 711 deaths, giving a case fatality rate (CFR) of 9.6%. In affected countries, outbreaks were contained by vigorous identification of cases and enforced quarantining of contacts3. In Taiwan, where an outbreak followed the return of an infected traveler returning from Guandong, China, 671 cases were identified and 131,132 people were quarantined4. The last case from this episode was reported in July 2003, although three small laboratory associated outbreaks have occurred since then involving 11 patients. The causative virus, the betacoronavirus, SARS CoV, has not been circulating in humans since. A fifth coronavirus was identified in 2012 in the UK following hospital admission of a patient with a SARS-like illness. Middle East Respiratory Syndrome (MERS) CoV has resulted in a limited number of outbreaks, mostly in Saudi Arabia and other middle eastern countries. Human to human transmission of this disease has, to date, been limited to close contacts of affected cases in households or healthcare settings. The CFR in this disease exceeds 30% 3.
Figure 1: Structure of Human Coronavirus (from Korsman S, Virology 2012 Pub Churchill Livingtone)
Virus Structure and Replication:
Human coronavirus particles are generally spherical, 120-160nm diameter and typically decorated with large (~20 nm), club- or petal-shaped surface projections (the “peplomers” or “spikes”), which give an image resembling the solar corona on electron micrographs of infected tissues and hence to the family name (Figure 1).3
Receptor Binding
Coronaviruses have a large single positive RNA stranded genome of 28-32 kilobase size (making it the largest RNA genome of the RNA virus family) enclosed in a nucleocapsid of helical symmetry (Figure 2). These viruses infect human cells via S (spike) protein binding to receptors on host cells, followed by the release of viral RNA into the cell cytoplasm. Various host receptors have been associated with the different human coronaviruses so far described: the host receptor for HCoV-229E is aminopeptidase N while HCoV-OC43 uses 2,3 or 2,6 alpha sialic acid receptors (as does influenza virus). The S protein of SARS CoV binds to angiotensin-converting enzyme 2 (ACE2) and of MERS CoV to dipeptidyl peptidase 4 (DPP4)5. SARS-CoV-2 has also been demonstrated to bind to ACE2, a transmembrane receptor that is widely expressed in lung, heart, kidney and gastrointestinal tissue6.
Intracellular replication
Following receptor binding, the virus must then access the cell cytoplasm. This is assisted by acid-dependent proteolytic cleavage of S protein by a cathepsin, TMPRRS2 or another protease, followed by fusion of the viral and cellular membranes. S protein cleavage occurs at two sites within the S2 portion of the protein, with the first cleavage important for separating the receptor-binding domain (RBD) and fusion domains of the S protein and the second for exposing the fusion peptide (cleavage at S2′). Fusion generally occurs within acidified endosomes, but some coronaviruses can fuse at the plasma membrane. Following this, the viral replicase gene, which consists of two open reading frames (ORFs) coding for two polyproteins pp1a and pp1ab. These polyproteins contain all the non-structural proteins (nsps) of the virus which are essential for intracellular replication. The polyproteins are cleaved to form individual nsps by proteases, including one or two papain-like proteases (PLpro) (depending on the coronavirus sp) and a serine-type protease, the Main (M)protease. Many of these nsps then assemble into the replicase-transcriptase complex (RTC) which replicates the viral RNA. Following replication and viral RNA synthesis, the viral structural proteins, S, E, and M are translated and inserted into the endoplasmic reticulum (ER). These proteins move into the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) where viral genomes encapsidated by N protein bud into membranes of the ERGIC containing viral structural proteins, forming mature virions.
Progeny virion assembly and budding
The M protein directs most protein-protein interactions required for assembly of coronaviruses but is not enough, alone, for virion formation. When M protein is expressed along with E protein, virus-like particles (VLPs) are formed, suggesting these two proteins function together to produce coronavirus envelopes. N protein enhances VLP formation, suggesting that the fusion of encapsidated genomes into the ERGIC enhances particle envelopment. The S protein is incorporated into virions at this step but is not required for assembly. The ability of the S protein to traffic to the ERGIC and interact with the M protein is critical for its incorporation into virions. Following assembly, progeny virions are transported to the cell surface in vesicles to be released by exocytosis (Figure 2).
Figure 2: Replication cycle of SARS-CoV-2 [1] Spike protein on the virion binds to ACE2, a cell-surface protein. TMPRSS2, an enzyme, helps the virion enter [2] The virion releases its RNA [3] Some RNA is translated into proteins by the cell’s machinery [4] Some of these proteins form a replication complex to make more RNA [5] Proteins and RNA are assembled into a new virion in the Golgi and [6] released. Sources: Song et al., ‘Viruses’, 2019; Jiang et al., ‘Emerging Microbes and Infections, 2012; ‘The Economist’.
In some coronaviruses, S protein that does not get assembled into virions transits to the cell surface where it mediates cell-cell fusion between infected and adjacent, uninfected cells. This leads to the formation of giant, multinucleated cells, which permit the virus to spread within an infected organism without being detected or neutralized by virus-specific antibodies7.
Route of Infection
The human coronaviruses may be spread via aerosol infection of the respiratory tract following inhalation of aerosol particles in the air. Large particle sizes contaminate the upper airways, but particles of <5 microns size can move into the lower respiratory tract. Coughing, spitting, sneezing and talking generate aerosols made up of mucus droplets containing the virus. In a study investigating cough aerosols, the Edmonton group demonstrated that cough aerosols are composed of droplets ranging from 0.1 to 900 microns size, of which 97 percent were less than 1 micron in size, and 99 percent less than 10 microns. While larger particles will tend to settle quickly on nearby surfaces, particles less than 2.5 microns size remain airborne for a longer time. Thus, most of the infectious particles produced by coughing will remain airborne and can be inhaled into the lungs8. Coronaviruses are relatively stable on a variety of surfaces and thus can also spread via fomite transfection by hand contact with virus particles on surfaces contaminated by respiratory secretions and subsequent touching the mucous membranes of the face (eyes, mouth, nose). Human coronaviruses can be detected in feces, and transmission via the fecal-oral route is also possible9.
Given these potential routes of infection, masking patients to provide a barrier to the coughing of aerosols into the surrounding air, isolation of cases away from others, strict personal hygiene with frequent hand washing, regular cleaning of potentially contaminated surfaces and protection against aerosol inhalation by attendants by use of respiratory protection equipment are all imperative to prevent transmission.
Pattern of Illness post infection
Asymptomatic Infection:
The proportion of infected individuals that do not develop symptoms is unknown, as the extent of population screening has been limited. Nishiura et al investigated infection rates among a group of 565 Japanese citizens returning from China in February 2020. Of the 565 returning subjects, 14(2.4%) had a positive PCR test for SARS-CoV-2 of which 5 (41.6%: 95% confidence interval (CI): 16.7%, 66.7%) were asymptomatic at the time of testing11. Mizumoto and colleagues investigated an outbreak of SARS-CoV-2 aboard a cruise ship, the Diamond Princess. A total of 634/3063 (20.7%) subjects tested were PCR positive for SARS-CoV-2 infection. Of these 320 (50.5%) were asymptomatic at the time of testing. As testing was conducted over a 14 day period and initially focused on symptomatic cases, the authors modeled these data to reflect variability in the latent period, which results in a lower estimate for the proportion of infections that remain asymptomatic – in this case 17.9% (95%CrI: 15.5–20.2%)12. Transmission of infection from asymptomatic carriers has been documented: ergo the lack of understanding of the proportion of infections that remain asymptomatic is urgently needed, both to better understand the impact of control measures as well as to correctly ascertain the risk of death following infection14. The broader testing strategy pursued in Germany is thought to be one reason for the low apparent case fatality rate (~0.7%) there compared to other EU countries such as the UK (5.2%), Italy (10.6%) and Spain (7.6%), where testing is restricted to hospitalized patients.
Symptomatic illness is associated with fever and persistent cough with some subjects complaining of fatigue, sore throat, headache, and diarrhea. Individuals may become rapidly short of breath with increasing difficulty breathing associated with declining blood oxygenation.
Reports from China and elsewhere suggest that males may be affected more severely than females, however, most patients (80%) have relatively mild, influenza-like symptoms and make a complete recovery within 10 days13.
A small proportion of predominantly older patients and those with pre-existing chronic diseases experience progressively more severe symptoms, with CT evidence of pneumonia and biochemical evidence of an exaggerated immune response potentially driven by multiple cytokines, IL-6, IL-8, IL-10, Interferon γ, and TNF-alpha which is often called a “cytokine storm”14,15. Activation of complement C3a and C5a may initiate cytokine storm and can cause thrombotic microangiopathy. It is known to be involved in many different causes of acute lung injury (ALI) and adult respiratory distress syndrome (ARDS) following viral infections16.
Based on limited evidence, children are in the minority among the hospitalized cases in China, accounting for less than 1% of affected cases13,17. Zheng et al reported a small case series of 25 children affected by COVID-19 in China18. The median age of the children was 3 years, with the most severely affected subjects being mostly in this younger age group. Presenting symptoms included fever [13 (52%)], followed by dry cough [11 (44%)], diarrhea [3 (12%)], nasal congestion [2 (8%)], dyspnea [2 (8%)], abdominal pain [2 (8%)] and vomiting [2 (8%)]. Clinical diagnoses in affected cases were upper respiratory infection in 8 cases, mild pneumonia in 15 cases and critical pneumonia in 2 cases. Both critical cases had congenital heart disease and one required renal dialysis. Among the children with pneumonia, the majority of those in the younger age range had bilateral pulmonary involvement on CT. The two critical cases were thought to have evidence of secondary bacterial infections contributing to their illness. None of the patients in this case series died. Dong and colleagues recently described the epidemiology of COVID-19 in 2143 children, including both confirmed and suspected cases, in China19. Children under the age of 5 accounted for 1/3 of the cases, and disease in this age group, particularly in infants <1, was more likely to be severe and critical than in older children. The proportion of severe and critical cases was 10.6 %, 7.3%, 4.2%, 4.1% and 3.0% for the age group of <1, 1-5, 6-10, 11-15 and ≥16 years, respectively.
Pregnant Women:
A small case series describing the outcome of pneumonia among 15 pregnant women in China suggested that disease was relatively mild and uncomplicated in these subjects, with normal delivery and perinatal outcomes reported20. Schwartz has summarised information from this and an additional case series from China21. Maternal-fetal transmission of viral diseases is mostly (except for herpes simplex) via the hematogenous route, in which the virus circulating in the maternal bloodstream enters the placenta, reaches the chorionic villous tree and fetal blood vessels, and is transmitted to the fetus. This mechanism of transmission has been shown not to occur with infection of pregnant women SARS-CoV and MERS-CoV, although the clinical infections caused by these coronaviruses have resulted in severe maternal pneumonia, maternal deaths, and early pregnancy losses. In the cumulated experience from published reports of 38 pregnant women with COVID-19, of whom 37 had rt-PCR-confirmed SARS-CoV-2 infection, there were no cases of either severe pneumonia or maternal deaths. Although some subjects had additional co-morbid conditions, some of which were obstetric, these did not result in life-threatening maternal SARS-CoV 2 disease.
Transmissibility
The transmissibility of infection and illness is a critical component of epidemic projections and health service planning. Transmissibility is usually described by the calculation of the reproductive number R0, representing the average number of new infections generated by an infectious person in a totally naïve population. The complete calculation of this is hampered by our non-understanding of the portion of infections which remain asymptomatic. However, based on the incidence of transmission from identified symptomatic cases to contacts, R0 for SARS-CoV-2 ranges from 1.4 to 322. This is higher than the estimated R0 for the 1918 pandemic influenza23. Thus, this epidemic, which appears to be highly transmissible, is likely to have a very significant impact on the health of populations worldwide.
One of the most impressive elements of the response of the global healthcare community to the COVID-19 outbreak has been the extremely rapid development and deployment of highly sensitive and specific tests to detect the SARS-Cov-2 virus. The first patient appears to have been hospitalized in Wuhan on 12th December and by the 2nd February, a comprehensive description of the genome of the virus was published24. Reverse transcriptase-polymerase chain reaction (RT PCR) reagents have been developed to detect the virus and distinguish it from other related coronaviruses and other common viral causes of cough and fever. While robust and well-established RT-PCR technology has allowed clinical laboratories with PCR machines to develop testing capability, the methodology is relatively low throughput and has been delivered through centralized services and validated molecular pathology laboratories. Samples need to be collected (throat and nasal swabs), couriered to the laboratory, tested, the results reviewed and provided to the patient/practitioner ordering the test. Although the test itself takes only a few hours, results can take several days to be delivered. The deployment of RT-PCR tests has been rather variable internationally, both in terms of the numbers of operational laboratories and in terms of the availability of testing kits. In the UK currently, capacity is limited and hovering at around 5000-8000 subjects tested per day as of 010420, although attempts are being made to increase this to a rate of 25000 per day. The life sciences community is working to develop variants of the RT PCR test with higher throughput and with faster turnaround times; examples include droplet digital PCR, and of particular interest to clinicians, near-patient automated PCR devices. As of 24th March, more than fifty commercially available tests (nearly all PCR based) were available across the globe claiming some sort of regulatory approval (CE-mark, FDA-EAU, CLIA lab) including several near-patient devices and kits.
RT-PCR tests are extremely sensitive and specific and therefore provide a “gold standard” for diagnosis of COVID-19 by the detection of SARS-Cov-2 genomic material. However, limitations of this method are that while it confirms the presence of viral RNA, it does not provide information on the continued presence of infectivity. This is an important consideration given the occasional report of a positive PCR test following previous negative assays in recovering patients. In addition, a PCR test does not detect prior infection or immunity to future infection.
Rapid Diagnostic Tests:
Other approaches are now in rapid development. Alternative means to detect the virus include the detection of viral proteins (immunoassays and analogous methods) and non-PCR based detection of the viral genome. None of these tests are currently available clinically but they do eventually offer the possibility of rapid, close to patient testing. The UK Government has established a process for the evaluation of such tests: https://www.gov.uk/government/publications/covid-19-evaluation-of-commercially-available-diagnostic-products/guidance-for-industry-on-evaluations-of-diagnostic-products-for-coronavirus-covid-19. and is providing grants to companies developing such technologies. The development of rapid diagnostic tests will need to address the question of sensitivity – rapid bedside testing for influenza virus has been used for screening purposes for several years but the high false-negative rate of these tests hampered patient care and limited public health disease control measures during the 2009-2010 pandemic, resulting in the reclassification of these from Class I tests (tests with low risk to public health requiring limited monitoring) to Class II devices in the USA24. Class II devices require special controls, examples of which include performance standards, post-market surveillance, patient registries, guidelines, design controls, and other appropriate actions to mitigate risk.
Antibody Testing:
The detection of an immune response to COVID-19 (serology) allows an understanding of who has been exposed (and been infected) and the degree to which individuals may have some immunity to future infections; this also facilitates better understanding of the spread of infection (as it has potential to identify asymptomatic infections). In similar viruses, the Spike (S) protein used to bind to host cells is immunogenic and the Receptor Binding Domain is the target of neutralizing antibodies25. However, there are a number of important questions yet to be answered including:
What is the cross-reactivity of immunoglobulins produced after infections with other coronaviruses (specificity)?
What proportion of infected individuals makes antibodies to SARS-CoV-2?
What magnitude of antibody response confers immunity?
How long does this immunity last?
Do previous Coronavirus infections influence the ability to generate antibodies to SARS-CoV-2?
Do previous Coronavirus infections provide some cross-protection from SARS-CoV-2?
This is a very exciting (if early) area of research and tremendous progress has been made, for example in the invention of detection methodologies for antibodies specific to SARS-CoV-226. However, it is important to remember that these tests are not suitable for acute diagnosis as it may take seven to ten days to seroconvert; equally, currently available assays may detect antibodies but may not provide evidence of immunity. Therefore, the full clinical utility of such tests remains to be established by further clinical research.
Viral and Antibody Kinetics in COVID-19
Limited information from case assessments investigating viral load kinetics have suggested that viral load increases post exposure reaching a peak at or shortly following onset of symptoms27,28. More severe illness is associated with higher viral load (1 log order higher) than in patients with milder disease. Viral load generally declines over a 10-15 day period post symptom onset, but may be sustained, and at higher level, in subjects developing severe pneumonia/ARDS29. The pattern of viral load dynamics is similar to influenza infection, implying that antiviral therapy given earlier in the disease course may prevent later complicated disease. This has implications for the design of clinical trials with antiviral therapies.
A recent series investigating antibody to SARS-CoV-2 viral proteins demonstrated that rising antibody levels can be detected from approx. day 7 of illness with most patients seroconverting within 14-21 days of onset. IgG and IgM antibody levels against the SARS-CoV-2 internal nucleoprotein and the surface spike receptor-binding domain correlated with neutralizing activity30.
Current Treatment
There are, currently, no specific antiviral therapies available for the treatment of COVID-19. Treatment of disease is currently supportive management based on first principles of respiratory support and management of complications.
Supportive Treatment
In the absence of specific interventions or availability of convalescent serum, management of COVID-19 is limited to the alleviation of symptoms, oxygen, continuous positive airways pressure and in more severe cases with ARDS and/or impending respiratory failure ventilatory support or exogenous corporeal membrane oxygen therapy. Approx 15-33% of COVID-19 affected hospitalized cases develop acute respiratory distress syndrome (ARDS). Factors that increase the risk of developing ARDS and death (which may occur in 40-50% of affected cases) include older age, neutrophilia, elevated lactate dehydrogenase level, CRP and D-dimer level and reduced platelet count.
Management of ARDS
Low tidal volume, plateau-pressure-limited mechanical ventilation is the primary treatment that has been shown to reduce mortality from ARDS. Tracheal intubation before the start of ventilatory support is a high risk, critical procedure in patients with COVID-19. Healthcare staff must apply the SAS principles: Safe – for staff and patient; Accurate – avoiding unreliable, unfamiliar or repeated techniques; Swift – timely, without rush or delay. Low tidal volume, plateau-pressure-limited mechanical ventilation is the primary treatment that has been shown to reduce mortality. Tidal volumes should be targeted to a lung-protective range (4-6 ml/kg ideal body weight). Informal reports from Italy and Singapore suggest that the driving pressures required are not very high, that patients require positive end pressures (PEEP) and respond well to prone ventilation. This suggests that the primary pulmonary pathology is likely to be small airway closure and atelectasis, rather than reduced lung compliance. Complications of ventilation include pneumothorax, ventilator-associated pneumonia, multiple organ failure, and, in the longer term, pulmonary fibrosis with prolonged respiratory failure.
Extrapulmonary Manifestations
Hepatic dysfunction (elevated transaminases) has been reported in 14% to 53% of patients in case series, more commonly in patients with severe disease. Evidence suggests that clinically significant liver injury is uncommon.
Cardiac injury is reported in 7% to 13% of patients in case series, with higher prevalence in patients who are severely or critically ill. Myocardial injury has been reported in > 25% of patients who are critically ill, and presents in two ways: acute myocardial injury and dysfunction on presentation or myocardial injury that develops as the severity of illness worsens. Arrhythmias have been reported in 16% of patients in case series. Fulminant myocarditis has been reported while cardiomyopathy has been reported in 33% of critically ill patients. It is unknown whether it is a direct cardiac complication of COVID-19 or due to overwhelming clinical illness. The long term consequence of infection on cardiovascular health is unknown.
Acute kidney injury (AKI) has been reported in 3-8% of cases, mostly those with other complications requiring ICU support: early recognition is important as AKI is associated with inpatient mortality >20%.
Disseminated intravascular coagulation is a feature in 71% of patient dying from COVID-19. It is frequently associated with other complicated illness in ICU.
As with any viral infection affecting the lungs, secondary bacterial infection and sepsis may further complicate the course of illness31. Elevated procalcitonin may enable earlier recognition of this potential and appropriate, early, use of antibiotics32.
Convalescent Serum
Convalescent serum is a strategy that has been exploited previously in novel infectious disease and is being explored in clinical trials. This approach has been reported to be effective in patients with SARS and MERS33,34. In a retrospective analysis use of convalescent plasma in SARS patients in Hong Kong, treatment was associated with a significantly reduced mortality and higher clinical success rate (defined as the proportion leaving the hospital by day 22) compared to those receiving only corticosteroid therapy35. Patients receiving convalescent plasma after day 16 fared no better than those receiving steroid alone35. With rising numbers of COVID-19 patients, consideration should be given to the preparation of convalescent plasma/serum from affected subjects for use in patients requiring hospitalization for more severe disease.
Conclusions
The emergence and rapid spread of SARS-CoV-2 represents a major emerging health threat to countries and populations around the world. Currently countries are enforcing public health measures designed to reduce spread of the disease within the population. Evidence from countries affected early in the outbreak suggests that these will successfully control spread, but comes with significant population disruption and potential for adverse effects on the world economy. An enormous effort is ongoing to understand the disease pathogenesis and to convert that understanding to the rapid scale up and production of therapeutic and prophylactic approaches to protect exposed populations. A range of promising avenues has been identified and will be discussed in the next chapters. In the interim, convalescent plasma/serum may offer an early approach to the specific management of disease in patients requiring hospitalization.
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Dong Y et al. Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China. Pediatrics. 2020; doi: 10.1542/peds.2020-0702
LIU D et al. Pregnancy and Perinatal Outcomes of Women With Coronavirus Disease (COVID-19) Pneumonia: A Preliminary Analysis. Am J Roentgenol. 2020:1-6. doi: 10.2214/AJR.20.23072.
Schwartz DA. An Analysis of 38 Pregnant Women with COVID-19, Their Newborn Infants, and Maternal-Fetal Transmission of SARS-CoV-2: Maternal Coronavirus Infections and Pregnancy Outcomes. Archives of Pathology & Laboratory Medicine 2020. In-Press.
Liu Y et al. The reproductive number of COVID-19 is higher compared to SARS coronavirus. Journal of Travel Medicine 2020. 27; https://doi.org/10.1093/jtm/taaa021
Biggerstaff M et al. Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a systematic review of the literature. BMC Infect Dis. 2014; 14: 480. doi: 10.1186/1471-2334-14-480.
Green DA, St. George K. Rapid antigen tests for influenza: rationale and significance of the FDA reclassification. J Clin Microbiol 2018; 56:e00711-18. https://doi.org/10.1128/JCM. 00711-18.
Wu, F et al. A new coronavirus associated with human respiratory disease in China. Nature 2020; 579: 265–269
Amanat, F., Nguyen, T., Chromikova, V., et al. A serological assay to detect SARS-CoV-2 seroconversion in humans. medRxiv preprint doi: https://doi.org/10.1101/2020.03.17.20037713.
Pan Y et al. Viral load of SARS-CoV-2 in clinical samples. Lancet Infect Dis 2020 https://doi.org/10.1016/S1473-3099(20)30113-4
Zou L et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med. 2020; (published online Jan 30.) DOI:10.1056/NEJMc2001737
Liu Y et al. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect Dis 2020. DOI:https://doi.org/10.1016/S1473-3099(20)30232-2
To K K-W et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis 2020. https://doi.org/10.1016/S1473-3099(20)30196-1.
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We know that Medical Affairs and Medicines Development Professionals around the world have been working non-stop to develop vaccines, treatments, testing, and medical devices in response to the COVID-19 pandemic. To aide in the distribution of information, we have provided below important clinical trial guidance from different sources for use during this pandemic.
We wish everyone health and safety during this difficult time!
The below document was released by ACRO – Association of Clinical Research Organizations
Considerations to Support Clinical Trial Monitoring Oversight During COVID-19, 13 March 2020
The emerging coronavirus (COVID-19) situation is increasingly impacting clinical trial oversight, particularly on-site monitoring. The Association of Clinical Research Organizations (ACRO) recommends that sponsors, CROs and sites introduce emergency interim measures so that clinical trial monitoring is maintained during this period. These guidelines will ensure that data quality is unaffected, clinical trial sites are supported and that the patients enrolled in clinical trials are kept safe. The use of centralized monitoring tools and technologies can supplement and support the recommendations outlined below. These practices and tools are already in place and do not require any additional sophisticated analytical tools or dashboards. Care should be taken that any remote monitoring activities implemented are proportionate to the risks identified. Further, they should not place any extra burden on clinical trial sites.
These recommendations should be considered in the following situations: • When sites have suspended or restricted all visitors (including clinical research associates (CRAs)) from accessing medical facilities, but where patient visits are still occurring • When local health officials have implemented regional quarantines • When local CRAs are unable to travel to the sites (for personal health reasons or because of travel restrictions)
The below document was released by the European Medicines Agency (EMA).
Guidance on the Management of Clinical Trials during the COVID 19 (Coronavirus) pandemic Version 1 (20/03/2020)
The European Medicines Agency (EMA), Good Clinical Practice (GCP) Inspectors Working Group, the Clinical Trials Facilitation and Coordination Group (CTFG, a working group of the Heads of Medicines Agency (HMA)), the Clinical Trials Expert Group (CTEG, a working group of the European Commission representing Ethics Committees and National Competent Authorities) and the European Commission (EC) acknowledge the impact of COVID-19 on the health system and broader society, and the impact it may have on clinical trials and trial participants1. Extraordinary measures may need to be implemented and trials adjusted due to e.g. trial participants being in self-isolation/quarantine, limited access to public places (including hospitals) due to the risk of spreading infections, and health care professionals being committed to critical tasks. Therefore, EMA, EC and HMA strongly support the efforts of the GCP Inspectors’ Working Group for developing harmonised EU/EAA-level guidance to mitigate the negative effects of the COVID-19 pandemic on the conduct of clinical trials.
The situation is evolving, and pragmatic actions may be required to deal with the challenges of conducting research, and in ensuring the rights, safety and wellbeing of participants. The points mentioned below are intended to provide guidance for all parties involved in clinical trials during this time.
Due to the urgency, this guidance is issued without prior public consultation. The sponsors should note that due to the rapidly evolving situation further updates to this guidance are possible and likely.
The below document was released by the FDA (Federal Drug Administration)
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic
Guidance for Industry, Investigators, and Institutional Review Boards (March 2020)
I. Introduction The Food and Drug Administration (FDA or Agency) plays a critical role in protecting the United States from threats including emerging infectious diseases, including the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to providing timely guidance to support continuity and response efforts to this pandemic. FDA is issuing this guidance to provide general considerations to assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic.
Given this public health emergency, this guidance is being implemented without prior public comment because the FDA has determined that prior public participation for this guidance is not feasible or appropriate (see section 701(h)(1)(C)(i) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 10.115(g)(2)). This guidance document is being implemented immediately, but it remains subject to comment in accordance with the Agency’s good guidance practices.
In general, FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required.
Figure 1, left to right: Honorio Silva, IFAPP Academy President, Tim Higenbottam, current President of FPM, Ichiro Uchida (https://icpm2018tokyo.com/data/speaker26.pdf_and Aya Nakae (Osaka University)
Each year, The FPM (Faculty of Pharmaceutical Medicine) Fellows are invited to nominate exceptional individuals for Honorary Fellowship. According to the FPM’s website, Honorary Fellowship is the highest honor FPM can bestow, it recognizes the recipient’s eminence within their own field and their outstanding contribution to pharmaceutical medicine.
On the recommendation of the Fellowship and Awards Committee, the Board of Trustees, may bestow Honorary Fellowship on persons of eminence who may or may not be members of FPM, and who have made exceptional contributions in the fields of research, teaching or the practice of pharmaceutical medicine, or medical or general science, or society. Such honours are strictly limited.
On November 13, 2019 during the FPM’s Annual Awards Ceremony, held at the Royal College of Physicians, London, Dr. Honorio Silva, IFAPP Academy President was awarded with the prestigious FPM Honorary Fellowship FFPM(Hon).
Figure 2: Past Presidents of the FPM Professors Peter Stonier and Alan Boyd with Dr. Honorio Silva (on right)
The below citation was delivered by Professor Peter Stonier FRCP FFPM for Honorary Fellowship of Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of UK.
“Professor Honorio Silva is president of the IFAPP Academy and immediate past president of IFAPP. IFAPP is the international umbrella organisation for pharmaceutical medicine, coming to its 45th anniversary next year.
After graduating in medicine at University of Buenos Aires Honorio Silva had postgraduate training in clinical pharmacology and internal medicine and conducted his clinical practice in these disciplines in his home country of Venezuela becoming assistant professor in the Department of Pharmacology Central University of Venezuela in Caracas.
However, it was in joining Pfizer in 1978 that Honorio’s professional and international career really took off. His early work focused on emerging countries in fostering a clinical research infrastructure and key projects together with medical education initiatives. This important and much needed effort soon took him beyond his day job, and into the world of academia and professional organisations. Here he gained national attention and with it many national awards for his achievements in clinical research, the development of new medicines and in medical education.
His international industry career also developed as Vice President Medical and Regulatory Affairs for Japan, Asia, Africa and Latin America. Honorio completed 30 years with Pfizer as Vice President Science and Medical Professional Development, with the global External medical affairs group.
Honorio’s career has been immersed in the international development and recognition of medicines development sciences and pharmaceutical medicine, and more recently through IFAPP in creating standards for certification in order to consolidate the discipline and profession.
None of this comes without considerable personal abilities and skills in teamwork and collaboration, building global cross functional teams, developing effective managerial and technical processes and analysing complex business and technical issues to achieve state of the art deliverables and solutions. Not to mention the dedication, energy and drive for his burning ambition – to Get The Job Done!
These qualities and attributes have not been lost on the Faculty with whom Honorio has been increasingly connected. The Faculty would like to cement this friendship and to ensure that Honorio’s important work in pharmaceutical medicine and professional development is conducted well within the tent rather than outside of it. For this reason Mr President, members and guests of the Faculty, in recognition of all his many accomplishments and a continuing expectation for more to come, I am delighted to present Prof Honorio Silva for Honorary Fellowship of the Faculty of Pharmaceutical Medicine.
A study that will provide much-needed insight for healthcare providers and pharmaceutical companies, allowing for a truly patient-centric approach with precision medicine.
“The ultimate goal of the All of Us Research Program is to collect information to lead to incredible discoveries in biomedical research and precision medicine, but along the way, we are going to transform lives. We are going to provide opportunities for people that historically have not had the opportunity to participate in research, and I think that’s a really important part of the program, and something that I feel really honored to get to be a part of.”
—Amy Taylor, regional vice president, Community Health Center, Inc.
What is the Precision Medicine Initiative?
The Precision Medicine Initiative (PMI) is a bold research effort to revolutionize how we improve health and treat disease. The PMI aims to leverage advances in genomics, emerging methods for managing and analyzing large datasets while protecting privacy, and health information technology to accelerate biomedical discoveries.
What is the All of Us Research Program?
NIH’s All of Us Research Program is a major piece of the PMI. All of Us will engage one million or more volunteers living in the U.S. to contribute their health data over many years to improve health outcomes, fuel the development of new treatments for disease, and catalyze a new era of evidence-based and more precise preventive care and medical treatment.
The above information, videos, and quotes were provided by the NIH, All of Us website. For additional information please visit: https://allofus.nih.gov/
The European Union Clinical Trials Regulation (EU CTR) 536/2014 includes a requirement for the submission of lay summaries. Study participants, advocacy groups, and, to a lesser extent, the general public have called for greater transparency in their quest for information on clinical studies. As a complement to other forms of clinical study disclosure such as registry postings and scientific publications, lay summaries may aid in the transparency of a sponsor’s clinical study results, thereby promoting trust, partnership, and patient engagement throughout the clinical study process. The data transparency field is changing rapidly; therefore, data owners should strive to stay abreast of the changes and deliver meaningful tools to their study participants and the public. Points to consider when developing lay summaries of clinical study results include regulatory drivers, the target audience, communication of complex data in a lay manner, and efficient processes for the development of lay summaries within one’s company.
Lay summaries help to provide transparency and understanding to the general public
Plain Language Summary
There is a rule in Europe that clinical studies (experiments in humans) must have a summary written in plain language. Summaries written in plain language help people who are not scientists or doctors understand complex medical information. People who participate in clinical studies, and others, may want to know information about clinical study results. Lay summaries are a way to share clinical study results, but they do not replace other ways that information is shared. Lay summary writers must think about how they can help readers understand the information. It is hard to describe the results of clinical studies in a way that everyone can understand. This article gives some ideas to think about when writing lay summaries.
Key Points
Lay summaries of clinical study results are a complement to other forms of clinical study disclosure that aid in the understanding of complex clinical study results.
The initial requirement for lay summaries began as a result of the EU Clinical Trial Regulation; however, evolving regulations and policies around the globe are shaping the future of clinical study disclosure.
Ensuring patient value should be of paramount importance when developing lay summaries.
1. What are Lay Summaries and Why are They Needed?
Lay summaries (also called layperson summaries, plain language summaries, lay language summaries, simple summaries, and trial results summaries) are plain language descriptions of the design and aggregate results of individual clinical studies (Fig.1)
Fig. 1 Excerpted pages from a published lay summary
Lay summaries are one way for industry to provide greater transparency to those interested in learning about clinical study results [2]. These documents are written specifically for study participants and the general public who have an interest in clinical study results, but who may have limited health literacy or scientific expertise. Health literacy is defined as the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions [3]. The goal of a lay summary is to aid study participants and the general public in understanding clinical study results. Not only does this effort help to demystify the clinical study process but it also provides the main results of clinical studies in a manner directed specifically towards people with low health literacy. The target audience is any person interested in research, and, as such, the audience is broad and may include study participants, healthcare professionals, caregivers, and the general public.
Companies providing lay summaries in advance of requirements are communicating respect for the needs and desires of the community
The data transparency field is changing rapidly, with recognition that the desires of patients and the general public may go beyond those driven by regulatory requirements. Although regulatory agencies do not currently require submission of lay summaries, some agencies have provided additional statements on the topic, as summarized below, in preparation for when the regulations come into effect. The commitment of a sponsor company to provide lay summaries in advance of regulatory requirements provides a meaningful way of communicating respect for the needs and desires of the community, particularly study participants.
The push for increased transparency in the clinical study space has presented industry and academia with an interesting choice—to proactively engage or only meet regulatory requirements. Currently, some transparency activities are not required per regulations and are implemented solely based on a company’s own policies on clinical transparency and data sharing. For example, the proactive release of clinical documents and datasets can occur through various mechanisms such as portals (e.g. clinicalstudydatarequest.com, yoda.yale.edu), registration and results disclosure (e.g. clinicaltrials.gov), or posting lay summaries of clinical study results to publicly available websites. Other transparency activities are regulatory driven, such as the release of redacted or anonymized documents for European Medicines Agency (EMA) Policy 0070.
2. What are the Current Regulatory Requirements?
2.1 European Medicines Agency: EU Clinical Trial Regulation 536/2014
The EMA initiated the call for the submission of lay summaries through the European Union Clinical Trials Regulation (EU CTR) 536/2014. Among other elements described in the regulation, sponsors must submit a summary of the results of the clinical study, together with a summary and the Clinical Study Report (CSR), irrespective of the outcome of the study. The summary must be provided in a ‘format understandable to laypersons’, with posting to the portal 1 year after the end of the trial (EoT) for studies in adults, and 6 months after the EoT for studies in the pediatric population, in all the EU languages in which the study was conducted (Fig. 2).
Fig. 2 EU Clinical Trial Regulation 536/2014potential timeline. EoT
end of trial (defined as the last visit of the last participant in all concerned
member states, or at a later point in time as defined in the protocol),
LS lay summary, Peds pediatric patients, mos months
Once the regulation is in application, all new interventional clinical studies will need to comply; however, the regulation includes three phases of implementation. Assuming the dates currently projected by the EMA, this would provide the following timescale for sponsors to submit lay summaries:
Phase 1: A 1-year introductory period where regulations are optional.
Phase 2: Spanning the second and third year of the transitory period; the regulation will be mandatory for new studies.
Phase 3: After the 3-year transitory period described above, the regulation will be mandatory for all studies (both ongoing and new studies).
To read this entire article you can download the PDF here:
“Third Strategic Pillar” of the pharmaceutical industry
Learn what McKinsey & Company has to say about the future of Medical Affairs, “A Vision for Medical Affairs in 2025”.
Are you ready for the future of Medical Affairs? In A vision for Medical Affairs in 2025, a new report released by McKinsey & Company, Medical Affairs is cited as the “third strategic pillar”[1], right along with R&D, and commercial & market access1 in the pharmaceutical industry. Essentially, Medical Affairs professionals are no longer acting as the supporting cast, they are now co-starring in the production.
As the pharmaceutical industry evolves and changes, those within it must adapt and develop the skills and competencies needed to address the emerging needs. Patients and physicians are seeking high-quality and reliable information, products, and services. Pharmaceutical companies are acknowledging the primary role that Medical Affairs Professionals play in providing this, and ultimately bridging the gap between the company and its stakeholders (physicians and patients). The need for qualified, competent, and agile Medical Affairs Professionals to fill this primary role within organizations has become apparent.
The IFAPP Academy/King’s College London, Medical Affairs in Medicines Development, Certification Program provides the training needed for Medical Affairs Professionals to not only become successful in their careers but ultimately provide a higher standard of care and service to patients and healthcare providers.
Around the turn of the century, a rather simple classification of public-private-partnerships (PPPs) in the world of medicine development sufficed. These PPPs consisted primarily of bilateral collaborations between pharmaceutical companies and academic institutes. Since then, these “simple” bilateral PPPs have been complemented by different and more diverse types of PPPs. On the one hand, PPPs emerged such as the Medicines for Malaria Venture (MMV) or the Drugs for Neglected Diseases Initiative (DNDI) with as major drivers charities, country donors, industry, and academic groups. These so-called product development partnerships (PDPs) focus on developing products for specific communicable diseases impacting health of patients in less affluent countries. On the other hand, Pharma-PPPs, such as the Innovative Medicines Initiative (IMI), emerged that focused on jointly tackling specific -precompetitive- issues in medicine development. The major players in the last category consisted of the pharmaceutical industry (large pharma), small, and medium sized enterprises (SMEs), academic institutes and–again- governmental funding programs (1, 2). Since then the background of participating stakeholders of PPPs has greatly diversified. Important new stakeholders joined the PPP consortia, including patient organizations, regulatory bodies, health technology assessment agencies, insurance companies, and IT-companies (see articles in this special issue, e.g., Aartsen et al.) All have their unique incentives to join, which makes the PPP concept more difficult to define and to evaluate in terms of its benefits. Nowadays, many PPP-flavors exist and the number and diversity continues to grow. Contributions to this special issue exemplify this current development in the PPP-world.
Added value: in the eye of the beholder or more concrete impact measures?
Early on, questions were raised about the assessment of performance and success-failure of PPPs (1–3). Performance indicators to look at were identified as: the input, the process, the output, the short-term outcome, and impact. See Figure 1 for details. The basis for this methodology was already developed and tested in other fields. What makes the Pharma-PPP case so special are the long timelines–years- to measure “impact.” The classical PPP projects have a typical running time of 4–6 years. The long-term outcome-and impact e.g., in terms of concrete new medicines can only be measured many years after finishing the project and on top of that there are many “diluting” contributing factors in the post-PPP years. Moreover, simply looking at the number of medicines developed based on the activities of a PPP significantly underappreciates the additional impact from knowledge transfer, ongoing collaborations, patents, spin-off companies formed, and last but not least the educational aspect PPP initiatives offer (See Figure 1). The true impact of the first generation of PPPs now becomes visible and we can review that according to the key performance indicators set out from the start [cf. (4, 5)].
Figure 1. Reported performance indicators to be considered in a research PPP performance measurement system, classified into 5 categories. Figure adapted from (2). 2. De Vrueh RL, Crommelin DJ. Reflections on the future of pharmaceutical public-private partnerships: from input to impact. Pharma Res. (2017) 34:1985–99. doi: 10.1007/s11095-017-2192-5 PubMed Abstract | CrossRef Full Text | Google Scholar
In that light, there is one question that was often raised in the early days and that can now be answered, i.e., the concern about the quality of the research output -read publications- of PPPs. Several studies made it clear (3, 4) that the impact of publications measured in terms of impact factor of scientific journals and number of citations of IMI and TI Pharma consortia was comparable–if not higher- than of articles published through “regular” academic groups efforts.
Sustainability: to stay or to perish?
What is the chance for a consortium to survive after finishing the first funding round? Before answering this question it should be clear whether the project, topic-wise, is supposed to be continued at all? Some projects simply do not have a horizon beyond their running time. They are set up to solve a particular -often concrete- problem. However, what if a prolonged existence is foreseen? Experience teaches us that then already in an early stage the question of sustainability should be addressed. For instance, in case infrastructure has been built up, such as databanks or test facilities, further strategies to continue activities after the first funding round should be subject of discussion early on. The article by Aartsen et al. in this special issue discusses various sustainability strategies developed for IMI projects in detail and lists “lessons learned.”
Evolution: PPP Quo Vadis?
The adoption of the “open innovation model” by the pharmaceutical industry has given the PPP concept a big push. Originally, the public partners were mainly academic and national or international public funding organizations. The large pharmaceutical industry with or without SMEs took care of the private side. Over time, the background of stakeholders in PPP consortia has diversified. Patient organizations and health insurance companies joined the consortia. Regulatory bodies such as EMA and FDA are becoming partners as well, although these institutions are very cautious to safeguard their independence from large pharma and other private stakeholders. Big IT organizations such as Google and Amazon (cloud-computing services) expanded the spectrum on the private side (Moreno et al.) as did medical device-diagnostics companies such as Siemens, Agilent, and Philips in the context of IMI. This expanding source of partners will change the character of PPP consortia. Also, the scope of activities evolved. As partners in first PPPs were jointly exploring science and collaboration in a truly pre-competitive field, a shift toward projects where partners share their strategic assets is now observed. E.g., in the IMI—European Lead Factory (see this issue: Karawajczyk et al.) industry decided to share some proprietary assets allowing competitors and public partners to boost their drug discovery programs. It demonstrates that the PPP concept has become a trusted way of working and partners now seem comfortable to evolve the model with activities closer to their core business.
These recent developments raise the question whether the original, rather narrow definitions of a PPP as mentioned at the beginning of this editorial will properly describe the PPPs in medicine development in the future. Partners outside pharma now join the game and change the dynamics and “culture.” The walls between the classical “silos” disappear rapidly.
The remaining question is then. PPP concept in the world of medicine development: Quo Vadis?
References
1. Denee TR, Sneekes A, Stolk P, Juliens A, Raaijmakers JA, Goldman M, et al. Measuring the value of public–private partnerships in the pharmaceutical sciences. Nat Rev Drug Discov. (2012) 11:419. doi: 10.1038/nrd3078-c1
2. De Vrueh RL, Crommelin DJ. Reflections on the future of pharmaceutical public-private partnerships: from input to impact. Pharma Res. (2017) 34:1985–99. doi: 10.1007/s11095-017-2192-5
3. Gunn M, Lim M, Cross D, Goldman M. Benchmarking the scientific output of the Innovative Medicines Initiative. Nat Biotechnol. (2015) 33:811–2. doi: 10.1038/nbt.3305
Keywords: editorial, public-private parternships, healthcare, innovation, medicine
Citation: de Vrueh RLA, de Vlieger JSB and Crommelin DJA (2019) Editorial: Public-Private Partnerships as Drivers of Innovation in Healthcare. Front. Med. 6:114. doi: 10.3389/fmed.2019.00114
Received: 02 May 2019; Accepted: 07 May 2019; Published: 31 May 2019.
Edited and reviewed by:Michel Goldman, Free University of Brussels, Belgium
This article was originally published on Frontiers in Medicine. Authors: Manuela Battaglia1, Pat Furlong2, Nico Martinus Wulffraat3, and Felicitas Bellutti Enders4
1Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Parent Project Muscular Dystrophy, Hackensack, NJ, United States
3Department of Pediatric Immunology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, Netherlands
4Allergy Unit, Department of Dermatology, University Hospital, Basel, Switzerland
Translational medicine works through the definition of unmet medical needs, their understanding and final resolution. In this complex and multi-disciplinary process patients have always been regarded as “end-users” or no more than “data provider.” Considering that the translational practice is nowadays highly inefficient (i.e., large intellectual and economical resources are wasted with limited impact on people health) here we propose to reverse the process: start from patients, engage them, and keep them at the center. A new partnership needs to be formed between the patients and the health care professionals, as well as the treating physicians, to make the most out of the current “health resources.” New patient-centric approaches are emerging but they remain isolated phenomena often difficult to implement. Here—with this perspective—we aim at thinking differently and learning from new experiences. We will provide some successful examples of change, and we will discuss new approaches to create a radical change in the way translational medicine is managed and how this would significantly impact people health and health care systems.
Introduction
The European Society for Translational Medicine has defined translational medicine as an interdisciplinary branch of the biomedical field supported by three main pillars: benchside, bedside, and community. The goal of translational medicine is to combine disciplines, resources, expertise, and techniques within these pillars to translate efficiently and effectively scientific research findings relevant to human diseases into knowledge that is beneficial for patients via new drugs, devices, or treatment options (1). Accordingly, translational medicine is a highly interdisciplinary field and includes academia, industry, and regulatory institutions. However, patients (who are the direct beneficiaries of translational medicine) are often excluded by this complex process.
In this perspective paper, we will discuss the impasse of translational medicine, the role that patients should have in this process (with concrete examples of success) and the future directions with the aim at fostering a science that really impacts on patients’ life.
The Impasse of Translational Medicine
Translational medicine is a process fundamental for the society as it aims at developing new interventions beneficial to the patients. However, translational medicine is at a historic moment of crisis. The process is becoming unsustainable in spite of enormous technological advances, since the technological explosion has not been accompanied by a reinforcement of quality in experimental designs, especially in the discovery phases. However, there is no clear path neither for clinicians nor for scientists regarding the process of how a discovery leads to an approved drug. The high level of failure of clinical trials in Phase II/III swallows up economic resources, generates exhaustion among researchers and clinicians and, most importantly, induces frustration among patients who see their hopes for a new drug to treat their disease, disappear (2). The high failure of clinical trials can be due to the inadequate study design, incorporating endpoints that provide limited or misleading information regarding the efficacy of the test agent, to the limited reproducibility of data, or also due to the high variability between tested subjects regarding their genetic background or the heterogeneity of their disease and also their comorbidities (3). Although it is now clear that even the failure of well-designed studies benefits both researchers and healthcare systems by, for example, generating evidence about disease theories and demonstrating the limits of proven drugs (4).
The Food and Drug Administration (FDA) publishes every year a list of all the drugs released on the market 1. Backtracking the initial publication on the mechanism or molecule leading to drug development shows—for the drugs released between January and September 2018—a median interval of 10 years (range: 5–37 years) before the drug is reaching the patient. This is becoming unsustainable as it creates tremendous social distress. At a time of global financial crisis, citizens perceive that vital resources are not being used efficiently and scientists fear to enter in a career path that is uncertain and not properly rewarded.
Thus, there is a great need to reconsider the translational medicine process and we do believe that moving the patients from “end-users” to “engaged collaborators” would transform them into agents of change. The standard business model is indeed to speak to the consumer. Apple for instance understands its consumer: it must first identify the customer, talk about the product and ask if the intended consumer would value the product. Is it any wonder why Apple is the first billion-dollar company? They know their consumer! In translational medicine, this concept is ignored. Patients are the ultimate users of health technologies and they can advocate and promote models for patient involvement among other stakeholders. Nothing will facilitate the dialogue among scientists, clinicians, and society more effectively than the creation of a pathway, constructed together, and bound by a common objective. This should lead to improved translational medicine efficiency and reduced waste of resources and energies.
Current Advances
The doctor-patient relationship in western countries has significantly evolved over the years. Prior to the last two decades the relationship followed a paternalistic model, where the patient sought help and the doctors used their skills to choose the necessary interventions or treatments to restore or improve patients’ health. Decisions of the doctors were silently complied by the patient (5). The social system has been challenged over the last 20 years: society has changed (being now multicultural), access to information is broader (social), media allow easier contact between patients and thus facilitated creation of patient’s organization. Therefore, critics have emerged, demanding a more active, autonomous and thus centered role for the patient who advocates greater control, reduced physician dominance, and more mutual participation.
This has led to the idea of the Shared Decision Medicine (SDM), which is a process promoted by the Institute of Medicine (IOM) as part of the strategy to improve the quality of health care in the United States. The IOM recommended that healthcare should be customized based on the patient’s needs and values, the patient should be given adequate knowledge and control to make decisions that affect his/her health, patients and healthcare providers should communicate and share information, and patients should receive information that allows them to make informed decisions. To this end, SDM is the joint involvement of patients and healthcare providers in making healthcare decisions that are informed by the best available evidence in regards to possible options, potential benefits and harms, and that consider patient preferences and values. SDM ensures patients get no more and no less of the care they need and want (6, 7). However, despite attention to principles and competences, there remains a lack of clear guidance about how to accomplish SDM in routine practice. Studies have not yet addressed the question about the impact on professionals. There might be the need to coach patients to be able to assess the value, risks, benefits, and burden of interventions. For organizations, a consistent shared decision-making might change patient experience evaluations and lead to a “satisfied patient” and fewer complaints or even legal issues. Clear outcome measurements of shared decision-making are needed as they would provide a more substantive evidence base to guide implementation (6).
Another, more recent, approach to bring the patients closer to the science that could impact their life is the “plan S.” Research funders from France, the United Kingdom, the Netherlands, and eight other European nations have unveiled a radical open-access initiative; they will mandate that, from 2020, the scientists they fund must make resulting papers free to read immediately on publication. The scientific papers would have a liberal publishing license that would allow anyone to download, read it or otherwise reuse the work leading to a science no more locked behind paywalls and freely available for everybody (8).
Increasingly, funding opportunities for translational biomedical research require studies to engage community partners, patients, or other stakeholders in the research process to address their concerns. However, there is little evidence on strategies to prepare teams of academic and community partners to collaborate on grants. A well-planned and feasible educational program designed to help community organizations and academic institutions to build infrastructure for collaborative research projects using a partnered approach is needed and some institutions are already investing in this important activities (9, 10).
Industry is today also very open to view patients as close collaborators and aims at connecting with them throughout the innovation journey, starting with validation of new concepts to the design of patient-centric trials. The customer journey is a term from marketing, describing the 5 cycles, which a client passes through before he decides to buy a product, or in medical terms, before he decides for one or the other therapy. Five phases mark this journey: awareness, favorability, consideration, intent to purchase (or in medical terms, intent to treat), conversion (decision to treat). For most pharma companies, this represents a major shift in thinking. It requires putting not the product but the customer at the center of the launch, and addressing customers’ emotional and behavioral needs as well as their clinical ones.
There are also tangible examples of success on how to move the patients at the center of the translational medicine process. Here we report two specific cases.
The Remarkable Story of a Mother and the Parent Project Muscolar Dystrophy
When doctors diagnosed her two sons, Christopher and Patrick, with Duchenne muscular dystrophy (DMD) in 1984, Pat Furlong didn’t accept the therapeutic nihilism, the fatalistic message from their doctor “there is no hope and little help.” DMD is the most common, lethal genetic disease diagnosed in childhood; it is an aggressive and ultimately fatal muscle wasting disease that primarily affects boys and it results in a progressive loss of muscle strength. Individuals with DMD lose ambulation in the early teens, require ventilation in the mid-teens and die before reaching the 3rd decade. Families who receive the diagnosis are in a race against time. They await new knowledge and scientific breakthroughs, possibilities to slow the degeneration. As of today, steroids are used to slow the decline, but there are no cures for DMD. In 1994, together with other parents, Pat Furlong founded Parent Project Muscular Dystrophy (PPMD) to change the course of the disease and ultimately end DMD. PPMD is today the largest most comprehensive non-profit organization in the United States focused on finding a cure for DMD 2. In her quest for a cure, she first realized that there simply wasn’t enough research into the disease and too many questions being left unanswered. Her first efforts focused on small investments in academic research and leveraging those investments. Due to the rarity of the disease (1 in 4600−5600 boys) and hence lack of potential profits there had been little interest at the onset from major pharmaceutical companies. Early in the fight, PPMD realized that the greatest source of advancement in basic science surrounding DMD would be through an investment by the National Institutes of Health (NIH) and related agencies. In 2000, the Duchenne community, through PPMD, employed a firm to lobby on their behalf in Washington DC and scored major legislative success with the introduction of legislation, intended to require government agencies such as NIH to significantly increase its investment in and coordination of research into the muscular dystrophy’s. That same year, at the insistence of PPMD, NIH held a scientific workshop on Duchenne, bringing in scientists from all over the world to advance the cause. This was a workshop of major significance in which attending scientists’ and researchers came to the realization that with the knowledge of the genetic basis of the disease and through multidisciplinary collaboration, something could be done to improve the quality of life and extend the lifespan of boys with DMD. On the tails of the earlier success with NIH, PPMD continued its Washington DC advocacy agenda and achieved another stirring victory. In December 2001, the Muscular Dystrophy CARE ACT was signed into law. This legislation dramatically increased NIHs investment in Muscular dystrophy research (from ~$17 millions to over $750 millions), including the funding of six Centers of Excellence. All of that, in addition to the earlier orphan drug act of 1983 incentivizing companies to invest in rare disease research, resulted in significant breakthroughs and new knowledge to fully characterize the pathology of DMD and to encourage industry interest in targeting relevant pathways. Today there are more than 40 ongoing clinical trials, whereas in 1999 there was 1 trial. Additionally, today there are more than 45 pharmaceutical companies investing in DMD. Current market estimates an 8-Billion-dollar investment in drug development. PPMD is currently working with FDA to develop a Master Protocol to enable access to trials across the Duchenne community, potentially leading to combination therapies and reach the highest priority of families (Figure 1).
Patient advocacy has come of age. Foundations focused on a specific disease provide substantial investments in research, organize the patient community, collect data to better understand disease progression, support the development of biobanks, inform regulatory interactions and assist patients navigate the healthcare environment. Advocacy efforts lead the ecosystem of research, therapy development, access and reimbursement. Her sons lost their battle with DMD in their teenage years, but Pat Furlong continues to fight—in their honor and for all the community to this day.
The Development of a Patient Council Within a Clinical Department
Another, yet different, example of success comes from the Department of Pediatric Rheumatology at the Wilhelmina Children’s University Hospital in Utrecht (The Netherland) focused on the study and cure of Juvenile idiopathic arthritis (JIA). JIA is the most common chronic rheumatic disorder in children and is a major cause of short-term and long-term disability. JIA is defined as having an inflamed joint before the age of 16 without a clear cause that persists for more than 6 weeks; it is a chronic disorder, which if neglected, can lead to serious complications.
In developing a network for biological research for patients with Childhood Arthritis doctors and scientists at the Wilhelmina Center of Excellence strongly think that input from and collaboration with patients and patient organizations is crucial. Patients, their parents, doctors and researchers all share the same common goal, namely that progress in basic science is translated in real tangible products for patients with childhood arthritis. In 2013 a patient council was formed in this Department. Together with professionals the JIA patient council explore research priority setting by reviewing the research topics, safety and efficacy of immunizations, as well as stopping medications. In addition to this, a jointly written application was obtained for a project with focus groups for patients that was also led by a parent. The patient council selected a topic which was the most frequent concern expressed by patients: the uncertainty patients feel due to the impact of the unpredictable course of their disease (pain, relapses) in their activities of daily life (activities at school for younger children and later work, sports and social contacts). Focus groups further analyzed the effects of the unpredictable course of the disease. Information was written for websites and two youtube movies were made. The group made of Dutch organizations of patients, parents and clinicians will collaboratively develop a research agenda for JIA, following the James Lind Alliance (JLA) methodology 3. The JLA is a non-profit making initiative established in 2004 and it brings patients, caregivers and clinicians together in Priority Setting Partnerships (PSPs) to identify and prioritize the top 10 uncertainties, or unanswered questions, about the effects of treatments. The aim of this is to make sure that health research funders are aware of the issues that matter most to patients and clinicians. In this process the input from clinicians, patients and their caregivers will be equally valued. Additionally, focus groups will be organized to involve young people with JIA. The involvement of all contributors will be monitored and evaluated. In this manner, the project will contribute to the growing body of literature on how to involve young people in agenda setting in a meaningful way.
This approach, despite still at its infancy, will inform researchers and research funders about the most important research questions for JIA and this will hopefully lead research agenda for research that really matters (11).
Current Obstacles and Future Directions
The examples provided show how patients and their care givers can be the catalysts of a change that is highly needed in translational medicine but they remain, as per today, sporadic cases led by unique human beings or by particularly inspired institutions. Many obstacles remain. Qualitative research showed that the involvement of patients and caregivers is challenging: real co-design does not happen by itself (12). First, specific educational programs are needed to improve the process of shared decision-making, for both partners, the patient and the physician. These programs are missing and importantly clinicians are often limited in their time-management. Educate and engage patients is a time-consuming process but health insurances—as well as hospitals—push more and more to reduce the time spent with patients, as costs of medication, exams, and personnel are dramatically increasing.
Scientists are even farther away from this process, as they often do not have direct contact with the patients. Current criteria for promotion in the medical field still rely heavily on individual research output such as high impact publications, h-index, grants, and invited lectures. There is tremendous pressure and on top of this pressure, there is really no space for a patient-centric view that needs time, patience and dedication. Especially in a system where these activities are not properly recognized and, as a consequence, rewarded. To change this, institutions need to ensure that their tenure and promotions systems are able to evaluate and recognize the contributions investigators conducting translational medicine make. Many institutions are working in this direction and, for instance, signed the Declaration on Research Assessment (DORA). DORA recognizes the need to improve the ways in which the outputs of scholarly research are evaluated. The declaration was developed in 2012 during the Annual Meeting of the American Society for Cell Biology in San Francisco4[4]. It is a worldwide initiative covering all scholarly disciplines and all key stakeholders including funders, publishers, professional societies, institutions, and researchers. It is a first step toward assessing research based on its own merits rather than on the basis of the journal in which the research is published.
In conclusion, translational medicine is a very complex branch of medicine. The constant challenges of teaching, researching, publishing, and competing for limited sources of funding, coupled with pursuing career aims and ambitions, can seem daunting. On top of this, we are also adding the patient-centric4 view, which adds another level of complexity. However, we believe that once the obstacles are overcome, the real inclusion of patients in the process of translational medicine will improve healthcare delivery to patients.
Author Contributions
MB conceived the topic, contributed to the topic discussion and wrote the manuscript. PF and NW contributed to the topic discussion and contributed to manuscript writing. FB contributed to the topic discussion and wrote the manuscript.
Funding
MB is supported by research grant from JDRF, NIH and the Italian Ministry of Health.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Citation: Battaglia M, Furlong P, Wulffraat NM and Bellutti Enders F (2019) Improving the Translational Medicine Process: Moving Patients From “End-Users” to “Engaged Collaborators”. Front. Med. 6:110. doi: 10.3389/fmed.2019.00110
Received: 10 October 2018; Accepted: 03 May 2019; Published: 21 May 2019.
Edited by:Wu Yuan, Johns Hopkins Medicine, United States
Reviewed by:Shi-Cong Tao, Shanghai Sixth People’s Hospital, China Marian Klinger, Opole University, Poland
