Covid-19: Should doctors recommend treatments and vaccines when full data are not publicly available?
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3260 (Published 24 August 2020) Cite this as: BMJ 2020;370:m3260Read our latest coverage of the coronavirus outbreak
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Dear Editors
As we going into the 6th week after this debate was published in late August, we are still no closer to full data access to several topical and highly influential papers, of which RECOVERY trial’s work on dexamethasone published online on 17 July 2020 (ref 1) is one.
The RECOVERY researchers announced their dexamethasone findings via press release 16 June 2020 (ref 2), although their actual non-peer reviewed preprint was only made available from 22 June 2020 (ref 3).
On the same day as the official paper publication of RECOVERY’s dexamethasone study (2 September 2020), the JAMA published 3 papers online, all of them involving randomized control trials (RCT) investigation the effects of corticosteriod on patient outcome in those critically ill from COVID-19.
Again, all of them decided to prematurely stopped their trial due to (perceived) lack of equipoise based on the results of the RECOVERY group.
REMAP-CAP (hydrocortisone) trial ceased on 17 June 2020 (ref 4), the day after the RECOVERY press release.
CoDEX (dexamethasone) ceased on 25 June 2020 (ref 5), after the non-peer-reviewed preprint become available.
CAPE COVID (hydrocortisone) trial ceased on 3 July 2020 also based on the preprint, but their last enrolment of study participants actually occurred on 1 June 2020 one month before (ref 6).
Of interest, CoDEX found IV dexamethasone plus standard care is associated with increased 28 day survival and days free of mechanical ventilation but failed to find any significant difference in mortality rates between IV dexamethasone plus standard care vs standard care only; one might argue that this is due to insufficient numbers recruited to detect a difference. Note also that patients requiring invasive ventilation in CoDEX have mortality rates 50% higher than the RECOVERY trial (61% vs 41%).
Added to the complex web is the contribution of WHO working group publishing a meta-analysis in JAMA on the same day (2 September 2020). Much of the data is driven by UK's RECOVERY trial, the largest study with low variance, with weighted average of 57% in the entire meta-analysis. The effect of the RECOVERY study led to the nebulous conclusion that the use of systematic corticosteroid (as a class effect) in critically ill COVID-19 patients, compared with usual care or placebo, was associated with a lower 28-day all-cause mortality.
Given the drastic effect of RECOVERY press announcements and preprints in stifling existing RCTs investigating corticosteroids in critically ill patients with COVID-19, and its bulk effect on the WHO meta-analysis reviewing this matter, I would strongly suggest that we need to be certain of the conclusions of the RECOVERY investigators, however proud we are that this study came from UK.
The RECOVERY group found the use of dexamethasone in patients hospitalized with Covid-19 resulted in lower 28-day mortality (by as much as one-third) among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Interestingly over a similar period as RECOVERY trial, the “overall mortality of covid-19 patients in intensive care units (ICU) has fallen from 59.5% at the end of March to 41.6% at the end of May, a drop of almost a third” (ref 8). This meta-analysis uses observational data from UK as well as other nations not involved in RECOVERY trial. Its authors suggest the possible reasons for reduction in mortality rate:
“It may reflect the rapid learning that has taken place on a global scale due to the prompt publication of clinical reports early in the pandemic. It may also be that ICU admission criteria have changed over time, for example, with more non‐invasive ventilatory management outside ICU. It is also likely to reflect the fact that long ICU stays, for example, due to prolonged respiratory weaning, take time to be reflected in the data.“ (ref 9)
The UK mortality rates appear to be one of the lowest in the European region in this paper; other European authors report 10-20% more deaths per ICU admission. Hence there may be a difference in treatment or criteria for ICU admission, amongst other possibilities. As such, it is possible dexamethasone may have different effects on these patients based on geographical location and patient demographics.
At the end, what does it mean?
The effect of the RECOVERY paper on world research on systematic corticosteroid treatment of COVID-19 is ground breaking, and therefore we need to be certain of the result and conclusion. The most transparent way to ensure unbiased assessment is by open data access.
I agree with Peter Doshi and David Healy; data transparency is no longer a “nice to have”. Nor should it be relegated to “in an ideal world” situation, particularly when one study single-handedly changed clinical practice in a (still) rapidly evolving healthcare crisis, and led to cessation of other relevant and potentially corroborating trials. To absolve the potential conflict of interests of the RECOVERY researchers when their data is cross-checked, their data need to be made available to other clinicians.
As I once remarked: “Before you stand on the shoulders of giants, watch what they are standing on” (ref 10)
References
1. https://www.nejm.org/doi/full/10.1056/NEJMoa2021436
2. https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160...
3. https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1
4. https://jamanetwork.com/journals/jama/fullarticle/2770278
5. https://jamanetwork.com/journals/jama/fullarticle/2770276
6. https://jamanetwork.com/journals/jama/fullarticle/2770277
7. https://jamanetwork.com/journals/jama/fullarticle/2770279
8. https://www.bmj.com/content/bmj/370/bmj.m2882.full.pdf
9. https://associationofanaesthetists-publications.onlinelibrary.wiley.com/...
10. https://www.bmj.com/content/355/bmj.i5440/rr-1
Competing interests: I had previously cautioned on making clinical decisions based on evidence by press release; studies by RECOVERY group included.
Dear Editor
The World is increasingly challenged with the ‘Unusual Difficulties’ which have become the ‘Unbelievable Hallmarks’ of the ‘Unprecedented Ravagingly Devastating 21st Century Storm’: The ‘COVID-19 Pandemic’! As a ‘Novel Coronavirus ‘SARS-CoV-2’’, the virus is characterized by ‘Rapidly Dynamically Transmuting Specifics’ disposing the ‘COVID-19 Pandemic Information’ as ‘Information in a Flux’ and an ‘Increasingly Difficult Work in Progress’. The ‘Global COVID-19 Pandemic Information Challenge’ is ‘Upholding Science and Standards’ to assure that ‘Continuously Evolving COVID-19 Pandemic Information’ is DEPENDABLE, RELIABLE and TRUSTWORTHY! This is the REAL CHALLENGE which signposts the ‘Unusual Difficulties’ typifying the ravaging and devastating ‘COVID-19 Pandemic’. Data represent ‘Information Transformed into Meaningful Usable Storable and Retrievable Entity and Statistics’. Therefore, the ‘Global Challenge’ concerning the ‘COVID-19 Pandemic Statistics’ is that they MUST be DEPENDABLE, RELIABLE and TRUSTWORTHY to be of ‘Impactful Pandemic Interventional Relevance and Outcome’! This is the crux of this ‘Communication’ on the bothersome COMPROMISE of SCIENCE and STANDARDS!!
We are aware of the ‘Avalanche of COVID-19 Research Outpourings/ Data’ in necessary response to the ‘Rapidly Dynamically Transmuting COVID-19 Pandemic Specifics’! The ‘Unusual Difficulties’ signposting some of the ‘COVID-19 Research Data’ is the COMPROMISE of the SCIENCE and STANDARDS of the ‘Robust Research Governance Pillars’ and the ‘Stiff Data Governance Principles’ [1-3]! Several communicated ‘COVID-19 Research Data’ have thus been regarded as ‘COVID-19 Research Waste’ [4]!! In previous ‘Communications’, some have suggested that, in the ‘Circumstances of Pandemics’ and because of the rapidly increasing devastations regarding the toll on Human Casualties and Economic Burdens, there should be ACCEPTABLE COMPROMISE of the SCIENCE and STANDARDS of the ‘Robust Research Governance Pillars’ and the ‘Stiff Data Governance Principles’ [5-8]! This is reportedly a consequence of the need to have urgent ‘Research Responses’ to the ‘COVID-19 Pandemic Rapidly Transmuting Information’! The imperative to guarantee and protect ‘COVID-19 Research Data Integrity and Reliability’ has been amplified in previous ‘Communications’ [9-12]!! We may regard this as part of the ‘Unusual Difficulties’ at the ‘COVID-19 Pandemic Outset’. Now, we have some new ‘Unusual Difficulties’!
Some now also suggest ACCEPTABLE COMPROMISE of the SCIENCE and STANDARDS of the ‘Robust Research Governance Pillars’ and the ‘Stiff Data Governance Principles’ in relation to evolving ‘COVID-19 Pharmaceuticals’: Drugs, Convalescent Serum/ Plasma, Vaccines etc! Specifically, the issue of ‘Full Data Transparency’ concerning the ‘Approval’ and ‘Prescription’ of ‘COVID-19 Pharmaceuticals’ in the ‘COVID-19 Pandemic Trying Times’ is exciting current ‘Pandemic Interventional Conversation’!! A recent ‘Communication’ was quite intriguing with ‘Opposing Dispositions’ enmeshed therein [13]!! While some regard ‘Full Data Transparency’ as ‘Nice to Have’ or ‘As Much as Possible’, others in the same ‘Communication’ insist on ‘Full Data Transparency’ as a ‘Sine Qua Non’ for ‘Approval’ and ‘Prescription’ of ‘COVID-19 Pharmaceuticals’ [13]!! In a Pandemic, it is argued that ‘Preprint Data’ which are not Peer-reviewed and ‘Adaptive Clinical Trials’ which are not subjected to the rigorous ‘Robust Research and Data Governance Standards’ are good enough for rapidly deploying Medical Treatments [14]! Additionally, it is disposed that STRICT COMPLIANCE with the ‘Robust Conventional Randomized Controlled Trials Standards’ has bogged down the World Health Organization, Centers for Disease Control and Prevention and the National Institutes of Health. They reportedly have been unable to clearly articulate definite consistent positions on several ‘Issues’: ‘Face Masks Use’, ‘Aerosolization of the Virus’, ‘Precise Clinical Data on SARS-CoV-2’ etc with over six months into the ‘COVID-19 Pandemic’ [15,16]! The RECOVERY Trial is also disposed as a ‘Case-in-Point’ for ‘Adaptive Clinical Trials’ for ‘Unpublished Data’ with ‘Closing or Adding Trial Arms’ guiding Treatments in the ‘COVID-19 Pandemic Era’ [17]! Much ‘Data Secrecy’ is encouraged with Preprints, Press Releases etc [18,19]!!
The ‘Opposing Disposition’ in the ‘Intriguing Communication’13 holds tenaciously to ‘Full Data Transparency’ for ‘Approvals’ and ‘Prescriptions’ of ‘COVID-19 Pharmaceuticals’ for the desired ‘TRUST’ and ‘CONFIDENCE’ undergirding ‘Medical Prescriptions’ [19]!! The disaster with Narcolepsy in some ‘Pandemrix Recipients’ in the 2009 H1N1 Swine Flu is a ‘Case-in-Point’ disposing ‘Data Secrecy’ by Manufacturers which was only revealed after a Lawsuit [20]!! Insistence on ‘Full Data Transparency’ will eclipse the possibility of ‘Under-reporting of Adverse Events in Publications and Unpublished Communications’ [21,22]!!!
The ’Unprecedented Political Pressure’ by ‘POLITICIANS’ which has consistently undermined the SCIENCE, FACTS and BEST AVAILABLE RESEARCH EVIDENCE (BARE) concerning the ‘Coronavirus (‘SARS-CoV-2’)’, ‘Coronavirus Disease 2019 (‘COVID-19’)’ and the ‘Coronavirus Disease 2019 Pandemic (‘COVID-19 Pandemic’)’ is now being further compounded by ‘Unexpected Unexplained Unprecedented Unscientific Posture’ by ‘SCIENTISTS’! The ‘Unusual Difficulties’ associated with the persisting ‘COVID-19 Pandemic’ are facilitated by ‘Scientists and Professionals’ to undermine the ‘Robust Research Governance Pillars’ and the ‘Stiff Data Governance Principles’ undergirding the SCIENCE and STANDARDS of ‘Approvals’ and ‘Prescriptions’ of ‘COVID-19 Pharmaceuticals’: Drugs, Convalescent Serum/ Plasma, Vaccines etc! There are, in fact, ‘Communications’ on ‘Stem Cells Therapy’ in ‘COVID-19 Pandemic’ [23,24] but the Food and Drug Administration warns appropriately [25]!! Strictly adhering to the ‘Robust Research and Data Governance Standards’ will assure that there is ‘TRUST’ and ‘CONFIDENCE’ to undergird and galvanize ‘EFFICACY’ and ‘SAFETY’ of ‘COVID-19 Pharmaceuticals’ to be endorsed and prescribed by ‘Medical Doctors’ in the ‘COVID-19 Pandemic Interventions’!! For ‘COVID-19 Pandemic’, it MUST be ‘POLITICS OUT’ and ‘SCIENCE IN’ and the WHO has previously recommended that ‘POLITICS’ MUST be ‘QUARANTINED’ IN THE ‘Pandemic’ [26]!! We are burdened by the ‘COVID-19 Research Waste’ and this is now being compounded by the emerging ‘COVID-19 Pharmaceuticals Catastrophe’!!! This possibly can enlarge the extant ‘COIVD-19 Infodemic’ [10-12]!! With this, the ‘Global Fight’ against the ‘COVID-19 Pandemic’ will increasingly remain ‘Impossible Work in Progress’!!!
This ‘Communication’ is a ‘Modest Contribution’ to the extant ‘Full Data Transparency Conversation’ concerning STRICT COMPLIANCE with the ‘Robust Conventional Randomized Controlled Trials Standards’ as a precursor for harvesting the necessary ‘Approvals’ for ‘COVID-19 Pharmaceuticals’ for deployment in the ‘Global Fight’ against the ‘COVID-19 Pandemic’! We already have ‘Unusual Difficulties’ with ‘COVID-19 Research Waste’!! A ‘COVID-19 Pharmaceuticals Catastrophe’ will be ‘ONE AVOIDABLE UNUSUAL DIFFICULTY TOO MANY’ (Referential disposition to the Former UN Secretary-General Ban Ki-moon; 2010) in the ‘COVID-19 Pandemic’!!
REFERENCES
1. Clinical Trials.gov. History of changes for study. NCT04280705, 1 May 2020. https://clinicaltrials.gov/ct2/history/NCT04280705?A=10&B=15&C=Side-by-S....
2. Yan W. Coronavirus tests science’s need for speed limits. New York Times 2020 Apr 14. https://www.nytimes.com/2020/04/14/science/coronavirus-disinformation.html
3. Hoffmann T, Glasziou P. What if the vaccine or drugs don’t save us? Plan B for coronavirus means research on alternatives is urgently needed. The Conversation, 21 Apr 2020. https://theconversation.com/what-if-vaccine-or-drugs-dont-save-us-plan-b...
4. Glasziou PP, Sanders S, Hoffmann T. Waste in covid-19 research. BMJ 2020; 369:m1847
5. Nassisi M, Audo I, Zeitz C et al. Impact of the COVID-19 lockdown on basic science research in ophthalomology: the experience of a highly specialized research facility in France. Eye (Lond) 2020; 34:1187-8
6. Conroy G. Preprints boost article citations and mentions. Nature Index 2019 Jul 9. https://www.natureindex.com/news-blog/preprints-boost-article-citations-...
7. Fry NK, Marshall H, Mellins-Cohen T. In praise of preprints. Microb Genom 2019; 5:e000259. Doi: 10.1099/mgen.0.000259. pmid:30938670
8. Karmakar S, Dhar R, Jee B. Covid-19: research methods must be flexible in a crisis. BMJ 2020; 370:m2668
9. Eregie C.O. COVID-19 Pandemic: The multifaceted picture of compromised COVID-19 research and the COVID Phenomenon’. https://www.bmj.com/content/369/bmj.m1847/rr-12 of 10th June 2020
10. Eregie CO. COCID-19 and the quadruple-barrel tragedy: matters still evolving for the works. https://www.bmj.com/content/369/bmj.m2197/rr of 19th June 2020
11. Eregie CO. COVID-19 Pandemic, the quest for urgent information and solutions and the paradox: making haste slowly to avoid ‘COVID-19 Research Waste. https://www.bmj.com/content/370/bmj.m2668/rr of 17th July 2020
12. Eregie CO. COVID-19 Pandemic, the quest for urgent information and solutions and the paradox: making haste slowly to avoid ‘COVID-19 Research Waste’; time for strategic ‘COVID-19 Research Retreat for a Decad’. https://www.bmj.com/content/370/bmj.m2668/rr-0 of 21st July 2020
13. Johnson RM, Doshi P, Healy D. Covid-19: Should doctors recommend treatments and vaccines when full data are not publicly available? BMJ 2020; 370:m3260
14. Lurie N, Manolio T, Patterson AP, Collins F, Frieden T. Research as part of public health emergency response. N Engl J Med 2013; 368:1251-5
15. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006; 3:e343.
16. Arabi YM, Mandourah Y, Al-Hameed F et al. Saudi Critical Care Trial Group. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med 2018; 197:757-67
17. Wise J, Coombes R. Covid-19: The inside story of the RECOVERY trial. BMJ 2020; 370:M2670
18. Group RC. Effect of dexamethasone in hospitalized patients with covid-19- preliminary report. MedRxiv 2020, doi:10.1101/2020.06.22.20137273
19. Jefferson T, Doshi P. Multisystem failure: the story of anti-influenza drugs. BMJ 2014; 4:348:g2263
20. Doshi P. Pandemrix vaccine: why was the public not told of early warning signs? BMJ 2018; 362:k3948
21. Golder S, Loke YK, Wright K, Norman G. Reporting of adverse events in published and unpublished studies of health care interventions: a systematic review. PLoS Med 2016; 13:e10022127
22. Joelving F. What the Gardasil testing may have missed. 2017. https://slate.com/health-and-science/2017/12/flaws-in-the-clinical-trial....
23. Turner L. Preying on public fears and anxieties in a pandemic: businesses selling unproven and unlicensed ‘stem cell treatment’ for COVID-19. Cell Stem Cell 2020; 26:806-10
24. Jargin S. Some aspects of stem cell therapy. Cyprus J Med Sci 2020; 5:183-5
25. FDA Warns About Stem Cell Therapies. Content current as of 09/03/2019. https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell....
26. Eregie C.O. COVID-19 Pandemic, ‘COVID Phenomenon’ and the politics of the science, facts, research evidence and ‘evidence-based medicine (EBM): the imperative for rekindling the ‘multiparameter-based medicine (MBM) in the 21st Century. https://www.bmj.com/content/369/bmj.m1336/rr-20 of 17th April 2020
Professor Charles Osayande Eregie,
MBBS, FWACP, FMCPaed, FRCPCH (UK), Cert. ORT (Oxford), MSc (Religious Education),
Professor of Child Health and Neonatology, University of Benin, Benin City, Nigeria and
Consultant Paediatrician and Neonatologist, University of Benin Teaching Hospital, Benin City, Nigeria.
UNICEF-Trained BFHI Master Trainer and ICDC-Trained in Code Implementation.
*Technical Expert/ Consultant on the FMOH-UNICEF-NAFDAC Code Implementation Project in Nigeria.
*No Competing Interests.
Competing interests: No competing interests
Dear Editor
Waiting for peer reviewed papers before implementation of a treatment during a pandemic, as recommended by a BMJ statistical advisor (1), will result in lost lives. We looked (2) at the likely number of lives saved through the decision by the RECOVERY trialists to publicise, by press conference, their Dexamethasone results (showing a statistically significant reduction in 28 day mortality among hospitalised patients from Covid-19). Whilst the scientific paper (3) was published 1 month after the press release, if this had been the first release of the results we estimated that more than 200 additional people would have died in the UK (2), and potentially many more elsewhere. It is notable that the published results (3) of the primary outcome were virtually identical to findings released in the press conference.
Peer reviewed publications do not prevent poor research being disseminated. The risk of poor data being released unchallenged can be minimised if all aspects of the trial (i.e., protocol) are published during the recruitment phase, which can be carefully examined before the results are available. We would also advise of the following limitations to using results prior to peer-reviewed publication. Firstly, the treatment should have been rigorously safety tested, which was certainly the case of Dexamethasone as it was already widely used for other purposes. Secondly, clinicians should take care to assess whether the patient fits with the population that was evaluated in the trial.
Therefore, in a pandemic, clinically important results for safe treatments should be released immediately once they are known and clinicians can be directed to the published protocol for fuller methodological and clinical details of the study.
References
(1) Wise J, Coombes R: Covid-19: The inside story of the RECOVERY trial. BMJ. 2020; 370: m2670
(2) Knowlson C, Torgerson DJ. Effects of rapid recruitment and dissemination on Covid-19 mortality: the RECOVERY trial F1000 F1000Research 2020, 9:1017
(3) RECOVERY Collaborative Group, Horby P, Lim WS, et al.: Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020; NEJMoa2021436.
Correspondence
catherine.knowlson@york.ac.uk
david.torgerson@york.ac.uk
Competing interests: No competing interests
Dear Editor
Professors Johnson, Doshi and Healy all make strong arguments for greater transparency vs greater agility in COVID-19 trials, but Doshi and Healy seem to suggest the same level of rigour should be applied regardless of the circumstances. They quite rightly argue that vaccines shouldn’t be rolled out to a healthy population without full disclosure of the side effects, but the same argument doesn’t really apply to treatments for those acutely ill on the cusp of death. Johnson makes the point that without adaptive trials like RECOVERY, treatments wouldn’t emerge quickly enough to keep up with a pandemic.
Consider buying a boat - we’d be rightly concerned if we found out it had left the factory without someone checking the hull for leaks, but if we were already on board and it started taking on water, we’d sooner put on an unproven life jacket than do nothing at all.
Competing interests: No competing interests
Dear Editor,
There is a third question to be addressed: the situation where an abundance of science points to a treatment that restores physiology but is dismissed by NICE/SACN./PHE for lack of RCTs. That the secosteroid hormone D3 has actions upon innate and adaptive immunity is well established. Its role in reducing the severity of COVID-19 is therefore to be expected and is indeed confirmed beyond reasonable doubt: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3669379
The problem is that, although D3 supplementation is recommended (in a perfunctory fashion) the advised dose is far too low to achieve a physiological serum 25(OH)D3. The advisory bodies also fail to embrace science showing that BAME groups are less responsive to 25(OH)D than caucasians. This science is publicly available but ignored by NICE and SACN. Doctors no longer have the time to follow the ca 5000 research papers published on D3 per year, and I resist citing chapter and verse here.
To summarise extensive publicly available science, the physiological serum 25(OH)D3 is between 100 and 150 nmol/L and the daily supplement needed to attain this is between 2000 and 4000 IU. PHE advise that 4000 IU pd is safe. The maximum rate of D3 generation per day from whole body UVB is between 10,000 and 20,000 IU. All this is published, even in books written for the general public. The D3 panels of NICE and SACN seem to be blocking the utility of correct, physiological D3 supplementation, thereby failing to protect the UK population in this pandemic. So the third question is: should doctors recommend 2000-4000 IU D3 per day?
Competing interests: No competing interests
Dear Editor,
Before any COVID-19 treatment or vaccine is made widely available, study protocols should be in the public domain [1]. However, data transparency is not enough. Political ambitions and other conflicts of interest may interfere with the reliability of data and objectivity of conclusions. Both questionable data and invented theories have been published in the past [2]. The transparency of studies on such vital topics as pandemic diseases should be complete including inspections of laboratories. This pertains to vaccines or e.g. marketing claims on stem cell (SC) treatments for COVID-19 [3].
High-quality evidence supporting the use of SCs in COVID-19 is scarce [4]. Some providers offer SC products that are both unapproved and unproven [5]. It is acknowledged even in the supportive literature that the survival rate of SCs, homing efficiency, accumulation of DNA damage in cultured cells, tumorigenic and immunogenic potential are the current challenges regarding SC applications. Like in other areas, it has been assumed that SCs exert beneficial effects through soluble paracrine factors. There are, however, no theoretic reasons to expect more developed and targeted paracrine functions from morphologically primitive SCs than from mature cells.
The main functions of SCs are mitosis, self-renewal and clonal expansion rather than the synthesis of salubrious substances. In any case, experiments with mature cells or cell-free preparations would be less expensive. Mature cells and cell-free preparations would have no tumorigenic potential. Substances imitating paracrine effects of cell therapies can be obtained from culture media; this approach may achieve a better dose standardization than cell implantations [6].
Furthermore, a majority of clinical trials for COVID-19 have used allogeneic SCs associated with risks of immune response and pathogen transmission. Immune reactions might add pro-inflammatory agents to the “cytokine storm” known as a mechanism of lung injury in COVID-19.
In conclusion, patients need evidence-based therapies and preventive measures for COVID-19 rather than products with unproven effects [3]. The studies should be carefully conducted, transparent, shielded from conflicts of interest and political ambitions. More details [7,8].
References
1. Johnson RM, Doshi P, Healy D. Covid-19: Should doctors recommend treatments and vaccines when full data are not publicly available? BMJ 2020;370:m3260.
2. Jargin SV. Misconduct in Medical Research and Practice. Series: Ethical Issues in the 21st Century. Nova Science Publishers, Inc., 2020.
3. Turner L. Preying on public fears and anxieties in a pandemic: businesses selling unproven and unlicensed “stem cell treatments” for COVID-19. Cell Stem Cell 2020;26:806-10.
4. Saldanha-Araujo F, Melgaço Garcez E, Silva-Carvalho AE, Carvalho JL. Mesenchymal stem cells: a new piece in the puzzle of COVID-19 treatment. Front Immunol. 2020;11:1563.
5. FDA Warns About Stem Cell Therapies. Content current as of 09/03/2019 https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell...
6. Terzic A, Behfar A. Posology for regenerative therapy. Circ Res. 2017;121:1213-5.
7. Jargin SV. Stem cells and cell therapy. Cardiology. 2010;117(3):198-9. doi:10.1159/000322147.
8. Jargin S. Some aspects of stem cell therapy. Cyprus J Med Sci. 2020;5:183-5. https://www.researchgate.net/publication/342536101_Some_aspects_of_stem_...
Competing interests: No competing interests
Dear Editor,
The trials will take a very long time to complete and arrive at conclusions. Different trials are often likely to come to different conclusions about the same Medicine or treatment modality. If data from each center participating in the same trial is analysed separately, the centerwise trends may differ. Even within the same centre, person to person response to the same treatment protocol will vary.
Question arises when there is no known medicine and the treatment modality is conclusively proven to be safe and effective, what a treating physician should do on the spur of the moment, when lightening speed of correct action will make a difference between a life saved and death?
A few pioneering innovations will be in order.
Remember Edward Jenner and Smallpox Vaccine; Remember Louis Pasteur and the discovery of Rabies Vaccine. Remember Christiaan Bernard and first Human to Human Heart Transplant Surgery.
But putting aside the works of the illustrious pioneers, even an average Physician in a non-emergency situation has to pick one out of many available treatment options. At this micro-level or for the individual patient and the treating physician, the macro-level trial results may not hold good.
Yet again for developing Universally Acceptable Guidelines there must be supporting trials with adequate statistical power.
This subject will always remain open for debate.
Arvind Joshi; MBBS, MD; FCGP, FAMS, FICP;
Founder Convener and President:
Our Own Discussion Group,
Mumbai, PIN400028;
Consultant Physician at Ruchi Diagnostic Center and Ruchi Clinical Laboratory, Sunshine CHS,
Plot 58, Sector 21, Kharghar, PIN 410210;
Maharashtra State, INDIA.
Competing interests: No competing interests
COVID-19 Pandemic and compromise of science and standards: Still on ‘COVID-19 Pharmaceuticals catastrophe’; before and beyond the ‘Vaccines Marathon Finish Line’
The ‘COVID-19 Pandemic’, an ‘Unprecedented Ravaging 21st Century Storm’, has excited ‘Unimaginable Unprecedented New Normals’ in ‘Human Existence’ and stimulated ‘Rapid COVID-19 Research Outpourings’ deployed for ‘Rapidly Dynamic Innovative COVID-19 Pharmaceuticals Production’! The ‘COVID-19 Pandemic-induced ‘New Normals’’ should not accommodate the COMPROMISE of the BEST PRACTICES in SCIENCE and RESEARCH; They MUST be STRCTLY UPHELD in ALL Circumstances!! Anything less is UNACCEPTABLE with several ‘COVID-19 Research Outpourings’: ‘COVID-19 Research Waste’ [1-6] and some ‘COVID-19 Therapeutics’ emerging as ‘COVID-19 Pharmaceuticals Catastrophe’ [7]!
This ‘Communication’ amplifies specifically the ‘Vaccines Story’ within ‘COVID-19 Pharmaceuticals Catastrophe’ [7,8]! For ‘Marathons’, MANY are at the ‘START LINE’ with ONLY a FEW at the ‘FINISH LINE’!! Many ‘Vaccine Products’ entered the ‘Preliminary Research-Investigations’ but much fewer progressed to the ‘Candidate Vaccines Status’ with further fewer progressing through the ‘3-Phase Clinical Trials’ and ONLY six currently in the ‘Phase III Clinical Trials’ towards the ‘Finish Line’!!! The ‘Vaccines Story’ is ‘Conceptualized-Contextualized-Technicalized’ as the ‘Vaccines Marathon’!!! The ‘Finish Line’ is the ‘Appropriate Regulatory Vaccine Approval’. There are several ‘Vaccines Story Issues’: ‘Issues BEFORE the Vaccines Marathon FINISH LINE’ and ‘Issues BEYOND’! Therefore, for the ‘Vaccines Marathon’, it is not ALL about the ‘FINISH LINE’!! This discourse looks at ‘BEFORE’ and ‘BEYOND’ the ‘FINISH LINE’!!!
BEFORE THE ‘VACCINES MARATHON FINISH LINE’
The ‘SCIENCE of Vaccines (VACCINOLOGY)’ has exposed the Complex ‘Processes-Procedures-Policies’ governing ‘Ultimate Vaccine Approval’ (‘FINISH LINE’) predicated on ‘Best Practices and Standards’ undergirding ‘EFFICACY-SAFETY-TRUST’! The World has equally witnessed ‘UNACCEPTABLE POLITICS’ undermining the SCIENCE of ‘Vaccines Approval’!!
The ‘Vaccine Products’ should be evaluated with the ‘Rigorous and Best Research Practices’ in the ‘Preliminary Investigations’ for harvesting ‘Candidate Vaccines’! There are, unfortunately, attempts with ‘Political Pressure’ to ‘Hasten and, possibly, Undermine’, the ‘Stiff Research Standards’!! The ‘Vaccine Production Precursor Diversity’ is instructive with implications for the ‘Capacity for Immune Stimulation-Response’: ‘Modified Viral Components as the mRNA’ and ‘Vector-mediated Products’ such as ‘ChAdOx1 nCoV-19’ (Adenovirus Vaccine Vector with added Genetic Sequence for the Spike Protein of SARS-CoV-2 from University of Oxford Researchers). Also, ‘Ad5-nCoV’ (Non-replicating Adenovirus with added Genetic Sequence for the Viral Spike Protein from China CanSino Biologics) etc [9-11]!! The ‘Vaccine Precursor Diversity’ has implications for the ‘Antibody Production, Antibodies Levels, Duration and Protection’!! The ‘Spike Protein’ is the most targeted but there are others: Membrane, Nucleocapsid, Envelope Proteins etc!!
The ‘Antibodies Type’ produced are also important: Neutralizing Antibodies being the most studied! The ‘Specific Receptor-Binding Domain’ in relation to the ‘ACE 2 Receptors’ also has implications for the ‘Vaccine Efficacy’ [12-14]! There are several ‘Other Issues’: The relative contributions of B Cells (Humoral Immunity) and T Cells (Cellular Immunity) to the ‘Vaccine-induced Immune Responses’!! It is also relevant highlighting the predominant ‘Immunoglobulin Classes’ produced in response to the ‘Vaccine Administration’: IgG, IgM, IgA, IgD and IgE. Test ‘Sensitivity-Specificity’ also depends on the ‘Molecular Tests’ (RT-PCR etc), ‘Serological Tests’ (ELISAs, LFIAs, CLIAs etc) and ‘Cellular Tests’ (TB-Quantiferon Type etc) in the ‘Clinical Trials’ [9]!! The ‘Immunoglobulins Type for the Test’ and ‘Institutional or Commercial Test Kits’ also have implications for the ‘Sensitivity-Specificity’ of the ‘Vaccine Performance’ in ‘Clinical Trials’! A combination of Humoral and Cellular Immune Responses is desirable!! Different ‘Candidate Vaccines’ have ‘Different Specific Advantages’ and no ‘One Vaccine’ disposes all the desired attributes!!
Other ‘Considerations’ in the ‘Vaccines Marathon’ are: Single Vaccine-Multiple Vaccines, Single-Multiple Doses and the Dose-Interval, High-Low Dose, Storage Temperature and other Specifications. Also, Antibody Response Time, Antibody Levels, Protective Antibody Levels, Duration of Protective Antibodies, Prevention of Infection-Diminishing Severity of Infection, Adverse Events, Population Diversity and Differential Antibody Responses: Elderly, Pregnant Women, Children, Pre-Existing Morbidities, Ethnic Minorities and Disadvantaged Populations etc!
Some ‘Candidate Vaccines’ have been ‘Precociously Approved’ by National Regulatory Authorities kowtowing to ‘Unacceptable Unprecedented Political Pressures’ without properly concluding the ‘Phase III Clinical Trials’! These have possibly circumvented and undermined the ‘Stiff and Tested Best Research Standards’ for ‘Candidate Vaccine Approval’!! This is ‘Vaccine Nationalism’ [15]! The ‘WHO Vaccine Approval Guidelines’ include, among others: At least 50% Efficacy, Temperature Stability, Potential for Rapid Scale-up, Proper Evaluation against Comparators, Long-term Disease Prevention etc; Several ‘Influence-Pressure Groups’ are pushing for ‘Anything is better than Nothing’ [16]!! The ‘SCIENCE of Vaccines Approval’ is forced to give way to the ‘POLITICS of Vaccines Approval’!! This may result in ‘Approved Vaccines’ with suspicious ‘EFFICACY-SAFETY-TRUST’ necessary for ‘Vaccine DEMAND and UPTAKE’!!!
BEYOND THE ‘VACCINES MARATHON FINISH LINE’
Beyond ‘Vaccines Approval’, there are ‘Huge Considerations’ to be addressed and surmounted to assure that the ‘SCIENCE of Vaccines Approval’ translates to ‘Vaccines as SOLUTIONS to the COVID-19 Pandemic’! Rushing to the ‘Vaccines Marathon FINISH LINE (Vaccines Approval)’ is one thing and ‘Vaccines DEMAND and UPTAKE’ is completely another!! A ‘Tantalizing Teaser’: Some ‘Considerations-Issues’ BEYOND the ‘Vaccines Marathon FINISH LINE’ will be disposed!!
The ‘Huge Considerations-Issues’ to be addressed BEYOND the ‘FINISH LINE’ include, among others: Massive Vaccines Production to meet the ‘Determined Population Needs’, Supply Chains and Distribution Logistics, ‘Inverse Equity Hypothesis’ with the POTENTIALITY for Worsening Health Inequalities within Population Diversity-Disparity Dyad etc! The POLITICS-induced erosion of the TRUST and CONFIDENCE in the ‘Available Approved Vaccines’ will adversely affect the DEMAND and UPTAKE of the Vaccines. With ‘POOR VACCINES UPTAKE’, the desired ‘Herd Immunity’ will increasingly become a ‘Pandemic Intervention Mirage’. ‘Approved Vaccines’ are not the SOLUTION to the ‘COVID-19 Pandemic’ BUT ‘Effective Mass Population Vaccines Uptake’ possibly is!!
The desired ‘Impressive Population Vaccine Uptake’ will possibly imply there may be a reasonable ‘Population of Vaccinated Persons’ but the actualization of the ‘Determinant Triad’ is yet another ‘Issue in the Work’: The translation of ‘Vaccination’ to ‘Immunization’ and ‘Immunization’ to ‘Protection’ (The ‘VIP Concept’)! The factors that undergird the ‘VIP Concept Actualization’ are not addressed herein!!
This ‘Communication’ is a ‘Modest Contribution’ to the ‘POLITICS and SCIENCE of Vaccines Marathon FINISH LINE Conversation’ with the discourse of ‘Matters in the Works’: BEFORE and BEYOND the ‘FINISH LINE’! For the desired ‘Impactful Interventional Role for Vaccines’, it MUST be SCIENCE IN and POLITICS OUT for the ‘COVID-19 Pandemic’!!
REFERENCES
1. Clinical Trials.gov. History of changes for study. NCT04280705, 1 May 2020. https://clinicaltrials.gov/ct2/history/NCT04280705?A=10&B=15&C=Side-by-S....
2. Yan W. Coronavirus tests science’s need for speed limits. New York Times 2020 Apr 14. https://www.nytimes.com/2020/04/14/science/coronavirus-disinformation.html
3. Glasziou PP, Sanders S, Hoffmann T. Waste in covid-19 research. BMJ 2020; 369:m1847
4. Eregie CO. COVID-19 and the quadruple-barrel tragedy: matters still evolving for the works. https://www.bmj.com/content/369/bmj.m2197/rr of 19th June 2020
5. Eregie CO. COVID-19 pandemic tragic octad: The evolving conceptual qualitative interventional equation to fight the pandemic. https://www.bmj.com/content/369/bmj.m2303/rr-9 of 24th June 2020
6. Eregie CO. COVID-19 Pandemic, the quest for urgent information and solutions and the paradox: making haste slowly to avoid ‘COVID-19 Research Waste’; time for strategic ‘COVID-19 Research Retreat for a Decad’. https://www.bmj.com/content/370/bmj.m2668/rr-0 of 21st July 2020
7. Eregie CO. COVID-19 Pandemic and compromise of science and standards: First was ‘COVID-19 Research Waste’ and now ‘COVID-19 Pharmaceuticals Catastrophe’. https://www.bmj.com/content/370/bmj.m3260/rr-4 of 1st October 2020
8. Eregie CO. COVID-19 Pandemic, vaccines, vaccinations and antibody therapies: The paradox of making haste slowly with cautious optimism. https://www.bmj.com/content/370/bmj.m2722/rr-2 of 27th July 2020
9. Bastos ML, Tavaziva G, Abidi SK et al. Diagnostic accuracy of serological tests for covid-19: systematic review and meta-analysis. BMJ 2020; 370:m2516
10. Folegatti PM, Ewer KJ, Aley PK et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-cOv-2: a preliminary report of a phase 1/2, single-blind, randomized controlled trial. Lancet 2020; S0140-6736(20)31604-4.
11. Mahase E. Covid-19: Where are we on immunity and vaccines? BMJ 2020;370:m3096
12. Antibodies Brouwer PJM, Caniels TG, Straten K et al. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. https://science.sciencemag.org/content/2020/06/15/science.abc5902
13. Deeks JJ, Dinnes J, Takwoingi Y, et al. Antibody tests for identification of current and past infection with SARS-CoV-2. Cochrane Database Syst Rev 2020; 6:CD013652
14. Eregie CO. Covid-19 Pandemic, SARS-CoV-2 antibodies and testing: Still searching for more facts. https://www.bmj.com/content/369/bmj.m2584/rr of 16th July 2020
15. Altmann D. Finding the best covid-19 vaccine should not be a race: 14th August 2020. https://blogs.bmj.com/bmj/2020/08/14/finding -the-best-covid-19-vaccine-should-not-be-a-race.
16. Torreele E. The rush to create a Covid-19 vaccine may do more harm than good. BMJ 2020; 370:m3209
Professor Charles Osayande Eregie,
MBBS, FWACP, FMCPaed, FRCPCH (UK), Cert. ORT (Oxford), MSc (Religious Education),
Professor of Child Health and Neonatology, University of Benin, Benin City, Nigeria and
Consultant Paediatrician and Neonatologist, University of Benin Teaching Hospital, Benin City, Nigeria.
UNICEF-Trained BFHI Master Trainer and ICDC-Trained in Code Implementation.
*Technical Expert/ Consultant on the FMOH-UNICEF-NAFDAC Code Implementation Project in Nigeria.
*No Competing Interests.
Competing interests: No competing interests