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A long and healthy life for all South Africans
National Department of Health
SAAHIP: Northern Gauteng
The quandary of pharmacotherapy for COVID-19 and the needfor rapid and transparent decision-making to inform COVID-19Guidelines
Trudy Leong and Andy Gray
National Department of Health, Essential Drugs Programme
15 October 2020
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Universal Health Coverage
Essential medicines
Health Technologies
One of the cornerstones of UHC is access to essential health technologies (safe, effective, quality, affordable)
- within an efficient healthcare system
In vitro diagnostic devices
Medical devices
Essentialequipment
Back in January 2020
WHO definition of UHC, https://www.who.int/health-topics/universal-health-coverage#tab=tab_1
Universal health coverage (UHC) is definedas “all people receiving quality healthservices that meet their needs withoutbeing exposed to financial hardship inpaying for the services”. Given resourceconstraints, this does not entail all possibleservices, but a comprehensive range of keyservices that is well aligned with othersocial goals
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Challenges facing UHC
TEN LEADING CAUSES OF INEFFICIENCIES:1. Medicines: underuse of generics and higher than necessary prices for medicines2. Medicines: use of substandard and counterfeit medicines3. Medicines: inappropriate and ineffective use4. Health-care products and services: overuse or supply of equipment, investigations and procedures5. Health workers: inappropriate or costly staff mix, unmotivated workers.
WHO world health report for financing of UHC, 2010
6. Health-care services: inappropriate hospital admissions and length of stay7. Health-care services: inappropriate hospital size (low use of infrastructure)
https://apps.who.int/iris/bitstream/handle/10665/44371/9789241564021_eng.pdf;jsessionid=A0020CB8374299DD0305F9409C575882?sequence=1
8. Health-care services: medical errors and suboptimal quality of care 9. Health system leakages: waste, corruption and fraud10. Health interventions: inefficient mix/ inappropriate level of strategies
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Health Technology Assessment I Health Compact
Presidential Health Summit Compact 2018
Stakeholder Agreement to strengthen the South African health system towards an integrated and unified health system, based on nine pillars
https://www.gov.za/documents/presidential‐health‐summit‐report‐9‐jan‐2018‐0000
Critical review of quality improvement in South Africa’s healthcare.
• “Decline in quality health care has caused the publicto lose trust in the healthcare system in South Africa”
• “…many quality improvement programmes[implemented], but did not produce the required levelof quality service delivery…”
• … “achieving a lasting quality improvement system inhealth care seems to be an arduous challenge”
Maphumulo et al, 2019 May 29;42(1):e1-e9.
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And then March 2020 dawned on us …
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COVID-19 changed the world…
• Patient ZERO registered in China on the 31st
of December 2019 in Wuhan China
• Disease then spread to all countries in the
world
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Case 1 32,683 493,183 683,242March 5, 2020 May 31, 2020 July 31, 2020 October 6, 2020
May 31, 2020 July 31, 2020 October 6, 2020
683 8,005 17,103
World Health Organization declares Covid‐19 a pandemic
March 11, 2020
South Africa President declares National State of
DisasterMarch 15, 2020
South Africa starts the National lockdown
March 27, 2020
COVID-19Casesregistered
COVID-19 Deaths registered
And had an impact on South Africa
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COVID-19 Response
• The COVID-19 pandemic has been devastating around the world and hasexposed some serious structural flaws in our response.
• Michael Lauer (from the US National Institutes of Health) stated that“[Research] is on full thrust. There's a tremendous amount of amazing workgoing on…..The rapidity with which new information, new data becomesavailable, new studies become published...is quite impressive. In somerespects, it's like something that we've never seen“
• COVID-19 has also exposed ways where clinical trial design, conduct, andreporting could be improved
• Some publications have been retracted following concerns raised regardingdata reliability
• Much of the trials are observational, subject to bias and confounding, or fromRCTs with limitations
• Preliminary RCT results may also be reversed as more data becomesavailable.
van Dorn A. Lancet. 2020 Aug 22;396(10250):523-524.
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Rapidly evolving evidence
338 Systematic
reviews
COVID-19 EVIDENCE: Prevention or treatment
5497 Primary studies (190
reported results)
238 Broad syntheses (e.g.
guidelines)
Global pandemic Evidence is rapidly evolving
Need to reliably speed up evidence synthesis
6073 articles
https://www.epistemonikos.org/
Research map of ALL clinical trials for COVID-19 (1780 trials; 994 trials recruiting patients):
Living map accessed on 8 October 2020 @ 10:25am https://covid-nma.com/
Living map of evidence: 8 October 2020 @ 10:25am
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South African COVID-19 response
Version 1 – March
2020
Version 2 –19 March
2020
Version 3 –27 March
2020
Version 4 –18 May
2020
Version 5 –24 August
2020
• MARCH 5, 2020: SouthAfrica reports its firstconfirmed COVID-19 case (atraveller)
• NDoH/NICD developedGuidelines for the clinicalmanagement of confirmedand suspected COVID-19patients, with continuousupdates
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Evidence-based medicine policy recommendations
Recommendations for use in COVID-19::
Guidelines:“….. Many medicines are being used based on invitro and observational data, such as vitamin D,vitamin C, beta-2-agonists and statins. None ofthese are currently recommended for theprevention or treatment of Covid-19, and some maydo more harm than good….”
NDoH/NICD Guidelines v5.0
RCT Evidence:“……Conclusion: The addition of high-doseintravenous vitamin C may provide a protectiveclinical effect without any adverse events incritically ill patients with COVID-19”.
Zhang et al, Research Square Preprint , 2020
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Vitamin C Infusion
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What is your recommendation?
QUESTION:Further to reviewing the abstract, should high dose IV vitamin C be recommended for critically illpatients with COVID-19?
• A poll will be conducted to obtain your opinion
• Followed by a short YouTube clip on Evidence Based Medicine
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Incidence of clinical improvement at D7: Vitamin C vs placebo
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All-cause mortality D14-28: Vitamin C vs placebo
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Time to death: Vitamin C vs placebo
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• Trial registered on ClinicalTrials.gov (ID: NCT04264533) beforepatient recruitment
• Intervention and control treatments same in the register & report• Primary outcome was the same: Ventilation-free/ IMV-free
days in 28 days• Some secondary outcomes did not correlate between the
register vs report
• Preprints are preliminary reports that have notundergone peer review
• They should not be considered conclusive, used toinform clinical practice, or referenced by the media asvalidated information
Critical appraisal
The study was terminated early (underpowered)"With the control of the epidemic, this trial was stopped early, and the number of qualifying COVID-19 patients did not satisfy the anticipated sample size(140)"
High risk of bias:• Randomisation: The allocation was probably not concealed"Each ICU was assigned with an independent random numeric table generated by
Microsoft Excel 2019 by the primary investigator alone. Each table had equal numbers of 1 and 2, which represented the placebo group (bacteriostatic water
infusion) and treatment group (HDIVC), respectively. Participants were enrolled in the corresponding group in an orderly manner.“
• Selection of the reported results: The protocol and statistical analysis plan were not available. Secondary outcomes reported in the registry was not reported in the preprint and vice versa.
Declarations: NoneFunding: Science and Technology Department of Hubei Province, and the Fundamental Research Funds for the Central Universities
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NEMLC
National Essential Medicines List Committee (NEMLC):
1. A non-statutory, advisory Committee appointed by the Minister of
Health, with four technical Expert Review Committees
2. Responsible for the development and management of the national EML
and Standard Treatment Guidelines (STGs)
3. Medicine selection is based on principles of equity and evidence-based
medicine and considers public health relevance, safety, effectiveness,
cost, affordability of the intervention and implications for practice
4. The review process involves extensive peer review with stakeholder
collaboration and is iterative - a typical review cycle is 2 to 3 years
5. Good governance is maintained throughout the review process
NEMLCNEMLC
PHCPHC Hospital Adult
Hospital Adult
Hospital PaediatricHospital Paediatric TertiaryTertiary
For the rational use of medicines in South Africa in accordance with the WHO Essential Medicines concept
EML satisfies the priority health care needs of the population
STG is an implementation mechanism of the EML
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NEMLC COVID-19 Subcommittee
NEMLC COVID-19 Subcommittee
NEMLC Recommendations (19 March 2020):• Subcommittee to provide input on therapeutics for the
clinical management of COVID-19• Recommendations inform guidelines and procurement• Review process adapted: virtual, real-time review
NEMLC Recommendations (19 March 2020):• Subcommittee to provide input on therapeutics for the
clinical management of COVID-19• Recommendations inform guidelines and procurement• Review process adapted: virtual, real-time review
Subcommittee established & developed:• Terms of Reference (TOR) - dynamic• Protocol template for rapid reviews - dynamic• Templates for PICO and rapid review report - dynamic
Available on the NDoH website:http://www.health.gov.za/index.php/national‐essential‐medicine‐list‐committee‐nemlc/category/633‐covid‐19‐rapid‐reviews
Communication pathways
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Why rapid reviews?
Universal Health Access
Need for quick decisions to guide procurement in the
context of a rapidly expanding global pandemic with
global demands on medicine supply.
• “…a streamlined approach to synthesising evidencein a timely manner - typically for the purpose ofinforming emergent decisions faced by decisionmakers in health care settings.” (Khangura, 2012)
• “Components of the systematic review process aresimplified or omitted to produce information in a shortperiod of time”
• “…a streamlined approach to synthesising evidencein a timely manner - typically for the purpose ofinforming emergent decisions faced by decisionmakers in health care settings.” (Khangura, 2012)
• “Components of the systematic review process aresimplified or omitted to produce information in a shortperiod of time”
Rapid review
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Narrative review
Scoping review
Rapid review
Systematic review & Meta‐analysis
HTA
Rapid reviews in context
Confidence and level of effort (time)
Narrative review
Scoping review
Rapid review
Systematic review
Metaanalysis
HTA
Others……..
CONFIDEN
CE
LEVEL OF EFFORT
high
lowhigh
12 months to years
Weeks to months
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Rapid review process
Steps in conducting a rapid review Key principles:
Rapid review report disseminated and emerging evidence monitored
Final rapid review report shared with Guideline Committee, MAC
Subcommittee re-iteratively reviews report - finalizes report with a recommendation
Review team submits draft report within 1 week of PICO approval
Review team identified and PICO question confirmed
Research question received & prioritised • #1 Transparency
• #2 Avoid bias
• #3 Ask good questions (PICO format)
• #4 Ensure good governance
• #5 Consensus process using an evidence to decision framework to make a recommendation
• #6 Meet delivery timeline
• #7 Continuous updates as evidence evolves
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Evidence To Decision framework I Example: remdesivir
EvidenceEvidence Other value judgementsOther value judgements Resource useResource use
What is the quality of the evidence? • Three small RCTs• 2 terminated early, underpowered• Meta-analysis of 3 RCTs (composite
outcome)
What is the evidence of benefit? • No impact on mortality• Shortened hospital stay (11 vs 15 days)
Do the benefits outweigh the harms? • No increased risk adverse events
Feasibility: can the recommendation be implemented? • Unregistered medicine• Limited supply globallyValues, preferences and acceptability?• No data, but likely to be valued and
acceptable by patients and healthcare workers
Equity and human rights? • Likely to have an impact on health
inequity
How large are the resource requirements?
Direct price of technology?• UnaffordableAdditional resources? • Laboratory monitoring required
Note: • Recommendation (strong/ conditional) is
agreed by consensus• The above‐mentioned factors influence
the direction and strength of the recommendation
Rapid Review of Remdesivir for COVID-19 Update; 24June2020 – accessible at: http://www.health.gov.za/index.php/national-essential-medicine-list-committee-nemlc/category/633-covid-19-rapid-reviews
24Evidence brief developed by NEMLC Subcommittee members
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Update of Remdesivir rapid review, pending
With the continuous monitoring of:• living maps, • clinical trial registries, and• COVID‐19 evidence alerts.
NEJM article, 8 October 2020 ‐ Final report of the ACTT‐1 study of remdesivir vs placebo waspublished.
Third update of the rapid review is currently underway.Initial review – 16 April 2020Second review (update) – 24 June 2020Third review (update) – 29 September 2020Fourth review (update) – pending
26Evidence brief developed by NEMLC Subcommittee members
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Update of Corticosteroid rapid review, pending
With the continuous monitoring of:• living maps, • clinical trial registries, and• COVID‐19 evidence alerts.
JAMA article of a prospective meta‐analysis was identified (September 2020): estimates 28‐day all‐cause mortality of corticosteroids (dexamethasone, hydrocortisone, methylprednisolone) vs usual care or placebo, amongst critically ill hospitalised adult COVID‐19 patients.
Second update of the rapid review is currently underway. Initial review – 23 June 2020Second review (update) – 6 August 2020Third review (update) ‐ underway
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Rapid reviews
CompletedCompleted In ProcessIn Process Going forwardGoing forward
• IVIG, 8 April • Tocilizumab, 15 April • Chloroquine/Hydroxychloroquine, 19 April• Remdesivir + 2 updates, 29 Sep• LPV/r, 22 April • Azithromycin, 11 May • BCG (prophylaxis), 27 May• Convalescent plasma, 19 June• Chloroquine prophylaxis, 18 June• Favipiravir, 25 June• Corticosteroids +1st update, 6 August• Interferon + 1st update, 31 July• Colchicine, 6 August• Heparin dosing for VTE + 1st update, 3 Sep
• Corticosteroids update
• Remdesivir update
• Colchicine update
• Chloroquine/Hydroxychloroquine, update
• COVID-19 Vaccine (in collaboration with NAGI and MRC)
Note: • Reviews are date stamped to identify updates• Reviews are published in an open access repository, on the NDoH website
http://www.health.gov.za/index.php/national‐essential‐medicine‐list‐committee‐nemlc/category/633‐covid‐19‐rapid‐reviews
• Links to the rapid reviews have also been included on the ffg. Websites:• NICD• SAHPRA
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Rapid reviews I Challenges
• Evidence evolves rapidly
• Recommendations are required urgently, sometimes before peer-reviewed publications
• Limited RCT data – much of the evidence is observational
• No local data yet
• Tight timelines and competing demands
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References
• WHO definition of UHC, https://www.who.int/health-topics/universal-health-coverage#tab=tab_1
• https://www.gov.za/documents/presidential-health-summit-report-9-jan-2018-0000
• https://covid-nma.com/
• https://apps.who.int/iris/bitstream/handle/10665/44371/9789241564021_eng.pdf;jsessionid=A0020CB8374299DD0305F9409C575882?sequence=1
• https://protect-za.mimecast.com/s/RnNgCElvGJf3EWAVTNeKU0?domain=dailymaverick.co.za
• https://www.iol.co.za/news/south-africa/sa-hospitals-stance-on-the-controversial-hydroxychloroquine-drug-as-covid-19-treatment-64ec87fc-6821-4b31-b631-
d427b37919ac
• https://bhekisisa.org/health-news-south-africa/2020-08-19-will-sa-buy-this-covid-drug-for-thousands-per-person-if-it-costs-less-than-r200-to-make/
• https://time.com/5840148/coronavirus-cure-covid-organic-madagascar/
• http://www.health.gov.za/index.php/national-essential-medicine-list-committee-nemlc/category/633-covid-19-rapid-reviews
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Acknowledgements
• National Essential Medicines List Committee, specifically the COVID-19 Sub-
Committee
• Reviewing teams for the COVID-19 rapid reports - including NEMLC Members,
NEMLC Expert Review Committee members and GRADE-SA Network
• Global Health Supply Chain – Technical Assistance, assisted with the slides
