Having been focused on manufacturing challenges for most of 2020, taking a time out to think about how best to garner "new prior knowledge" needed to facilitate development of evidence for repurposing option for the SARS-COV-2 cases and COVID-19 disease.

1. The 2020 chaos
and validity of
scientific
evidence
Ajaz S. Hussain, Ph.D.
WWW.LINKEDIN.COM/IN/AJAZSHUSSAIN
11/12/2020 Ajaz | Insights 1

2. Current
interests from
multiple
viewpoints
• The National Institute for Pharmaceutical
Technology & Education, Inc. or NIPTE to build an
academic “third leg of the stool”
• Life more broadly – adult development and
professional development
• From a tenured academic position in 1994 to
several visiting professorships
• US FDA negotiator (quality topics) at ICH in 2005
to training regulators at several agencies around
the globe
• VP/Global Head/Chief Scientific Officer – Complex
generics & biosimilars (Sandoz/Novartis and
Wockhardt) and Tobacco (based) vaccines and
MRTPs –iQOS® (Philip Morris International)
• Advisor, mentor to CEO’s and MD’s and students
11/12/2020 Ajaz | Insights 2

3. “Third leg of the stool” and Adult
Development: A grand challenge
• “To Err is Human” (IOM 1999) to a new, comprehensive
vision of professional development is needed . . .
“Redesigning Continuing Education (CE) in the Health
Professions” (IOM 2009),…..
• There are major flaws in the way CE is conducted,
financed, regulated, and evaluated.
• Focus on meeting regulatory requirements rather than
identifying personal knowledge gaps
• Regulatory organizations that oversee tend not to look
beyond setting and enforcing minimal, narrowly
defined competencies
• A new, comprehensive vision of professional
development is needed . . .
• Broadly – the justice system is considered the
“third leg” to keep in check the executive and
legislative branches; but justice takes time and
in the “experience economy” with fake news we
confront a grand challenge
3

4. Ajaz | Insights 11/12/2020 4

5. Hypothetical
“repurpose” project
justification and
evidence: Melatonin
or cyclosporin
(illustrative scenario
for this discussion)
11/12/2020 5
Ajaz | Insights

6. Repurposing, “New Prior
Knowledge” & Maturity of
Socio-technical Systems
11/12/2020 Ajaz | Insights 6
Figure: Network-based measurement of disease manifestations associated with COVID-19.
From: Zhou Y, Hou Y, Shen J, Mehra R, Kallianpur A, Culver DA, et al. (2020) A network
medicine approach to investigation and population-based validation of disease
manifestations and drug repurposing for COVID-19. PLoS Biol 18(11): e3000970.
https://doi.org/10.1371/journal.pbio.3000970

7. 11/12/2020 Ajaz | Insights 7
Public Health
Method validation: Calibration, repeatability & reproducibility
Accuracy (false positive/negative)

8. “Adequate and well-controlled”
investigations are further
defined in 21 CFR 314.126.
“evidence consisting of adequate and well-controlled investigations, including clinical
investigations, by experts qualified by scientific training and experience to evaluate the
effectiveness of the drug involved, on the basis of which it could fairly and responsibly
be concluded by such experts that the drug will have the effect it purports or is
represented to have under the conditions of use prescribed, recommended, or
suggested in the labeling or proposed labeling thereof.” The FD&C Act
11/12/2020 Ajaz | Insights 8

9. Daubert v. Merrell
Dow
Pharmaceuticals,
Inc.
Atomization
Conflating Admissibility
with Sufficiency
Credibility
Ajaz | Insights 9

10. Weight of, and Totality of
Evidence for the Real-world
Evidence: Fairly and responsibly be concluded by such experts that the
drug will have the effect it purports or is represented to have under the
conditions of use prescribed, recommended, or suggested in the
labeling or proposed labeling thereof.
11/12/2020 Ajaz | Insights 10

11. 11/12/2020 Ajaz | Insights 11
(Multiple Review Cycles – Delays)
What questions need to be answered?
How sure/confident one needs to be?
What assumptions are accepted?

12. In uncertainty current
thinking changes
expectations
• FDA Guidances to support the accelerate
development of prevention and treatment options
for COVID-19
• COVID-19 Public Health Emergency: General
Considerations for Pre-IND (Investigational New
Drug application) Meeting Requests for
COVID-19 Related Drugs and Biological
Products
• COVID-19: Developing Drugs and Biologics
for Treatment or Prevention
• Guidance on Conduct of Clinical Trials for
Medical Products during COVID-19
Pandemic.
• FDA Emergency Use Authorization
Information and list of all current EUAs

13. Why in the year 2020
we are experiencing
chaos and struggling
to assure validity of
scientific evidence?
Ajaz | Insights 11/12/2020 13
HTTPS://WWW.CPHI.COM/CONTENT/DAM/INFORMA/CPHI/EN
/CPHI-INSIGHTS/HLN19-CPHI%20INSIGHTS-2019-
INDUSTRY-REPORT.PDF
Ajaz S. Hussain. Chaos to Continual Improvement

14. Ajaz | Insights 11/12/2020 14
Cyclosporin A inhibits the replication of diverse coronaviruses. J
Gen Virol. 2011 Nov; 92(Pt 11): 2542–2548.
Cyclosporine has a potential role in the treatment of SARS.
J Infect. 2013 Jul; 67(1): 84–85.
Melatonin usage (odds ratio [OR] = 0.72, 95% CI 0.56–0.91)
significantly associated with a 28% (52% in African
Americans) reduced likelihood of a positive laboratory test
result for SARS-CoV-2. Zhou Y, Hou Y, Shen J, Mehra R,
Kallianpur A, Culver DA, et al. (2020) PLoS Biol 18(11):
e3000970. https://doi.org/10.1371/journal.pbio.3000970

15. 11/12/2020 Ajaz | Insights 15
Sars-Cov-2 infected cases or COVID-19 patients
Test Based vs. Symptom Based Strategy?
Variable risk with age, comorbities, better than placebo?
Assumption of validity of test methods and health records?

16. HTTPS://WWW.PMISCIENCE.COM/RESOURCES/DOCS/DEFAULT-SOURCE/LIBRARY-DOCUMENTS/PMI_SCIENTIFIC_UPDATE_SEPT_2016_0.PDF
Expectation Management
11/12/2020 Ajaz | Insights 16

17. HTTPS://WWW.PMISCIENCE.COM/RESOURCES/DOCS/DEFAULT-SOURCE/LIBRARY-DOCUMENTS/PMI_SCIENTIFIC_UPDATE_SEPT_2016_0.PDF
11/12/2020 Ajaz | Insights 17

18. 11/12/2020 Ajaz | Insights 18

19. 11/12/2020 Ajaz | Insights 19
Sars-Cov-2 infected population,
COVID-19 patients, or patients on Rx CsA?
Reduction in likelihood of “cases” to
COVID-19, disease progression and/or
mortality?
Off-label (Physician judgment)
Right to Use
Emergency Use
NDA (505(b)(2)/BLA

21. Additional informaiton
Related to illustrative scenario generated for this discussion
11/12/2020 Ajaz | Insights 21

22. 2352 Studies found for: Therapy | Covid19
11/9/2020 HTTPS://CLINICALTRIALS.GOV/CT2/RESULTS/MAP?TERM=THERAPY&COND=COVID19&MAP=
11/12/2020 Ajaz | Insights 22

23. CYCLOSPORIN
HTTPS://CLINICALTRIALS.GOV/CT2/RESULTS/MAP?TERM=CYCLOSPORIN&COND=COVID19&MAP=
11/12/2020 Ajaz | Insights 23

24. Cyclosporine has
a potential role
in the treatment
of SARS.
J Infect. 2013 Jul;
67(1): 84–85.
• “there is tantalizing in vitro evidence
for cyclosporine as an anti-
coronavirus agent, as well as having
a potential disease-modifying role in
SARS through the inhibition of virus-
mediated IL-2 induction.”
11/12/2020 Ajaz | Insights 24

25. Cyclosporin A inhibits
the replication of
diverse coronaviruses.
J Gen Virol. 2011 Nov;
92(Pt 11): 2542–2548.
• “Low micromolar, non-cytotoxic
concentrations of cyclosporin A (CsA)
strongly affected the replication of severe
acute respiratory syndrome coronavirus
(SARS-CoV), human coronavirus 229E and
mouse hepatitis virus in cell culture, as was
evident from the strong inhibition of GFP
reporter gene expression and a reduction of
up to 4 logs in progeny titres. Upon high-
multiplicity infection, CsA treatment
rendered SARS-CoV RNA and protein
synthesis almost undetectable, suggesting
an early block in replication.”
11/12/2020 Ajaz | Insights 25

26. Cyclosporin:
Indications,
Contraindications,
and Warnings
Ajaz | Insights
11/12/2020
• Kidney, Liver, and Heart Transplantation
• Rheumatoid Arthritis
• Psoriasis
• Contraindications
• Warnings
• Boxed Warning
• Only physicians experienced in management of systemic
immunosuppressive therapy for the indicated disease should prescribe
Cyclosporine Oral Solution USP MODIFIED. At doses used in solid organ
transplantation, only physicians experienced in immunosuppressive
therapy and management of organ transplant recipients should prescribe
Cyclosporine Oral Solution USP MODIFIED. Patients receiving the drug
should be managed in facilities equipped and staffed with adequate
laboratory and supportive medical resources. The physician responsible
for maintenance therapy should have complete information requisite for
the follow-up of the patient.
• Cyclosporine Oral Solution USP MODIFIED, a systemic
immunosuppressant, may increase the susceptibility to infection and the
development of neoplasia.
26

27. Evidence for
repurposing CsA
for Sars-Cov-2
infections and/or
COVID-19 disease?
• Off-label prescription by any licensed
physician (see Boxed Warning)
• Right-to-Use?
• Emergency Use Authorization?
• NDA, 505(b)(2)?
Ajaz | Insights
11/12/2020 27

28. Question: Does
cyclosporine added to
standard treatment of
hospitalized patients
with COVID19
infection improve their
prognosis? NCT04392531
• Arms and Interventions
• Group A (control) to receive “standard treatment”
according to hospital standard of care protocol.
• Group B cyclosporine added to the “standard
treatment”
• Primary Outcome
• “reducing the severity of COVID19 infection in
hospitalized patients”
• Secondary Outcomes
• Mortality Rate, Number of Days in hospital,
Number of days in ICU beds, ….
• Change in CRP, ferritin, …, D Dimer, IL-6, ….., Viral
Load, specific antibodies
• Randomized parallel assignment, open label
• 120 participants
11/12/2020 Ajaz | Insights 28

29. Prevention of
Cytokine Release
Syndrome (CRS) With
Cyclosporine in
Patients with
Moderate COVID-19
(Phase I) NCT04412785
(recruiting, University of
Pennsylvania, estimated
completion December 2021)
• Question: Is CSA “safe” in COVID-19 patient population requiring
oxygen supplementation but not requiring ventilator support
• Primary outcome: Safety will be measured by assessing (a) the
proportion of participants requiring increase in oxygen
requirements, transfer to intensive care unit, and/or
mechanical ventilation, (b) changes in absolute lymphocyte
counts, (c) changes in creatinine clearance, and (d) incidence of
secondary bacterial infections complicating COVID-19
hospitalization
• Question: Does CsA exhibit antiviral and anti-cytokine effects as
measured in laboratory tests?
• Secondary outcomes: SARS-CoV-2 clearance (PCR negativity) at
Days 7 and 14 by deep nasal swab, and laboratory correlatives
of CRS/ Hemophagocytic lymphohistiocytosis (D-dimer,
ferritin, and IL-6)
• How sure/confident?
• 20 patients admitted to hospital with laboratory confirmation
of SARS-CoV-2 infection (see inclusion/exclusion criteria),
open label.
• What assumptions accepted?
• ?

30. Other CsA
related
questions
posed
• NCT04540926: Utility of Low Doses of
Corticosteroids and Cyclosporine Combined With
Enoxaparin, in Patients With COVID-19 Pneumonia
at the ISSSTE Regional Hospital, Puebla, During the
Contingency Period Due to the SARS-Cov2 Pandemic
• NCT04451239: Combined Topical Corticosteroid and
Topical Cyclosporine-A for Management of COVID-
19 Keratoconjunctivitis; a Pilot Study
• NCT04420364: Maintenance Versus Reduction of
Immunosuppression for Renal Transplant Patients
Hospitalized With COVID-19 Disease
• NCT04569851: Clinical Characteristics and
Prognostic Factors of Patients With COVID-19 Using
Big Data and Artificial Intelligence Techniques
(BigCoviData)
Ajaz | Insights
11/12/2020 30

31. Melatonin effects - circadian
rhythm and cell protection due to
its anti-inflammatory and
antioxidative effects.
Studies found for: Melatonin | COVID-19
HTTPS://CLINICALTRIALS.GOV/CT2/RESULTS/MAP?TERM=ME
LATONIN&COND=COVID-19&MAP=
3
1
11/12/2020
Ajaz | Insights

32. Melatonin -
circadian rhythm
and cell
protection due to
its anti-
inflammatory
and antioxidative
effects
• NCT04474483 State University of New York at
Buffalo: Pilot Phase II randomized, double-
blind, placebo-controlled clinical trial to
evaluate safety and efficacy of melatonin (10
mg dose three times a day for 14 days) in
outpatient adult patients suspected to be
afflicted with COVID-19.
• Primary outcome measure: Cumulative
Incidence of Treatment-Emergent Adverse
Events [ Time Frame: 28 days ]
• Secondary outcome measures:
Hospitalization, COVID-19 related
symptoms and rate of resolution, 28-day
mortality.