BCG Vaccine
Health Impact Profile
Diabetes Care Industry
May 2020
Confidential
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BCG Impact Profile
Diabetes Care Industry

Health Impact Score: 6.8/10

Description
The Bacillus Calmette–Guérin (BCG) vaccine
is a tuberculosis immunization that has been widely
administered since its discovery in the 1920s. It is currently
being studied for an additional application in Type 1
Diabetes treatment. The clinical trials use the Tokyo172 strain of BCG in a treatment regimen of one
annual dose of the vaccine and at a cost of $200.

Research
Facility

The Faustman Lab at
Massachusetts General Hospital

Name of Study

Repeat BCG Vaccinations for theTreatment of Established Type 1
Diabetes.

Trial Status

Phase I Completed, Phase II
Currently Underway

FDA
Application

BCG Tokyo-172 Strain –Investigational New Drug
Application (IND) for Type 1
Diabetes Phase II Trials

Websitehttps://www.faustmanlab.org/

1 - Low

Industry, Innovation and Infrastructure

Reduced Inequalities

10 - HighBoundless Analysis▶

The analysis compared the Phase I clinical findings for BCG(Tokyo-172 strain) in addition to insulin therapy alone,
across available administration devices including syringebased injection, pen-based injection, and insulin pump.

▶

Boundless scores BCG 6.8/10 per patient impact for its
public health and socioeconomic benefits. The HealthImpact Score is based on performance indicators such as
Invasiveness, Efficacy, Quality Adjusted Life Years (QALYs)
gained, Severe Complications and Cost Savings. The scorerationale can be found in Appendix C.

▶

Across all metrics considered, BCG inclusive therapies
outperformed regimens that include insulin alone. Basedon encouraging Phase I results, BCG has the rare potential
to both improve clinical outcomes relative to the current
standard of care, and simultaneously reduce systemic costs
for Type 1 Diabetes care.

▶

If approved, BCG can deliver significant cost savings forpatients and payers. A 50% reduction in insulin
requirements reduces the annual cost of Type 1 Diabetes
care by more than 15%.

▶

A reduction in the risk of severe hypoglycemic events
accounts for additional savings, considering the cost of
inpatient care and glucagon for emergency self-treatment.

▶

In a five-year trial, BCG achieved a 1.18% reduction in
Hemoglobin A1C compared to the Type 1 Diabetes
control group, which experienced a reduction of 0.03%.

▶

BCG also had zero reported hypoglycemic events for theentire duration of the Phase I clinical trial. Multiple studies
have established the risk of death from hypoglycemia,
separately finding that 4-10% of people with Type 1
Diabetes die from severe hypoglycemic events despite
insulin therapy.

Alignment with SDGs
Good Health and Well-Being

Per Unit Impact(REFERENCE: https://care.diabetesjournals.org/content/35/9/1814)

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Lead Scientist▶ Denise Faustman, MD, PhD – Dr. Faustman is Director of the Immunobiology Laboratory at the Massachusetts General

Hospital (MGH) and an Associate Professor of Medicine at Harvard Medical School. She is currently leading a human clinical
trial program testing the efficacy of the BCG vaccine for reversal of long-term Type 1 Diabetes. Her research accomplishments
include the first scientific description of modifying donor tissue antigens to change their foreignness, the identification ofinterrupted T cell education through MHC class I, and the identification of autoimmune T cell sensitivity to TNF. These
achievements have earned her awards including the National Institutes of Health and National Library of Medicine’s “Changing
the Face of Medicine Award” as one of 300 American physicians (one of 35 in research) honored for seminal scientificachievements in the United States, the “Oprah Achievement Award” for “Top Health Breakthrough by a Female Scientist,”
and the “Women in Science Award” from the American Medical Women’s Association and Wyeth Pharmaceutical Company
for contributions to autoimmune disease research. Dr. Faustman has been senior author on over 100 peer-reviewed papers,
and her research has been highlighted in publications including Science, Nature, The Wall Street Journal, The New York Times,
Los Angeles Times, The London Financial Times and Scientific American. She earned her MD and PhD from Washington
University School of Medicine, in St. Louis, Missouri, and completed her internship, residency, and fellowships in Internal
Medicine and Endocrinology at the Massachusetts General Hospital.

BCG Clinical Trials
Clinical traits of the Phase I clinical trial participants, across the three cohorts:n%FemaleAge

Average Age of
Onset

Years Since
Diagnosis

BCG - T1D

944

45 ± 326 ± 419 ± 3

Placebo - T1D

30

49 ± 329 ± 320 ± 3

Reference - T1D4047

40 ± 226 ± 213 ± 1p-value (BCG - T1D vs Placebo - T1D)

0.51

0.64

0.93

p-value (BCG - T1D vs Reference - T1D)

0.11

0.99

0.05

p-value (Placebo - T1D vs Reference - T1D)

7

0.53

0.15

Clinical trial results for BCG treatment, placebo treatment and reference/control groups:
HbA1c (%)
T1D BCG Treated
T1D Placebo Treated
T1D Reference Population
p-value
BCG vs Placebo
BCG vs Reference
Placebo vs ReferenceYear 07.36 ± 0.44
7.10 ± 0.55
7.08 ± 0.07

Year 5
6.18 ± 0.34
7.07 ± 0.41
7.33 ± 0.17

Year 6
6.44 ± 0.34
7.18 ± 0.62

Year 7
6.25 ± 0.26
7.17 ± 0.46

Year 86.65 ± 0.36
7.22 ± 0.38

p=0.02p=0.02p=0.73p=0.02p=0.0008

p=0.0002

Technology▶ Bacillus Calmette–Guérin (BCG) vaccine was first introduced in 1921 as a tuberculosis (TB) immunization. It is still widely

administered in many countries almost 100 years after its initial use and is included on the World Health Organization’s Listof Essential Medicines.

▶ In addition to its primary use for TB prevention, BCG (in the form of an infusion) has also been the standard treatment
option for bladder cancer patients since 1977.

▶ BCG is currently being evaluated for new applications in Type 1 Diabetes. Phase I human clinical trials were completed at
Massachusetts General Hospital to assess safety and findings were published in 2012.

▶ Phase II trials began in 2019 and include 150 patients. The primary readout of clinical findings is expected in 2023.

Operations▶ Massachusetts General Hospital is located in Boston and is the largest teaching hospital affiliated with Harvard Medical
School. Its research program is the largest in the world.

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Health Highlights
Summarized below are most relevant impact categories and codes that refer to the United Nation’s Sustainable
Development Goals (SDGs). The associated metrics highlight the most important factors that explain how this technology isimpacting healthcare.

Patient Cost Savings

Patient cost savings are measured as a reduction in direct medical costs to patients, including insulin
therapy, administration devices, inpatient and outpatient care and pharmacy expenses. The cost ofcare for Type 1 Diabetes outcomes and comorbidities is considered on a risk-adjusted basis.
Promoting effective, low-cost interventions, when available, can reduce the overall cost burden of
Type 1 Diabetes care.
Relevant code: SDG 3

Quality Adjusted Life-Year (QALY)The number of healthy life years gained for therapies that include BCG compared to insulin alone.
Funding for clinical trials is a scarce resource that must be allocated to treatment options that havethe potential to generate impactful outcomes if approved. Reducing HbA1c in a safe mannertranslates into an improved quality of life and additional life-years. Regained life-years reduce thedifference in life-span between a healthy patient and one diagnosed with Type 1 Diabetes.
Relevant code: SDG 3

Expanding Access to Care Through Innovation

The average annual cost of Type 1 Diabetes care is roughly $18,000, a price which many uninsured
individuals and low-income community members cannot afford. As a result, a sizable share of people
with Type 1 Diabetes resort to insulin rationing, the practice of taking less insulin than required,increasing the risk for high blood glucose and ketoacidosis. Interventions that reduce daily insulin
requirements safely can decrease the prevalence of this dangerous practice, and reduce the impactof economic inequality among people with Type 1 Diabetes.
Relevant codes: SDG 9 SDG 10

Clinical Improvements

Hemoglobin A1c is the primary measure of blood glucose control in a clinical setting, offeringsignificant insight into the overall state of a patient’s management of Type 1 Diabetes. While there
are several ways to reduce HbA1c, methods involving the increase of the insulin dosages potentiallylead to a higher risk for severe hypoglycemia, both a dangerous and costly consequence. Novelinterventions that demonstrate efficacy without daunting side-effects can improve the clinicalmanagement of Type 1 Diabetes and become a core element of the new standard of care.
Relevant code: SDG 3

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Benchmarking and Conclusions

The present spider chart depicts the performance of BCG against traditional insulin therapies from 1 (worst) to 10 (best). The
values are obtained by comparing the average of each resulting HKPIs for the company against its comparable treatments aswell as a baseline of not having diabetes at all (10 out of 10). The scope of this study includes Phase I trial results for BCG
treatment compared to the placebo treatment group and broader population of Type 1 Diabetes patients that do not receive
BCG. These early clinical findings stand in place of future results of Phase II trials, as the focus of this report is to determine thepotential health benefits of funding additional research for BCG as a Type 1 Diabetes treatment. The potential health benefitsof BCG are significant. Typically, new treatment options represent a tradeoff between an improvement in the standard of care
at a higher cost. Considering the dire need to reduce systemic healthcare costs, BCG could fulfill this objective affordably andwithout sacrificing the quality of care.
To determine the socioeconomic benefits conferred by BCG, we examined Quality Adjusted Life-Years (QALY’s) gained andpayer cost savings. Examining the impact of BCG on HbA1c and severe hypoglycemia, the two factors contributed 0.5482 and
0.1700 QALYs respectively, totaling 0.7182 QALYs by year 5. The placebo group, serving as proxy for conventional insulin
therapy, only gained 0.0002 QALYs by year five. The cost and savings associated with BCG inclusive treatments were also
assessed. A model was constructed using pricing and patient-level spending on insulin, non-insulin pharmacy and medical care.
Considering these factors, BCG projects sizable cost savings relative to the current standard of care. The inclusion of BCG andassociated 50% reduction in insulin requirements resulted in savings of 16.5% - 22.2% at the patient level, across the threetreatments examined. Hypoglycemia was included on a risk adjusted basis, assuming a conservative 30% decline for BCG
treatment relative to the broader Type 1 Diabetes patient population. At the payer level, this risk reduction is meaningful, as asingle event requiring hospitalization can cost $16,000, almost doubling the cost of annual care for a patient.
High levels of glucose in the blood can have a multitude of negative effects in the body, especially in blood vessels, which
increases the risk of heart disease and stroke, kidney disease, vision problems, and nerve problems. Studies have shown that a
1% reduction in HbA1c, the measure of glucose present in the blood, can cut the risk of microvascular complications by 25%. It
was estimated that, on average, BCG could reduce between 85% and 88% of the cost of current approaches used to reduce
HbA1c by 1%. On the other hand, when glucose levels are too low, patients can experience severe hypoglycemia, a potentiallyfatal event where they need another person's assistance to help them increase glucose levels. Approximately 20% of the
population with T1D experience at least one severe hypoglycemic event annually, and BCG is expected to reduce this number
close to zero. Also, T1D patients must deal with needles on a daily basis. Studies estimate that 28% of the adults managing
diabetes with injections have needle fear. It is expected that BCG would reduce invasiveness, considered as injections, pen
shots, cannula changes or tests, by 53%.
There are several other factors beyond this study that garner consideration. Insulin rationing is the practice of taking insufficientamounts of insulin when one cannot afford the required dose. This practice can result emergency interventions and even death.
Reducing insulin requirements lowers the annual cost of insulin and may allow more patients to move away from rationing.
Improving blood glucose control is associated with reduced risk of many other conditions, representing additional benefits interms of lower costs and improved quality of life.
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Health Key Performance Indicators (HKPIs)
We evaluated the public health and socioeconomic inputs and impacts for the BCG vaccine considering its ability to reduce
HbA1C levels and thus reduce the need for insulin injection.

Quality Adjusted Life Years

Quality Adjusted Life Years (QALYs) are a measure of theadditional health and length of life gained by patients from anintervention, adjusted for the quality of life experienced during
these years. The estimate of QALYs gained is based on adding
BCG therapy to standard treatment.

▶ Drawing on estimates from the Cardiff Type 1 Diabetes
Model, a decline in HbA1c levels of 1% accounts for a gain of
0.5482 discounted QALYs.

0.8
0.7
0.6

QALYs Gained▶ Based on estimates of the effect of BCG on HbA1c levels atyear five.

Quality Adjusted Life Years Gained with BCG
Versus Insulin Alone

0.5
0.4
0.3
0.2
0.1

▶ The observed reduction in hypoglycemia frequency
contributed an additional 0.17 QALYs, a gain which begins to
accrue within the first six months of treatment.

0.00040
BCG Inclusive Treatments

Insulin Only

▶ Assume annual discount rate of 3.5% per year, based on
validated T1D model inputs, and accounting for a 5-year lagin achieving a reduction in HbA1c levels.

Net Payer Savings

Annual projected savings from using BCG therapy in addition
to standard insulin therapy. Estimates are provided relative toeach of three methods of insulin delivery without BCG.

▶ Payer spending was calculated by netting outpatient cost
sharing. Cost-sharing estimates for insulin were drawn frompublished statistics on out of pocket expenses for T1D
patients enrolled in Medicare Part D. Discounts and rebates
are not publicly disclosed as they are determined throughprivate negotiations. An estimated rebate of 22.8% from list
price was included.

Net Payer Saving in Millions▶ Based on the projected total cost of treating people with
T1D in the U.S.

Net Payer Savings$2,500$2,000$1,500$1,000
$500
$0
-$500
-$1,000
100% Insulin 100% Insulin 100% Insulin BCG + 50% BCG + 50% BCG + 50%
Injection w/ Injection w/
w/ Pump
InsulinInsulinInsulin w/
SyringePen
Injection w/ Injection w/
Pump
SyringePen▶ Actual savings may vary across payers, as each payer has its
own unique cost-sharing arrangements and bargaining
power for treatments considered in this model.

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Health Key Performance Indicators (HKPIs)
We evaluated the public health and socioeconomic inputs and impacts for the BCG vaccine considering its ability to reduce
HbA1C levels and thus reduce the need for insulin injection.

Annual Cost of Care Per Patient▶ Insulin accounted for 31% of total spending for the averagepatient in 2016 and represents a significant cost saving
opportunity if BCG is approved for Type 1 Diabetes.
▶ Non-insulin pharmacy (other scripts) is considered a fixed
cost across all subsets, due to limited insight into the types
medications and conditions that are captured in the data
set.

Total Annual Cost of Care Per Patient$25,000
Annual Cost of Care per Patient

Average annual cost of care for T1D patients by treatment
regimen for payers, including insurance companies andgovernment programs. Inputs include insulin, non-insulin pharmacy(other scripts), medical spending (in/outpatient, procedures).

$20,000$15,000$10,000$5,000$0100% Insulin 100% Insulin 100% Insulin BCG + 50% BCG + 50% BCG + 50%
Injection w/ Injection w/
w/ Pump
InsulinInsulinInsulin w/
SyringePen
Injection w/ Injection w/
Pump
SyringePen▶ Medical spending (in/outpatient, procedures) is the largest
component of average total spending, contributing 47% of
all costs.
▶ Due to the absence of any reported hypoglycemic events
during Phase I trials for BCG, average medical spending was
adjusted to consider significant reduction in associatedexpenses, including glucagon and inpatient treatment (on arisk adjusted basis).

Efficacy Cost

▶ An average insulin dose of 60 units per day for traditional
insulin therapy was assumed, along with a 50% (30 units)
reduction after BCG administration.

Millions

Efficacy
Cost of Treatment / 1% HbA1c Reduction

Efficacy was assessed in terms of the average cost to payers fora 1% reduction in HbA1c. HbA1c, develops when hemoglobin
joins with glucose in the blood becoming ‘glycated’, part of thenatural process when the body processes sugar. An HbA1c test
can measure changes in blood sugar levels over a period ofweeks/months. For people with diabetes, the higher the HbA1c,
the greater the risk of developing diabetes-related
complications. A 1% reduction translates to an average
reduction in blood glucose levels of 1.6 mmol/L. Studies haveshown than a 1% reduction cuts the risk of microvascularcomplications by 25%*.

40
35
30
25
20
15
10
5
0
Insulin
Injection

Insulin Pen

Insulin Pump

BCG +Injection

BCG + Pen BCG + Pump

▶ HbA1C reduction for syringe-based injection and pen wasconsidered 0.04% per year, for pump 0.016% to 0.05% peryear and for BCG 0.16% per year.
▶ On average BCG is projected to reduce 85%-88% of the costper 1% HbA1c reduction*Source: UK Prospective Diabetes Study, https://www.dtu.ox.ac.uk/ukpds/

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Health Key Performance Indicators (HKPIs)
We evaluated the public health and socioeconomic inputs and impacts for the BCG vaccine considering its ability to reduce
HbA1C levels and thus reduce the need for insulin injection.

Invasiveness▶ Insulin Injection and Pen require 3 to 7 applications per day,while Pumps are changed every 2 to 3 days.

Invasiveness – Frequency of Administration
7,000
Injections & Diagnostics / year

Invasiveness measures the number of times the treatment andrelated procedures (including testing/diagnostics) are needed
within a year. Needle phobia is anxiety at the thought ofinjections or blood glucose testing, leading to attempts toavoid them*. Injections and blood glucose testing can be
distressing, as studies estimate that needle fear affect 28% of
adults managing diabetes with insulin injections**.

6,000
5,000
4,000
3,000
2,000
1,000
0

▶ For Insulin measurement as a minimum it was considered aContinuous Glucose Monitor changed every 2 weeks, and as
a maximum a Self Glucose Monitor 10 times a day. This
metric does not measure the potential psychological effectof a patient wearing a Pump inserted under the flesh all day.

Insulin
Injection

Insulin Pen

Insulin Pump

BCG +Insulin
Injection

BCG +Insulin Pen

BCG +Insulin Pump

▶ For BCG, the number of injections and Self Glucose
Monitoring applications decreased in half, while the cannula
and Continuous Glucose Monitor were unchanged.
▶ On average, there is a 53.3% reduction in Invasiveness incomparison to Injection, Pen and Pump when BCG is
included.

Severe Complications - Hypoglycemia▶ BCG cohort n=9 reported 0 severe hypoglycemia events
over a span of 5 years.
▶ Of the 9 participants, 3 reported zero severe hypoglycemic
events over an 8-year span (including the original five-year
period).

Severe Complications
25

Severe Hypoglycemic Events / year
(per 100 patients)

This metric measures the annual number of severe
hypoglycemic events per 100 patients with T1D. During
severe hypoglycemic events, glucose levels are so low that anindividual cannot treat his or herself and requires assistancefrom another person. Patients with severe hypoglycemia getvery tired, may lose consciousness and can even experience
seizures or convulsions.

20

15

10

5

0
Insulin Injection

Insulin Pen

Insulin Pump

▶ Across the broader T1D patient population, around 20%
experience on or more hypoglycemic events annually.

*Source: Understanding the psychological impact of diabetes and the role of clinicalpsychology, https://www.diabetesonthenet.com/download/resource/4378**Source: Prevalence and outcomes of fear of needles and associated psychological conditions
among patients managing diabetes, https://www.valueinhealthjournal.com/article/S10983015(16)01393-0/fulltext

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APPENDIX A: Methodology
Key Goals
Key goals of this analysis were to:
1. Examine patient healthcare and cost performance in conjunction with financial data to arrive at patient andsocioeconomic metrics for the BCG vaccine versus traditional insulin therapies.
2. Provide equitable comparisons among relevant existing practices within healthcare system.
3. Incorporate a variety of methodological considerations that are relevant to the diabetes care industry and which were
expected to bear upon the results.
To ensure that these key goals were reached, an independent industry expert reviewed the study and assumptions to ensurethat the methodology was coherent with industry standards. The expert review and commentary notes are provided inAppendix C.

Methodology
To address the first goal, Boundless reviewed the BCG clinical trial results as well as performed a detailed diabetes industry
analysis to obtain relevant studies and or models. At the core of the methodology is an impact assessment model createdby Boundless where we utilized inputs from a model validation study by McEwan et al. based on Cardiff Type 1 Diabetes(CT1DM) Model, which demonstrates the QALY impact of changes in HbA1c and hypoglycemia. Additional studies used to
inform this report were conducted by Health Care Cost Institute, Kaiser Family Foundation, Centers for Medicare &Medicaid Services and the American Diabetes Association.
Each metric compares BCG’s impact on the need for insulin against conventional diabetes treatments. Metric construction
for industry alternatives relies on comparisons, for which we relied on scientific literature, industry reports, white papers, aswell as assumptions provided by the industry expert. The impact metrics are reported graphically using bar charts toillustrate a baseline result value, along with sensitivity bars reflecting a range of possible result values around deployment
scenarios and key variables.

Research Approach▶
▶
▶
▶

Leveraged industry accepted models and data from diabetes studies previously conducted.
Reviewed and incorporated detailed information from the BCG Phase I clinical trials.
Identified sources of uncertainty and quantified their impact on results.
Included important financial and operational variables to estimate the cost of production.

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APPENDIX B: List of Heath Key Performance Indicators (HKPI)HKPIMetric Description

Unit of Measure

Information Needed

Invasiveness –Frequency ofAdministration

Number of times the treatment andrelated procedures (including
testing/diagnostics) are needed, within
a year.

Invasive procedures(injections &diagnostics) / year•••

Efficacy

Quality-Adjusted
Life Year (QALY)

Safety – Severe
Hypoglycemia

Payer Cost
Savings

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Average cost to payers for a 1%
reduction HbA1c

Average total costof treatment /% change in HbA1c•

Number of years gained from BCG withinsulin vs. insulin alone, adjusted for apatient’s quality of life during theadditional years gainedYearsgained/quality oflife•

Annual incidence of severe
hypoglycemia

Number of severe
hypoglycemic
events / year•

Average total costof current
treatments – risk
adjusted cost of
BCG inclusive
treatment•

Cost of treatments for all Type 1
Diabetes patients in the US

•

•
•

•

•
•

Number of doses of BCG in full
regimenTotal (estimated if necessary)
number of insulin injections per
year for BCG cohort vs. control
group (or individuals w/T1D not
in study)
Total (estimated if necessary)
number of invasive diagnostic
test per year for BCG cohort vs.
control group (or individuals
w/T1D not in study)
HbA1c test results for BCG vs.
control group (just insulin)
Average cost of BCG and insulin(payer data source)Life expectancy for T1D patients
across all treatment options
Health utility values for T1Dcomplications
Validated QALY model for T1D,
including HbA1c changes andrisk of severe hypoglycemia
Frequency of hypoglycemic
events for individuals with T1D(baseline)
Frequency of hypoglycemic
events for individuals after BCG
treatment – or estimates basedon improved control of blood
glucose levels
Average cost of insulin per
patient (payers)
Projected lifespan of T1D
patients based onstage/progression of T1D
Change in insulin dose after
receiving BCG

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APPENDIX C: Independent Expert Review
Independent Industry Expert
Sarah Dykstra, PhD in Health Care Management and Economics at the Wharton School. Sarah’s research explores
how government and insurance policies influence physician treatment patterns and health outcomes. Her current
projects focus on value-based payment reforms and state opioid policies. Sarah has a BA in global health from
Boston University and a PhD in health care management and economics from the University of Pennsylvania. She
previously worked in policy analysis for the Center for Global Development and for Innovations for Poverty Action
managing a maternal and child health impact evaluation in Sierra Leone.

Summary of Expert Review
A recent phase 1 clinical trial demonstrated promising results for the potential of the BCG vaccine to be used astherapy for patients with Type 1 diabetes. Although the results were based on a small sample, with 9 patients in thetreated 5-year follow-up cohort, the study found significant reductions in key metrics, including patients’ HbA1clevels and likelihood of hypoglycemia events.
Boundless Impact Investing has used the results of this study to evaluate the potential of combining BCG therapy
with standard insulin therapy with respect to six indicators. The indicators selected are highly relevant and represent
outcomes that are important to both patients and payers. The analysis is well-documented and performed in linewith standard health economic analyses.
Due to the size of the clinical trial and limited publicly available data related to spending, the analysis relies on a
few assumptions that are worth noting. First, the evaluation of QALYs gained through the introduction of BCG relies
on an existing study, the Cardiff Type 1 Diabetes Model, to assess the impact on an outcome via a surrogate
endpoint. This study provides estimates of the QALYs gained as a result of a 1% reduction in HbA1c levels,
permitting the extrapolation of the clinical trial’s results. The key assumption here is that morbidity and mortality
resulting from HbA1c reductions achieved through the BCG vaccine are similar to those achieved through existing
strategies of glycemic control in T1D patients. Only a future study of the BCG vaccine could validate thisassumption. In addition, this analysis uses estimates from 1% reduction in HbA1c levels rather than the estimate of
1.18% from the clinical trial; this represents a conservative estimate of the potential effect on QALYs and isreasonable given the level of uncertainty in the results from the clinical trial.
The analysis of the impact on cost of care per patient and net payer savings relies on published estimates of
average annual health care spending among T1D patients in the U.S. across types of care, negotiated rebates forinsulin and copayment rates. While the assumptions made are reasonable, it’s important to note that these figures
may vary substantially based on the payer and patient population examined. Two HKPIs examined, invasivenessand severe complications, rely solely on the results of the initial phase 1 clinical trial.
In sum, this analysis demonstrates that, based on the results of the phase 1 clinical trial, the BCG vaccine may havethe potential to achieve both significant improvements in health outcomes and substantial cost savings. Whether
these improvements can be realized is dependent upon greater precision in the estimates of the effectiveness of
the BCG vaccine.

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APPENDIX D: Independent Expert Review
Independent Industry Expert
Dr. John Doupis is a former Fellow of the Joslin Diabetes Center at Harvard Medical School. Currently he directs
the Diabetes Division and Clinical Research Center of Iatriko Paleou Falirou Medical Center in Athens, Greece aswell as the Internal Medicine and Diabetes Department of the US Naval Hospital in Athens, Greece. Dr. Doupis has
also served as a Tutor for Diabetes Diploma and MSc in Diabetes at Cardiff University Medical School in the UK
since 2012.
His special areas of interest are Type 1 and Type 2 Diabetes and its complications, especially the Diabetic foot andObesity, as well as the new glucose sensing technologies and insulin pumps. In these fields, he has participated in a
substantial number of studies, most of which have been either published in International journals or presented ininternational congresses. He is also the instigator of “D-partner,” an artificial intelligence app fordiabetes management.
Dr. Doupis has given numerous lectures in national and International congresses presenting more than 200
papers. In addition, he has authored many chapters in Diabetes related books, published in the USA and in Europe
and is a member of the editorial advisory board of several diabetes related medical journals. He has extensive
teaching experience at Harvard Medical School, Athens University Medical School and Cardiff University Medical
School. He is a member of the Hellenic Diabetes Guidelines board and serves as Advisor of the National Authority’s
Committee for Insulin Pumps and Sensors.

Summary of Expert Review
The BCG vaccine is a very well-known and widely used vaccine for tuberculosis prevention. Recent data support
evidence for the potential use of this vaccine for the management of Type 1 Diabetes.
Although available data on this topic is relatively limited, and the sample size of the patients in Phase 1 trial is small(9 patients followed up for 5 years), the results come from a high level research center directed by a leading
scientist in the field, and are quite impressive and promising, providing a new and safe concept for Type 1 Diabetes
management utilizing novel therapeutic pathways.
Boundless Impact Investing analyzed data mainly from this Phase 1 clinical trial and made reasonable assumptions
due to limited data availability. The analysis was comprehensively presented helping those not familiar with the
topic to quickly understand the diabetes-related health impact of the BCG vaccine as a novel, effective andinexpensive treatment approach for Type 1 Diabetes.
Type 1 Diabetes management requires a continuous effort from both the patient and the physician. Better glucose
control with less hypoglycemia rates as proposed by the BCG vaccine use, may consequently lead to the reductionof diabetes related complications and hospitalization. This along with the reduction of daily insulin requirementsshows that BCG may also reduce the total direct and indirect costs as nicely analyzed by Boundless Impact
Investing, based on published estimates of the average annual health care spending among Type 1 Diabetes
patients in the U.S.
Furthermore, estimates of the QALYs from the trial were reasonably calculated as the result of the HbA1c andhypoglycemia rate reduction in the BCG treated group at year five, compared to the control group.
Invasiveness calculations were based on reasonable assumptions, as the number of times the treatment and all
related procedures are needed within a year.
Overall, I believe that this is a quite efficient analysis of the currently available data of this topic, providing a clear
sense of the health-related impact of the BCG vaccine as a promising treatment option for Type 1 Diabetes.
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APPENDIX D: Score Rationale & Profile Sponsor
Health Impact Score
The health impact score is a number (1=worst to 10=best). This number represents an overall indicator of acompany’s health impact performance against its most relevant industry competitors. The value is obtained bycomparing the average of each resulting HKPIs for the company against its comparable treatments as well as abaseline of not having diabetes at all (10 out of 10). The score for each metric is also displayed in the summary
Spider Chart of the profile of each product.
The BCG Vaccine is ranked as having an overall great performance when compared to traditional forms of insulin
therapies. On average BCG is projected to reduce 85-88% of the cost of achieving a 1% HbA1c reduction, as
opposed to traditional insulin. There is a 53.3% reduction in invasiveness in comparison to Injection, Pen andPump when BCG is included. A 1 % decline in HbA1c accounted for a gain of 0.5482 discounted QALYs five years
after receiving the first dose of BCG. Using a formulaic comparison to measure relative performance across all
HKPIs, the BCG Vaccine scored a 6.8 out of 10 on health performance.

FYI Diabetes
FYI Diabetes is a family-founded nonprofit organization dedicated to funding promising research focused on
curing diabetes, new innovative technologies that improve the quality of life for diabetics and raising awareness ofdiabetes through education and health screenings. FYI Diabetes supports the advancement of clinical trials
using the Bacillus Calmette-Guérin (BCG) vaccine to prevent and reverse autoimmune diseases including Type 1
Diabetes.

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