FROM THE ANTIMICROBIAL RESISTANCE RESEARCH PROGRAMME

Lack of access to medicine is amajor driver of drug resistance.
How can pharma take action?
JUNE 2022

Antimicrobial resistance (AMR) is rising faster than expected.
Worldwide, more than one million people die of AMR each year,
most of them in low- and middle-income countries (LMICs).
Resistant infections can rapidly spread without appropriate accessto essential antibiotics and antifungals. Yet, the issue of responsibly providing access for people living in resource-poor settings has
been largely overlooked. Pharmaceutical companies are only using
a limited number of the opportunities that exist to expand accessin poorer nations, resulting in significant gaps. This study setsout how companies and their partners are using a combinationof access strategies to cut through the complexity and address
access at a local level.

Appropriate access to antimicrobials

ACKNOWLE DG E M E NTS

The Access to Medicine Foundation would like to thank the following
people and organisations for their contributions to this report.
FU N D E RS

UK Foreign, Commonwealth and Development Office
The Dutch Ministry of Health, Welfare and SportAXA Investment Managers
Wellcome Trust

R ES E ARCH TE AM

E D ITO R IAL TE AM

E XPE RT R E VI E WE RS

Moska Hellamand

Marjolein van der Boon

Anthony McDonnell, Center for Global Development (CGD)

Martijn van Gerven

Eleanor Bley Griffiths

Jean-Pierre Paccaud, Jennifer Cohn, Global Antibiotic

Fatema Rafiqi

Rachel Jones

Research and Development Partnership (GARDP)AD D ITI O NAL CO NTR I B UTO RS

The Access to Medicine Foundation is grateful to the following for theirthoughtful contributions to the development of this paper: Andy Gray
(University of KwaZulu-Natal); Dame Sally Davies (UK Special Envoy on
Antimicrobial Resistance); John Rex (F2G Ltd., AMR.Solutions, Advent
Life Sciences, McGovern Medical School in Houston, Texas); Katherine
Klemperer (CGD); Marc Mendelson (University of Cape Town, Groote
Schuur Hospital); Nelesh Govender (University of the Witwatersrand,
National Institute for Communicable Diseases at NHLS in South Africa);
Neel Lakhani, David Ripin (CHAI); Yann Ferrisse (GARDP).
R ES E ARCH AN D E D ITO R IAL SU PPO RT

Camille Romero
Diane Dinar-Farjon
Anna Massey

ACCESS TO M E D I CI N E FO U N DATI O N

The Access to Medicine Foundation is an independent non-profit organisation based in the Netherlands. It aims to advance access to medicine inlow- and middle-income countries by stimulating and guiding the pharmaceutical industry to play a greater role in improving access.
Naritaweg 227-A
1043 CB, Amsterdam
The Netherlands
For more information about this publication, please contact Fatema
Rafiqi, Research Programme Manager
frafiqi@accesstomedicinefoundation.org+31 (0) 20 215 35 35
www.accesstomedicinefoundation.org

2

Access to Medicine Foundation

Table of contents

4	About this paper
5	Introduction
AMR is rising fast. Lack of access is making the problem worse.
8	How can pharmaceutical companies expand access?
A wide range of strategies are available to companies.
11	What is the state of play for companies looking to bring antibiotics and antifungals to more people?
The antibiotic market is broken. How can we fix it?
16	Case studies
Companies that are using a combination of access strategies tomake specific medicines more widely available.
25	Discussion
Collaboration between stakeholders is a key ingredient.
29	Recommendations
What can stakeholders do to expand appropriate access?
31

Appendix34	Definitions
36

References3

Appropriate access to antimicrobials

About this paper
This paper is part of the Access to Medicine Foundation’s Antimicrobial Resistance(AMR) Research Programme, which takes an in-depth look at how the pharmaceutical industry is responding to the growing challenge of drug-resistant infections. The
Research Programme has assessed companies’ performances in AMR Benchmark
reports published in 2018, 2020 and 2021. These provided data-driven analysesof actions by companies with a major stake in the anti-infectives space, including
research-based pharmaceutical companies and generic medicine manufacturers.
This paper builds further on a key finding of the 2021 AMR Benchmark, namely thatpharma companies are making limited use of the many ways to improve access toantibiotics and antifungals in low- and middle-income countries (LMICs) – and where
access strategies are in place, that they remain focused on a small set of countries,
people and diseases. However, the Benchmark also noted that there are tangible waysthat access can be improved, making a real difference to millions of people if deployed
more widely. This paper set out to uncover the systemic factors that may be preventing companies from prioritising access, as well as identifying case studies and recommendations for companies and other stakeholders such as governments, procurement
agencies and regulatory bodies.
This is the first of three stand-alone studies that the AMR Research Programme will
publish in 2022 - 2024.
HOW WAS TH E PAPE R D EVE LO PE D?
The case studies, discussion and recommendations in this thematic study have beendrawn from research published in the 2021 AMR Benchmark, as well as from interviews
held with companies and experts in the AMR field. It was further informed by sources
available in the public domain. Information from these sources was cross-checked
directly with companies and their partners to ensure accuracy.
SCO PE O F TH E RESE ARCH
Companies
This study includes case studies on research-based pharmaceutical companies andgeneric medicine manufacturers that are marketing antibacterial and antifungal medicines in LMICs. The following companies are specifically mentioned: Cipla, MSD, Pfizer,
Sanofi, Shionogi and Viatris.
Products
This study includes examples of on-patent, off-patent and generic antibacterial andantifungal medicines, specifically: amoxicillin, beta-lactams, cefiderocol (Fetroja®/
Fetcroja®), ceftaroline (Zinforo®), ceftazidime/avibactam (Zavicefta™), ceftolozane/
tazobactam (Zerbaxa®), colistin, doxycycline, flucytosine, fosfomycin, liposomal
amphotericin B, metronidazole and (benzyl)penicillin.
EXPE RT REVI EWE RS
Anthony McDonnell, Center for Global Development (CGD)
Jean-Pierre Paccaud, Jennifer Cohn, Global Antibiotic Research and Development
Partnership (GARDP)SOU RCES
Sources for this study include interviews with companies and experts, company websites, partner websites, proprietary data from IQVIA, as well as information from theFoundation’s 2021 AMR Benchmark and the 2021 Access to Medicine Index. It also
draws on information available in the public domain, including peer-­reviewed literature,company and global health reports, policy literature and government documents.
4

Access to Medicine Foundation

I NTRO DUCTI O N

AMR is rising fast. Lack of access is making
the problem worse.
Antimicrobial resistance (AMR) is rising even faster than anticipated. Drug-resistant

IN BRIEF

infections are already causing millions of preventable deaths each year. In 2019

▶ AMR is rising fast, with the world’s

alone, there were an estimated 4.95 million deaths associated with AMR and morethan one million people died as a direct result of antibiotic resistance. If the current
1

situation is not addressed, the death toll will continue to increase.
Antibiotic and antifungal medicines are not only vital in treating infections. They

poorest countries bearing thebiggest burden.
▶ A lack of access to antimicrobials
is making the problem worse.

also play an essential role in preventing infections, for example after surgery, for▶ Improving access, supported byimmunocompromised people, such as those with HIV/AIDS, and for people under-strong stewardship, must get

going aggressive cancer treatments. These medicines are also critical tools in

more attention from pharma

protecting newborns, whose immune systems have not yet fully developed, fromcompanies, governments andbacterial and fungal infections.

procurers.

3

The world’s poorest countries experience the greatest rates of infectious disease
and the highest levels of antibiotic resistance – but it is precisely these countries
that suffer the biggest gaps in access to the right treatment. Further, while many
global health discussions focus on curbing AMR, the lack of access to essential

How many people are dying from drug-resist-antibiotics and antifungals for people living in low- and middle-income countries

ant infections
How many people are dying from AMR?

(LMICs), especially for the most vulnerable and marginalised populations, does not

700,000 deaths directly due to AMR in 2014

receive the same level of attention.
Access to antibiotics and antifungals is vital and must increase
It is absolutely crucial that every patient has access to the right antibiotic or
antifungal medicine at the right time, no matter where they live in the world. Thiscan sound paradoxical, because overuse or misuse of antibiotics and antifungals is
also a major driver of resistance.4
However, when antibiotics and diagnostics are unavailable, it not only has a hugetoll on those directly affected by disease, but also poses a danger to the wider

1.27 million deaths due to AMR in 2019
Out
4.95 million
in 2019
4.95ofmillion
deathsdeaths
were associatedthatwithwere
AMRassociatedin 2019 with AMR
Sources: The Review on Antimicrobial Resistance(Jim O’Neill), 20142 and the GRAM report1

population. This is because if the right treatment is not accessible doctors have toresort to suboptimal treatments, which gives pathogens an opportunity to develop
resistance.

How lack of appropriate access drives antimicrobial resistance (AMR)
1. No access to antibiotics: the infection canspread unchecked among a population and may
develop resistance due to natural selection,
despite the absence of antibiotics.

2. Lack of access to the right antibiotic: thewrong antibiotic kills only some susceptible
pathogens and allows for pathogens withresistant genes to survive and spread unchecked.
This is the highest driver of resistance.
Resistant pathogen

3. Access to the right antibiotic: the rightantibiotic is the most likely to cure the infection
and stop further spread of AMR.

5

Appropriate access to antimicrobials

While AMR is a global issue, a lack of access to antibiotics and antifungals is
especially urgent in LMICs, where many medicines have not been registered with

Where areare people
people facing
facing theWherethe highest
highest risk
risk ofofdying fromfrom AMR?
drug-resistant infections?
dying

national regulatory bodies, which means they cannot be sold or distributed to the

Deaths
Associated with resistance
Attributable to resistancepatients who need them.5–8 As a result, the people who face the highest risk ofinfection and the highest rates of drug resistance have the hardest time getting the150

antibiotics they need to survive severe bacterial and fungal infections. This is why it
Deaths (rate per 100,000 population)is critical that pharmaceutical companies, governments and procurers take action
to ensure access to antibiotics and antifungals.
But it is equally critical that access is ‘appropriate’. ‘Appropriate access’ meansthat essential medicines are made available, affordable and accessible while also
ensuring they are covered by strong stewardship practices, i.e., making sure that
antibiotics and antifungals are being used responsibly so they stay effective for as
long as possible.
To turn around this lack of equity, we must expand our focus beyond stewardship and the hunt for replacement antibiotics. Furthermore, access to medicinesand diagnostics already on the market must get the same level of attention as novel

100

50

Ea

W

es
te

rn
st sube
C rn s Saenu h
So tra b-S ara
a n
ut l she ub har Afr
rn -S an ica
su ahAb- ara fric
Sa n
a
ha Af
ra ricna
So AfrSo
ut Ea ut icahhe strn ern Asi
La E aHi
tin uro
gh
Am pe
-in
er
co
ic
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0

ones, particularly in the world’s poorest regions.

The human toll of AMR

Error bars show 95%
uncertainty intervals• 1.27 million deaths per year are directly attributable and almost 5 million deaths per year are

Source: the GRAM report1
Source: The Lancet

associated with antibacterial resistance.
• Death rates due to resistance are highest in Western sub-Saharan Africa with 27.3 deaths outof 100,000. The four regions with the highest burdens are in sub-Saharan Africa, followed bySouth Asia.
• E. coli bacterial infections account for most deaths attributed to resistance, followed by K.
pneumoniae, S. aureus, A. baumannii and S. pneumoniae.
• Lower respiratory infections, bloodstream infections and intra-abdominal infections have themost global deaths attributed to antibacterial resistance.
Source: The Global Research on Antimicrobial Resistance (GRAM) report, published in The Lancet in January2022, the most comprehensive study yet of the extent of AMR globally.1

How many people are dying from themost deadly drug-resistant pathogens
E. coli

220,000

How lack of appropriate access drives AMR

K. pneumoniae

190,000

When the right, first-line antibiotics and antifungals are not locally accessible, aS. aureus

180,000

likely to cure the patient’s infection, but it can also contribute to AMR. Pathogens

A. baumannii

130,000

can adapt to the pressure of antibiotics by selecting genes that are resistant to theS. pneumoniae

120,000

doctor may resolve to prescribing a less effective alternative. Not only is this lessantibiotic. The wrong antibiotic kills only some susceptible pathogens and allows for

Source: the GRAM report1.
These numbers are estimates.

the pathogens with resistant genes to survive and spread unchecked. When firstline treatments are unavailable, doctors may also resort more quickly to antibiotics
that should be second- or third-line treatments, which should be held in reserve inorder to protect their effectiveness for as long as possible. Lack of access to diagnostics exacerbates this problem, making it even harder for doctors to prescribe
the correct antibiotic.
The implications for AMR are even wider when no antibiotics or antifungals areavailable and the patient does not receive any treatment. Appropriate access to theright treatment not only prevents suffering and death, but it also helps to control
the spread of infection and limit the rise of AMR. When infections are allowed tospread unchecked among a population, pathogens may develop resistance due tonatural selection, despite the absence of antibiotics.
What antibiotics and antifungals are needed?
To support the appropriate use of antibiotics, the World Health Organization(WHO) has grouped essential antibiotics into three categories: Access, Watch andWhich infectious diseases have themost deaths attributed to AMR?
Lower respiratory
infections

415,000

Bloodstream
infections

375,000

Intra-abdominal
infections

208,000

Tuberculosis
Urinary tract
infections

84,00065,000Source: the GRAM report1.
These numbers are estimates.

6

Access to Medicine Foundation

Reserve, also called the AWaRe classification (see box below). Antifungal medicines
have not been categorised in this way, though it is important that they are alsoclassified to ensure their appropriate use. The rising incidence of fungal infections
and antifungal resistance is now receiving greater attention, however, including thepush for more drug development.9 While WHO uses the AWaRe classification toprioritise groups of antibiotics, we still rely on pharmaceutical companies to makethem available, accessible and affordable.

WHO AWaRe Classification
The majority of antibiotic and antifungal medicines are older, off-patent products that fall underthe Access category. ‘Access’ antibiotics are typically first- and second-line treatments thatshould always be accessible to treat common infections. They are widely needed medicines,
such as doxycycline, a broad-spectrum first-line antibiotic for chlamydia and cholera; and benzylpenicillin, used to treat syphilis.
Making Access antibiotics available for everyone, under strictly observed stewardshippractices, also helps to preserve the effectiveness of Watch and Reserve antibiotics. While bothshould be accessible, Watch antibiotics should only be prescribed for a limited set of indications
and Reserve antibiotics should only be used as last-resort treatments against the most resistantbacteria.10
Reserve antibiotics in particular are intended to treat multi-drug-resistant and extensively
drug-resistant infections and should only be used “when all alternatives have failed or are notsuitable.”10 If pathogens develop resistance to Reserve antibiotics, also known as non-renewable
antibiotics, there are currently no more options left in the medicine cabinet.

Where are companies filing antibiotics and antifungals for registration?
The AMR Benchmark examined registration filings from 17 companies. There are various reasons why a company may or may
not file a product for registration in a specific country, including market size and financial opportunities, government pricepolicies, local regulatory requirements and data needed for registration.
Where are companies filing antibiotics and antifungals for registration?
● 0 filings ● 1-10 filings ● 11-30 filings ● 30-50 filings ● > 50 filings ● Registration filings not assessed.
This analysis focused on low- and middle-income countries
where the need for better access to medicine is greatest.

More products have been filed for

There are 14 countries in which none of theFiling for registration is a vital first step

registration in Brazil, South Africa, the148 products examined have been filed forto introduce a product into a country, as

Philippines, India and Thailand. They

registration, including Somalia and Southit allows it to be imported and sold.

provide greater revenue opportunities

Sudan.

due partly to large patient populations.
Source: 2021 AMR Benchmark

7Appropriate access to antimicrobials

How can pharmaceutical companies expand
access?
Since 2017, the Access to Medicine Foundation has been tracking how a cross-­

IN BRIEF

section of pharmaceutical companies active in the antibiotics and antifungals field▶ A wide range of strategies are

ensures access to these products in low- and middle-income countries (LMICs).
This research shows that pharmaceutical companies are only utilising a limited
number of opportunities to expand access to their antibiotics and antifungals
in LMICs, resulting in a significant gap in access to essential medicines in thesecountries.
The latest AMR Benchmark report, published by the Foundation in 2021, foundavailable to companies for improving
access appropriately and sustainably.
▶ Currently they are only using afraction of the options available.
▶ For each essential antibiotic or
antifungal, companies shouldthat just one third of the products analysed were covered by an access strategy inconsider the full range of accessthe 102 resource-limited countries in scope (see figure).8 A wide range of accessstrategies in the toolkit.

strategies were considered in the report, including technology transfers, equitablepricing strategies and voluntary licensing agreements.
Pharma can break the pattern of inaction
While there are many ways to improve access to vital antibiotics and antifungals inpoorer countries, these are not being widely used. While pharmaceutical companies
expect governments to prioritise stewardship measures and prevent an influx of
low-quality medicines, governments expect companies to communicate which antibiotics or antifungals they are planning to introduce into their health systems. This
leads to a stalemate that affects people in poorer countries the most. Low-income
countries (LICs), home to nearly 700 million people, are particularly overlooked bycompanies’ access strategies even though the pharmaceutical industry can save
lives by reaching more people with more products, both old and new. Access strategies by pharmaceutical companies need to increase in quality and reach in order tocover a wider range of countries, people and treatments.
A toolkit of access strategies for companies
For each antibiotic or antifungal, pharmaceutical companies should consider the fullrange of access strategies in the toolkit to work out what is most useful to reachvulnerable populations living in LMICs. Tangible access strategies are highlighted
and explored in this report, including in several case studies where companies have

Number ofof antibiotics
antibiotics &Number& antifungals
antifungals covered
covered bybyat least
least one
one access
access strategy
atstrategy
On-patent medicines 7 10
On-patent vaccines

13 5

Off-patent/generic
medicines

0

34

97
50

Covered byat least one
access strategy

The next pages provide an overview, as well as definitions, of the access strat-150

Not covered byaccess strategy,
or coverage is
unknownaddressed access to specific antibiotics and antifungals.
egies available to pharmaceutical companies and other key stakeholders. This

100

Source: 2021 AMR Benchmark. The Benchmark
examined the portfolios of 17 companies.

includes approaches to enable availability such as registration, but also ways toexpand access to underserved populations, such as patient assistance programmes
and equitable pricing policies. Increase of local availability via technology transfers
to qualified manufacturers is also vital in regions where there is a dependency on
importation, for example in sub-Saharan Africa.

Newly approved products identified by the
AMR Benchmarks

In addition to what pharmaceutical companies can do, this report also draws

2021

attention to steps other stakeholders, such as governments and procurement agen-2020

cies, can take to enable the supply and production of essential antibiotics and antifungals in LMICs. This includes working with healthcare professionals to collect andshare data about which antibiotics are needed where, creating conditions to ensurea sustainable market for novel products, and streamlining registration proceduresfor generic products.

20
Adapted antibacterial
medicines in themarket

9

2

2

2

4

6

8

10 12

New antibacterial
medicines in themarketSource: 2021 AMR Benchmark

8

Access to Medicine Foundation

THE TOOLKIT OF ACCESS STRATEGIES FOR PHARMACEUTICAL COMPANIES

Action to improve the availability and accessibility of medicine is urgently needed,with each antibiotic and antifungal being used responsibly to ensure it stays effective for as long as possible. For each antibiotic and antifungal, companies should
consider the full range of access strategies in the toolkit.

A PHARMACEUTICAL COMPANIES• Off-patent/generic medicines• On-patent medicines

1

Registration in LMICs

ENABLING LOCALPRODUCTION IN LMICs

6 Participation in tenders
7 Participation in pooled
procurement

DEMANDPRICINGSTRATEGIESWORKING WITH
PROCURERS

4 Capacity building
5 Voluntary licensing

SUPPLY

2 Participation in public-private
partnerships (PPP)

3 Technology transfers

SU

P
LY

SUPPLYPOSSIBLE ACCESSSTRATEGIES FOR
PHARMA COMPANIESPB GOVERNMENTS+ NATIONAL/REGIONAL
REGULATORY
BODIES

8 Equitable pricing policies
9 Tiered pricing policies
10 Price caps
11 Patient assistance programmes

DEMAND
12 Early Access Programme

13 Product donations

C INTERNATIONALHEALTHORGANISATIONSDEMAND

SUPPLYD HOSPITALS, PHARMACIESAND PATIENTS IN LMICS

A CLOSER LOOK – WHAT DOES EACH STRATEGY ENTAIL?

1 Registration in LMICs: Filing for registration is a vital first

medicine or vaccine to a manufacturing site in a country

step towards introducing a medical product into a country, as

where that product is needed, along with the technology

successful registration means that a product is now allowed­necessary to manufacture it.

to be imported and sold.
4 Capacity building: A pharmaceutical company forms part-nerships with local stakeholders to increase capacity (e.g.,
2 Participation in public-private partnerships (PPP):by training staff or obtaining equipment and other necessaryPartnerships between public or civil society organisations andresources) in order to strengthen the supply chain.

the private sector (i.e., the pharmaceutical industry) that work
DE
M
P
U
Voluntary licensing: AS voluntary license is an authorisation
LY

towards mutually defined goals based on public needs. Such

P

LY

5

ments, risks, rewards and responsibilities.

given by a patent holder to a generic medicine manufacturer,A

long-term partnerships are characterised by sharing invest-

ND

allowing the manufacturer to produce a patented medicine or
vaccine, often at a lower cost. The license usually sets quality
Enabling local production in LMICs

requirements and defines the countries in which the licensee
can sell the product.

3 Technology transfers: A pharmaceutical company

transfers knowledge about the process to make a specific9Appropriate access to antimicrobials

Working with procurers

Stakeholders
There are different roles for each stakeholder in the anti­

6 Participation in tenders: Tenders are competitive proce-biotics and antifungals market.

dures where bids are invited from companies that can provide
medicines to procurers (e.g., governments or health organisa-

A Pharmaceutical companies: Pharmaceutical companies

tions). They can be an effective tool for procurers to secure ahave a role in expanding access to their antibiotics and anti-

volume of medicines or vaccines at a specific price.

fungals in LMICs through the variety of access strategies
displayed here.

7 Participation in pooled procurement: Pooled procure­ment

means procurers (e.g., governments or health organisations)

B Governments + regulatory bodies: Local governments

combine resources and order volumes in order to purchasecan play a valuable role in enabling pharmaceutical companies

medicines.

to expand access in their countries, for example by providing
data to highlight demand for different antibiotics and antifungals. Regulatory bodies, for example, can harmonise andPricing strategies

simplify registration procedures.

These can be used by pharmaceutical companies to addressaffordability and help ensure that their products are not

C International health organisations and procurers:

financially out of reach for the people who need them, or theProcurement agencies, such as governments and interna-

health systems that need to procure them.

tional health organisations, have a role in selecting suppliers
for their procurement. They can influence pricing as well as

8 Equitable pricing policies: Prices are set within the ability

the diversity of the supply chain.

of specific populations to pay, with reference to a range ofsocio-economic factors.

D Hospitals, pharmacies and patients in LMICs: Healthcare

professionals and patients can ensure stewardship policies
9 Tiered pricing policies: Also known as differential pricing,are followed so that antibiotics and antifungals are used

this refers to when buyers with different income levels – e.g.,

appropriately.

low-income or high-income countries – are charged different
prices for the same product.
10 Price caps: A maximum price that can be charged for a

product, usually negotiated between a government and apharmaceutical company.
11 Patient assistance programmes​: Programmes initiated bypharmaceutical companies that provide financial assistanceor free-of-charge medicines for a defined patient population
with limited ability to pay.

12 Early Access Programmes: A pathway allowing patients toaccess patented or generic medicines that have not yet beenregistered in a country. These programmes typically include
medicines for serious or life-threatening diseases when there
are no other treatment options available.

13 Product donations: Short-term donations or long-term

donation programmes based on the needs of a specific population. Donations of antibiotics may be made in emergency
situations, such as conflict or natural disasters, or to eliminate
a neglected tropical disease (NTD). For people living in poverty, donations may be their only chance of getting access tothe treatment they need.

10

Access to Medicine Foundation

What is the state of play for companies
looking to bring antibiotics and antifungals
to more people?
Antibiotics are essential medicines for all healthcare systems – yet the antibiotic

IN BRIEF

market is fundamentally broken. Tough market conditions are characterised by frag-▶ The antibiotic market is unstable,

ile supply chains, low margins for older medicines, small patient numbers for newer
medicines, and are compounded by variations in regulatory requirements. Numerous
pharmaceutical companies have left the anti-infectives market in recent years.11
The few companies that remain active in this space face some hurdles whenwith fragile supply chains and toughmarket conditions.
▶ Insight into local demand, diversifying
supply chains and long-term

they seek to introduce a product to a specific market. The incentives and choices

procurement strategies via tenders

they face differ between whether the product is novel and therefore on-patent, or

can mend the go-to-market model

whether it is an older, off-patent or generic medicine.

for older medicines.
▶ Access to on-patent medicines is

O FF- PAT EN T/G EN ER I C M ED I CI N ES

low in poorer countries. Working

Challenges with the go-to-market model for generic medicineswith partners on manufacturing and

The market for older, off-patent/generic products in low- and middle-income

implementing access programmes

countries (LMICs) – while serving many more patients than on-patent products –can help to deliver access at scale.

is challenging and uncertain. The complex and diverse challenges in the off-patent/
generic market for antibiotics and antifungals result in a lack of registration filingsof these essential medicines, especially in LMICs.
Companies lack insight into market opportunities, but are aware of thin profit
margins, resource-intense registration procedures and fragile supply chains. The
outcome of these challenges is that generic medicine manufacturers may only
enter bigger LMIC markets with clearer demand and higher sales volumes, and skip
poorer countries with smaller markets where people are most affected by antimicrobial resistance (AMR). In other cases, companies may opt out of the off-patent/
generic market for antibiotics and antifungals in LMICs entirely.
There are three structural factors that, tackled together, can facilitate the development of a replicable and scalable go-to-market model for such products in LMICs:
1. Insight into local demand via patterns of infection and resistance
Understanding local demand is key for companies that want to introduce theirgeneric antibiotics and antifungals into a new market. Without data on local
demand, it is more challenging for a company to assess whether the resources
invested and costs incurred when entering a new market are a reasonable
investment. Generic medicine manufacturers often do not have operations set up ina large proportion of LMICs. These companies have historically prioritised countries
with larger patient numbers and a greater capacity to pay for medicines, such as

Out of 19 surveillance programmes bycompanies identified by the 2021 Benchmark,five were running in at least one Africancountry.
High-income countries are consistently covered,
while countries in Central Asia and Africa are
Out of 19 surveillance programmes identified bysporadically covered by company surveillancethe 2021 Benchmark, only X were running in an
programmes.
African country,

Brazil, China, India, Kenya, Nigeria and South Africa.
Insight into local demand is necessary to make the case for registering generic
medicines, which is a vital first step to introducing a product into a market because
it allows importation and sale. The 2021 Benchmark found that only 14% of off-­
patent/generic products are filed for registration in 10 or more out of 102 LMICs it
covers. When companies fail to register medicines in LMICs, this has consequences
for local drug resistance. In South Africa, for example, many Access antibiotics areunavailable, so Watch antibiotics - broad-spectrum antibiotics with a higher poten-

Source: 2021 AMR Benchmark

tial for resistance - are routinely taken as a first-line treatment.
The level of local demand can be demonstrated by data from surveillance programmes, which track the rise of resistance and spread of infection in a given

11

Appropriate access to antimicrobials

region. This shows where there is an unmet medical need for a specific product,
which is important to decide whether and where to file for registration. Surveillance
programmes are typically run by governments and public health authorities. The
data is used to measure and respond to the spread of resistant infections and prioritise objectives for stewardship policies. In 2015, the World Health Organization(WHO) launched the Global Antimicrobial Resistance and Use Surveillance System(GLASS), which is the first global collaborative effort to standardise AMR surveillance. In LMICs, however, the use of surveillance programmes can be scarce, making
it difficult to map out the need for a specific product.
Another way to offset barriers to registration is to harmonise the regulatory
procedures used by countries in a region, or by using collaborative registration
procedures (CRP). Both of these approaches reduce the need for companies togather and submit different data sets for each country in which they want to introduce their products. Regulatory harmonisation and CRP can increase the numberof countries where companies file for registration. For example, the prospective
African Medicines Agency (AMA) can be helpful in simplifying the registration­procedure in participating countries.
2. Strengthened supply chains of APIs and finished products
Shortages and stockouts can be prevented by strengthening the supply chain for­medicines across all stages, from active pharmaceutical ingredients (APIs) to ­finishedproducts. A fragile and fragmented antibiotic supply chain is at greater risk of ­failure,
which can lead to stockouts and shortages and higher distribution costs. These­factors further erode the slim margins that characterise the market for generic­medicines and can increase the final price for the patient.
Manufacturing of key ingredients, or APIs, for antibiotics is concentrated in a few
regional hubs - mainly India and China. China, for example, is home to about 40%
of global production of APIs.12 Yet, antibiotic supply chains can be complex, withmany players. This leads to low visibility and accountability, with little alignment toensure supply matches demand. As a result, some populations face shortages, whileothers are offered poor quality medicines, or gain excessive access to antibiotics
that should be tightly controlled to keep resistance in check. The fragility of supply
chains for medicines has been further highlighted during the COVID-19 pandemic.
Closures of borders, spikes in demand, and supply interruptions have overwhelmed
and affected governments, pharmaceutical companies and health systems alongwith individual patients.
To strengthen supply chains, manufacturers can move away from single-sourceor limited supply chains of both APIs as well as finished products for antibiotics andantifungals. This may involve expanding the raw material supplier network and looking carefully at which suppliers to use. Technology transfers, capacity building, andcollaborations between multinational corporations and local manufacturers can allstrengthen supply chains and boost local availability of essential medicines.13
3. Sustainable procurement via tenders
Margins in the generics medicine market are slim, but tenders can be a way to­enable sustainable access to essential medicines. With hundreds of companies
manufacturing generic medicines, there is fierce competition to supply specificproducts. Further, because generic versions of the same medicine are by definition
identical, companies can predominantly compete on price but also on, for example,
supply conditions. This gives greater negotiating power to buyers, such as governments and other procurers, that typically use competitive tendering to procure
medicines in bulk. These tenders are generally structured so as to reward the­lowest bidder. Therefore, competitive tenders lead to more affordable prices
for patients, yet they can also lead to an unattractive market if the sales volume
expectation, as well as the price, is low.

12

Access to Medicine Foundation

The biggest complexity here lies in sales volume expectations, since it is hardfor pharmaceutical companies to predict demand. If demand for a product ispoorly understood, this can be aided through estimations of pooled demand by­procurement agencies. There is increasing awareness among buyers that promoting
long-term sustainability should be a key decision-making factor in procurement,
however this has yet to become mainstream practice. Encouraging long-term sustainability includes looking beyond pricing and quality of medicines at security andcontinuity of supply. This way, tenders can enable continuous access to antibiotics
and antifungals.
However, most patients living in LMICs pay out of pocket and tenders typicallydo not cover products that are paid this way, nor do they mean that pharmaceuticalcompanies should not use other access strategies to reach more patients in LMICs.
For example, the 2021 AMR Benchmark found that for a total of 148 antibacterial
and antifungal medicines, only 26% of off-patent/generic medicines are cov­ered byaccess strategies, compared to 41% of the on-patent medicines.
O N - PAT EN T M ED I CI N ES

Why on-patent antibiotics and antifungals are not introduced at scale
The number of novel, on-patent antibiotics and antifungals currently available isvery limited. Pharmaceutical companies that remain active in antibacterial andantifungal R&D are mainly focused on developing new antibiotics that will work

Antibiotics and antifungals covered by accessstrategies in the 2021 Benchmark

against multidrug-resistant infections, such as tuberculosis. The result is thatsuccessful new medicines are almost always classified as Reserve antibiotics,
prioritised for last-resort treatment and subject to stringent stewardship protocols.

131
medicines

17
medicines

On-patent antibiotics are usually only introduced in countries with an unmet
medical need and where specific conditions are met, including a financially viable
and sustainable market or payment model, and a health system that can prevent
misuse and overuse. The latter means the country should have suitable healthcare
infrastructure for stewardship measures, such as accurate and up-to-date treat-

Only 26% of off-patent/
generic medicines arecovered by accessstrategies

41% of on-patent
medicines are coveredby access strategies

ment protocols, essential diagnostics, and healthcare professionals with an understanding of resistance patterns, in order to avoid the development of resistance toSource: 2021 AMR Benchmark. This analysis

novel antibiotics. Many poorer countries do not have these systems in place and asassessed the portfolios of 17 companies.

a result, novel, on-patent antibiotics and antifungals are not introduced at scale topatients living in LMICs.
Differences in local health systems create a further layer of complexity.
International health organisations can take steps to address these further challenges. For example, in Ethiopia, where the limited reserves of foreign exchange aremanaged by the National Bank of Ethiopia, local distributors must depend on theamount of foreign exchange allocated to them, reducing the opportunities to purchase essential medicines. International health organisations, alongside companies,
are among the key stakeholders making medicines available. For example, Clinton
Health Access Initiative (CHAI) has a local programme that aims to increase accessto diagnostics and antibiotics to treat pneumonia, which causes 18 percent of allchild deaths in the country.14
To meet these challenges in the on-patent market, governments of high-income
countries and international organisations have been exploring push and pull incentives designed to stimulate pharmaceutical industry engagement and investment in
antibiotic R&D. Firstly, organisations such as CARB-X and several governments arepushing for more antimicrobial R&D by using market-entry rewards, subscription
models and grants. This could lead to more new product launches, thereby widening the pool of treatment options. Secondly, as a pull incentive, England’s National
Health System (NHS) implemented the world’s first antibiotic subscription modelin April 2022. Pfizer and Shionogi will supply their antibiotics ceftazidime/avibactam and cefiderocol to the NHS for a fixed fee of GBP 10 million a year each.15 Thismodel is intended to prevent over-prescription. If it is successful, use of this model
could help LMICs to demonstrate a financially viable and sustainable market.
13

Appropriate access to antimicrobials

There are three, currently underutilised, approaches that can ramp up access to
on-patent antibiotics and antifungals:
1. Mechanisms that make on-patent MDR-TB medicines widely available
The successful development of bedaquiline in 2012 prompted the development of a
successful, detailed stewardship model for a novel, on-patent medicine.
Bedaquiline, as well as other on-patent medicines that treat multidrug-resistantor extensively drug-resistant (MDR/XDR) tuberculosis (TB), are exclusively procured and provided via the Global Drug Facility (GDF) Stop TB Partnership. Thispartnership coordinates the supply of medicines to TB programmes run by national
governments with high burdens of this disease.
The partnership also supports in-country stewardship practices and surveillance
programmes. As a result, national TB programmes have uninterrupted access tohigh-quality, affordable medicines while also ensuring that these precious medicines are carefully stewarded. While more needs to be done, more than 140 countries have received TB medicines and diagnostics via the GDF partnership, reachingalmost 34 million adults and 2.5 million children since 2011.
MDR-TB medicines are also eligible for the WHO Prequalification process,where WHO assesses whether medicines meet certain standards of quality, safety
and efficacy. Prequalified medicines can be purchased by or through international
procurement agencies without registration, making them more easily available topatients in LMICs. WHO has expanded the scope of its Prequalification process
to products for other diseases, which creates opportunities for companies to also­efficiently expand access to antibiotics and antifungals using this process.
2. Local manufacturing and technology transfer are vital but limited
Local manufacturing makes it easier for products to reliably reach people living
in a particular country or region, particularly in the face of import restrictions anddisrupted supply chains. Disruptions to security of supply have been particularly
prevalent in sub-Saharan Africa during the COVID-19 pandemic, where up to 90% of
all medicines consumed are imported.17
Pharmaceutical companies can transfer their technology and expertise to­manufacturing partners in LMICs to increase local capacity. This improves accessto companies’ products while decreasing regions’ dependency on international supply chains and reducing the risks of shortages and stockouts.

10 companies support local manufacturing projects across 14 low- and middle-income countries
Of the 17 companies covered by the Benchmark, 10 report they are supporting local manufacturing in at least one of 102 LMICs.
This map shows the countries where at least one project is taking place.
10 pharma companies support local manufacturing projects across 14 low- and middle-income countries● Countries where companies are supporting local manufacturing

Source: 2021 AMR Benchmark

14

Access to Medicine Foundation

Despite the opportunity to form local partnerships, few such transfer initiatives
exist for both on-and off-patent antibiotics and antifungals. Decisions by companies
to transfer their technology depend heavily on the presence of local partners withthe right skills and quality standards. Finding suitable manufacturers to produce
on-patent products is particularly complex, due to the medicines’ novel chemical
structures.

How SMEs bring new products to market
Biotechs and small- and medium-sized enterprises (SMEs) are developing the bulk of thepipeline of novel, late-stage antibiotics and antifungals.16 In general, these companies do not yet
have products available on the market and depend on research funding to survive. Yet, due tothe lack of a healthy market for new products and the lack of acquisition of SMEs by large pharmaceutical companies, these SMEs must navigate the so-called financial “valley of death,” where
research funding runs out before financial returns of products kick in. When SMEs struggle tosecure resources to complete the development of their product and support its launch, often
leading to bankruptcy, this results in the loss of their pipelines of promising products. However,some SMEs are turning to partnerships with local companies in emerging economies, such as
China, India and South Africa, to reach worldwide markets.

3. Voluntary licensing agreements to ensure sustainable supply
To allow technology transfer for on-patent products, research-based companies
can use (non-exclusive) voluntarily licensing, which allows local generic medicine
manufacturers to produce and sell on-patent products. However, these licenses are
seldomly used for antibiotics and antifungals.
License agreements are more commercially attractive for generic medicine manufacturers when they are exclusive or only a few manufacturers can participate.
When this is the case, research-based companies may have more bargaining power
regarding the requirements to be included in the license, for example on access,quality of the product, stewardship and proper waste management for production.
However, such exclusivity does not drive competition between generic medicine
manufacturers, which means pricing of products might also not be competitive.
Affordability of products is further worsened when manufacturers need to warrant
appropriate use, compensate low sales volumes with higher prices, and in case theproduct is difficult and costly to manufacture, as previously seen in the case of delamanid (Deltyba®), an antibiotic used to treat MDR-TB.18,19 In fact, to date, no voluntary licence has been issued yet for a novel antibiotic, other than for delamanid.
In sum, while the market for antibiotics and antifungals is fundamentally unstablewith fragile supply chains and tough market conditions, there are factors that cancontribute to better access to essential off-patent/generic medicines in LMICs.
Insight into local demand, diversifying supply chains and long-term procurement
strategies via tenders can mend the go-to-market model for older medicines.
On-patent medicines are not introduced at scale because poorer countries often
do not have suitable healthcare infrastructure or stewardship measures in place.
Yet effective partnerships such as the Global Fund to fight AIDS, Tuberculosis andMalaria, increasing local manufacturing via technology transfer and the use of voluntary licensing can expand access to patented products. The following six casestudies include practical examples of how pharmaceutical companies have used
access strategies to make both off-patent/generic and on-patent medicines more
widely available.

15

Appropriate access to antimicrobials

Case studies
Only a handful of cases show tangible ways access was addressed in LMICs.
What are companies doing?
This paper builds on one of the keys findings of the 2021 AMR Benchmark, namelythat pharmaceutical companies are making limited use of the many ways toimprove access to antibiotics and antifungals in low- and middle-income countries(LMICs). Where access strategies are in place, they remain focused on a small set ofcountries, people and diseases.
In developing this paper, the authors could only identify a handful of examples ofways pharmaceutical companies used access strategies to make off-patent/genericand on-patent antibiotics and antifungals available in LMICs. However, these casestudies show that there are tangible steps that companies can take to address
access. Using the right combination of access strategies can make a real difference
to millions of people if deployed more widely.
These case studies have been drawn from research published in the 2021 AMR
Benchmark, as well as from interviews held with companies and experts in the AMR
field. It was further informed by sources available in the public domain. Informationfrom these sources was cross-checked directly with companies and their partners
to ensure accuracy.

▶ Case study 1:
Metronidazole, Sanofi, Nigeria▶ Case study 2:
Colistin, Cipla, India▶ Case study 3:
Flucytosine, Viatris, South Africa▶ Case study 4:
Liposomal amphotericin B, Cipla, India▶ Case study 5:
Cefiderocol, Shionogi, LMICs▶ Case study 6:
Ceftazidime/avibactam, Pfizer, Ghana

16

Access to Medicine FoundationC A SE S T U DY 1

Access to metronidazole via technology transfer and capacity
building
Via technology transfer in Nigeria, Sanofi has provided local patients with­sustainable access to metronidazole, a much-needed Access antibiotic to treat
gastro-­intestinal infections

Product: Metronidazole (Flagyl®)
Use: Broad-spectrum Access antibiotic(nitroimidazole class) indicated in pro­

What does this case study show?
Sanofi demonstrates it is possible for pharmaceutical companies to produce­products locally to high standards. To successfully transfer technology and build
capacity locally, companies must consider factors such as unmet medical needs,
clinical guidelines and the time needed to identify and onboard local partners who
can ensure product quality.

phylaxis and treatment gastrointestinal
and parasitic infections.
Scale: In 2019, intra-abdominal
infections (including gastrointestinal
infections) alone accounted for around
800,000 deaths associated with anti­
microbial resistance (AMR) globally.1

A ready path to financial returns
In sub-Saharan Africa only Kenya, Nigeria and South Africa have a relatively size­able
manufacturing industry, with several companies producing for local markets and insome cases for export.17 Supply chains remain international and fragmented, withmany raw materials and active pharmaceutical ingredients (APIs) sourced acrossborders. As a result, Africa produces less than 2% of the medicines it consumes
while its population accounts for nearly 17% of the world’s population.21
In Nigeria, where 70% of medicines are imported,22 Sanofi has performed technology transfers for an off-patent antibiotic called metronidazole (Flagyl ). Since®

2008, Sanofi’s transfers have allowed local partners to produce metronidazole,a first-line Access antibiotic on the 2021 WHO Model List of Essential Medicines.
Metronidazole treats gastrointestinal infections but has wide-ranging use. In

Company: SanofiPartner(s): Pharmaceutical manufacturer, May & Baker Nigeria Plc.
Country: Nigeria
Impact: May & Baker produces nearly
half a million boxes of metronidazole
annually for the Nigerian market.
Worldwide, Sanofi sold more than 32
million packs of metronidazole in tablet,
injectable and liquid form in 2017.20

Nigeria, it is mostly used for community- and hospital-acquired infections and­as a surgical antibiotic prophylaxis.23 With a market presence in Nigeria, Sanofi
embarked on manufacturing products locally to meet its own quality standards.
With a population of more than 200 million people,24 the country has a large­market and, as metronidazole is relatively easy to produce, offered a ready path
to financial returns.
Proactive approach to transferring technology
To produce metronidazole in Nigeria, Sanofi had worked with a local partner since2008. However, in 2015, Sanofi started partnering with May & Baker, once the subsidiary of a British chemical company that Sanofi had pre-existing links with, andone of the leading producers in Nigeria with Good Manufacturing Practice (GMP)
certification from the World Health Organization (WHO). In 2019, two technology
transfers were completed that involved upgrading plant production to state-ofthe-art manufacturing and Sanofi was issued approved registration by the Nigerian
Regulatory Authorities (NAFDAC).
The company’s transfers and training have built capacity to implement analyticalmethods, process validation and production of validation batches, preparation ofvalidation protocols and reporting for pharmaceutical products, and enabled May& Baker’s plant to meet GMP quality standards. Annually, May & Baker produces
about half a million boxes of metronidazole (tablets and liquid suspension) for the
Nigerian market. Its plant produces the antibiotic from active pharmaceutical ingredient (API) stage to final product, with packaging material manufactured locally but
raw materials coming from India, China and the United Kingdom .

17Appropriate access to antimicrobials

Import of medicines in Africa is much higher

Sanofi demonstrates best practice through continuing support. At first, May &Baker produced metronidazole tablets without coating, which lead to the medicine
tasting bitter, discouraging patients from continuing treatment. When the Nigerian
government asked for coating to be added, Sanofi sourced a UK supplier, dealt withpermissions and regulations, and provided technical support at May & Baker for

than
local
productionin Africa is much higher
Importof medicines
than local production
Africa produces less than 2% of the
medicines it consumes.

the coating technology. Sanofi performs annual quality reviews at the May & Baker
plant, carries out quality and Health, Safety and Environment (HSE) audits every
three years, and makes monthly reviews and quarterly site visits. Through technology transfer and corrective/preventative actions, Sanofi also improved the plant for
production of other medicines. To ensure appropriate use of metronidazole, Sanofi
does not promote this product to healthcare professionals, as it is strictly soldthrough distribution partners, and sales volumes are determined by supply-on-demand only.

In Nigeria, with a population ofover 200 million people, 70% of
medicines are imported.
Source: United Nations Africa Renewal,
2017 21, American Journal of Tropical
Medicine and Hygiene, 202022

Nigerian push and pull towards local manufacturing
Since 2019, the Nigerian government has stipulated that importing companies must, for adefined list of essential products, provide an action plan to localise production within 5 years.25 If
companies do not manufacture their products locally or through a local partner, they run the riskof losing product registrations.
In 2022, WHO announced that NAFDAC is the fourth African regulatory system that has
achieved a high maturity level in WHO classification and is now globally recognised as aneffective regulatory system. This status can further boost manufacturing capacity in the country
as it ensures medical products entering the market are safe, effective and produced according
to international quality standards. For example, Nigeria was chosen as a recipient of mRNA technology by the WHO mRNA Technology Transfer Hub, an initiative that builds capacity in low-andmiddle-income countries (LMICs) to produce mRNA vaccines.26

Next steps for local production in Nigeria
New challenges have come up in Nigeria with the government’s requirement for
production by local partners. Although this is a big incentive for pharmaceuticalcompanies to engage in local manufacturing, it also poses risks. Sanofi also sells
penicillin, beta-lactams and amoxicillin; for antibiotics that are trickier to make, suchas beta-lactams, it may take considerable time to find the right partners, transfer
technologies and meet quality standards. If challenges become severe and there islittle potential for return on investment, nor guarantees for stewardship, companies
may opt to leave the market or not enter it at all. To avoid such outcomes, the government could engage with companies to provide them with enough time to adjust
to the new stipulations.

18

Access to Medicine FoundationC A SE S T U DY 2

Access to colistin based on response to expert-signalled
demandBased on clearly defined demand, Cipla was able to provide access to colistin in
India. Colistin is an antibiotic used to treat multidrug-resistant infections in thelower respiratory and urinary tract.

Product: Colistin
Use: Colistin, administered as an injection, is an off-patent Reserve antibiotic

What does this case study show?
This case study shows that generic medicine manufacturers can work with experts
to determine and respond to demand in a particular country or region. Colistin is
a Reserve product, but the same principle applies to Access antibiotics, many ofwhich are older and also off-patent.

listed on the 2021 WHO Model List of
Essential Medicines used to treat multidrug-resistant Gram-negative bacteria,
including lower respiratory tract andurinary tract infections.
Scale: In 2019, lower respiratory infections accounted for more than 1.5 million

The need for older, generic antibiotics
Some older, generic antibiotics may no longer be produced or supplied by companies because of a lack of expected profit and a lack of awareness of or misunderstood demand, even though these medicines are still clinically useful. Most
older antibiotics are produced by multiple companies, yet those living in low-and­middle-income countries (LMICs) have very little access to these products since
they are filed for registration in only 5 out of 102 LMICs on average.

8

One example of how older antibiotics can be made available is colistin, which is
an off-patent antibiotic discovered in the 1940s. Since colistin can have side effects
related to toxicity in the kidneys, it was largely abandoned in the 1970s due tosafer alternatives. As resistance to other commonly used antibiotics increased in
the 1990s, colistin was then seen as an alternative for the treatment of multi­drug-

deaths associated with antimicrobial
resistance (AMR) globally.1
Company: Cipla
Partner(s): Infectious disease specialists,
Indian regulatory authority
Country: India
Impact: In 2020, Cipla distributed
colistin to 500 Indian hospitals, treating
20,000 patients in India per month.

resistant bacteria. It is now listed on the 2021 WHO Model List of Essential Medicines
in the Reserve group for the treatment of multidrug-resistant pneumonia and urinary
tract infections. The AMR Benchmark recommends that this antibiotic is made available by companies in LMICs, provided there are good stewardship practices in place toprevent toxicity and excessive use and reduce the risk of driving resistance.
Responding to local demand and ensuring stewardship
In 2007 in India, an infectious disease expert from a large private hospital made a direct
approach to the generic medicine manufacturer Cipla to request access to colistin
at their hospital after hearing the company’s global medical officer speak at a private­hospital event. At the time, the 50-year-old antibiotic was little used in India except inprivate hospitals, which imported the medicine from the UK to treat individual patients.
Cipla launched its own survey in India and found high levels of unmet ­medical need.
It then contacted an active pharmaceutical ingredient (API) supplier in Denmark anddiscussed with regulatory authorities in India how it might proceed to make the ­productavailable. High unmet medical need obviated the need for c­ linical trials, so Cipla conducted a Phase IV pharmacokinetic study and one effectiveness and safety study. After
successful trials, Cipla introduced colistin to the Indian market. Fifteen years later,
colistin is now widely available for human health in India and supplied by many different­companies, while still being an essential target for stewardship measures.
To ensure appropriate use of colistin, Cipla has supported education on treatment
guidelines for healthcare professionals and provided guidance on susceptibility testing – analysing pathogens’ vulnerability to antimicrobial medicines – to monitor the useof colistin in Indian ICUs. Cipla also supported an educational initiative titled Because
Kidney Matters on minimising kidney toxicity in patients that receive colistin.
Cipla repeated this formula, proving how effective responding to demand signalledby local experts is, when it answered a similar call to make (intravenous) fosfomycin
available. Fosfomycin is a Reserve antibiotic, like colistin, and is primarily used to treat
lower urinary tract infections. Cipla now sells this product in India, manufactured by athird party.

19

Appropriate access to antimicrobials

C A SE S T U DY 3

Access to flucytosine via partnerships and a clinical accessprogramme
Because of extensive partnership and a successful access programme, patients inSouth Africa with cryptococcal meningitis (CM) have access to flucytosine, a much
more effective treatment than a previous standard of care.

Product: Flucytosine
Use: An antifungal medicine used to treat
HIV-associated cryptococcal meningitis

What does this case study show?
With the flucytosine access programme, several stakeholders played an importantpart to ensure local availability to flucytosine despite an initial lack of registration bycompanies. Even though manufacturers were not yet ready to file for registration,action came through a clear push from South African specialists who wanted toensure patients could access better treatment.

(CM) in combination with liposomal or
deoxycholate amphotericin B.
Scale: CM is one of the leading causes ofdeath in people with advanced HIV/AIDS,
leading to about 180,000 deaths a year,
mostly in Africa.27
Company: Viatris

A new combination to treat CM
Flucytosine is a generic product with huge relevance for treating disease in Africa.
CM is one of the leading causes of death in people with advanced HIV/AIDS, leading to about 180,000 deaths per year globally, mostly in Africa.27 Undiagnosed anduntreated, the disease is fatal. In February 2020, the Lancet Infectious Diseases journal suggested almost 140,000 deaths occur annually in sub-Saharan Africa as a result

Partner(s): CHAI, MSF, Unitaid, Global
Fund, PEPFAR, FHI360, Strides, DNDi,
FARMOVSCountry: South Africaof CM.28 Yet, more than seven in ten people will survive with early, optimal treatment.

Impact: Viatris has supplied flucytosine

Results from an Antifungal Combinations for Treatment in Africa (ACTA 2018)

to 1,595 patients in South Africa as partclinical trial showed use of flucytosine (versus fluconazole) in combination withof this programme.

amphotericin B reduced deaths due to CM by about 40%. This strengthened calls
29

to increase access to the product as a “humanitarian, as well as a scientific imperative.”30 Flucytosine is now a life-saving component of new WHO-recommended
preferred and alternative treatment regimens for CM and it has received WHO
Prequalification.

Many HIV-positive patients living in low- and middle-income countries (LMICs) with CM will notreceive the right therapy, if any at all. In sub-Saharan Africa and elsewhere, where flucytosine has
been unavailable, healthcare professionals may combine amphotericin B with fluconazole or give
fluconazole on its own, which is never recommended due to inferior treatment outcomes.

Barriers to access
Flucytosine was developed in 1957 and has been off patent for decades, but its
production costs remain high, which leads to barriers in access. Reasons for thedelay in providing flucytosine to those who need access to it are interconnected andcomplex. At government level, the product is widely seen as unaffordable. Among
healthcare professionals in Africa, knowledge about flucytosine/amphotericin B islow, with few healthcare providers likely to choose flucytosine over fluconazole.

Cryptococcal meningitis (CM) is a leading causeof death in people with HIV/AIDS
CM is one of the leading causes of death inpeople with advanced HIV/AIDS, leading toabout 180,000 deaths globally per year, 140,00
CM
is a leading
cause of Africa.
death in people with HIVof whichin sub-Saharan

On top of that, standard formulations of flucytosine – four oral doses per day, withtablets often needing to be crushed and given by nasogastric tube if a patient has areduced level of consciousness – are difficult to use in low-resource settings.
Generic medicine manufacturers, expecting low demand and seeing little opportunity for profit or even return, have been reluctant to invest time and resources tofile for registration, scale up manufacturing and distribution operations, and makethis product available to populations in need.

75% of HIV patients who die ofCM live in sub-Saharan Africa
Source: Ending Cryptococcal Meningitis
Deaths by 2030 - Strategic Framework27

20

Access to Medicine Foundation

In South Africa, a country with a high HIV prevalence rate, flucytosine was registered by theSouth African Health Products Regulatory Agency in December 2021. Before that, the government’s so-called Section 21 exemption allowed clinicians to obtain unregistered flucytosine for
specific patients.31 This route supports patients on a case-by-case basis, but it does not ensure
broad access to unregistered medicines.

Birth of a clinical access programme in South Africa
Following the successful conclusion of the clinical trial for the combination of flucytosine with amphotericin B, pressure from clinicians in South Africa led to the establishment of a clinical access programme in 2018, aiming to bridge access gaps. In theongoing programme, Viatris is involved as supplier and Unitaid has provided funds
through a Clinton Health Access Initiative (CHAI) grant in order to ensure its continuation. Médecins Sans Frontières (MSF) initially set up the programme to procureand supply flucytosine to South Africa’s tertiary public sector hospitals before theproduct became widely available, after urging of the Southern African HIV CliniciansSociety and with support from South Africa’s National Department of Health.
Flucytosine has now been approved as part of the preferred treatment regimen
for CM in the South African National Essential Medicines List and in 2020 Viatris
filed for registration in South Africa, making more widespread uptake possible.
Registration was granted in December 2021.
Access programmes as transitional mechanisms
This access programme can be seen as a transitional mechanism to facilitate wider
access to medicine and to produce evidence of a market and a product’s importance to public health. Access programmes can demonstrate market potential andmotivate companies to file for registration, such as previously done for rifabutin fortuberculosis, direct acting antivirals for hepatitis C, and delamanid for drug-resistant tuberculosis. As such, programmes like this may form part of the solution to dismantle a vicious cycle of perceived low demand, although they should not be seen
as an alternative to sustainable widespread access to antibiotics and antifungals.
New developments for other countries
There are some new developments that can improve access to flucytosine in other
LMICs.32 Through the Global Fund, the U.S. President’s Emergency Plan for AIDS
Relief (PEPFAR) and FHI360, a non-profit human development organization, Viatris
underwent an independent dossier evaluation to allow global procurement prior toreceiving WHO Prequalification.
Viatris also worked with the Drugs for Neglected Diseases initiative (DNDi) to
develop a sustained-release formulation of flucytosine to facilitate twice daily dosing instead of the current four times daily. In early 2022, new Phase I clinical trialsof various prototypes of this modified release formulation were launched withFARMOVS, a clinical research organisation affiliated to the University of the Free
State in South Africa, with the aim to strengthen local capacity. Phase II studies ofthe most favourable prototype from Phase I are planned for Tanzania and Malawi.
Coordinating with partners to manufacture the product in India, Viatris reduced
the price from USD 110 to USD 75, and increased capacity to manufacture more
quickly. Viatris also worked with partners to allow procurement prior to WHO
Prequalification. Countries making use of this process include Botswana, Lesothoand Nigeria. CHAI reports that Viatris received WHO Prequalification and after aquality audit, Strides, another generic medicine manufacturer, gained FDA approval.
The company has yet to file for registration in South Africa.

21

Appropriate access to antimicrobials

C A SE S T U DY 4

Access to liposomal amphotericin B in response to agovernment request
Due to an effective response to a government request, more patients in India wereable to access liposomal amphotericin B during the COVID-19-related mucormy­
cosis epidemic in 2021.
In 2021, a mucormycosis epidemic broke out in India. Multiple risk factors contributed to this epidemic: a high background prevalence of mucormycosis in India,
undiagnosed or poorly controlled diabetes, COVID-19–induced immune dysregulation and therapies such as steroids, which cause immune suppression. The diseasereached an epidemic stage while many patients could not access basic healthcare
due to the COVID-19 pandemic surge.
In response to a request from the Indian government, Cipla rapidly scaled up
manufacturing of liposomal amphotericin B and quickly found contract manufacturers to scale up manufacturing drastically. The contract manufacturers temporarily
stopped manufacturing other products to prioritise this product. This case showsthat if pharmaceutical companies and governments work together, they can step up
to address issues that are time-sensitive and high demand in nature.

Product: Liposomal amphotericin B
Use: Liposomal amphotericin B can beused to treat mucormycosis, also called‘black fungus’ colloquially. The producthas a better safety profile than amphotericin B, a version of the medicine
without the drug delivery method called
liposome.
Scale: In India, prevalence of mucormycosis is estimated to affect 140 people
per one million.33
Company: Cipla
Partner(s): Government of India, contract manufacturers
Country: India

Black fungus in India
Mucormycosis is a very rare fungal infection with an overall mortality rate of approx. 50%.34 It iscaused by exposure to mucor mould which is commonly found in air, soil, plants, compost andanimal dung.33 In India, prevalence of mucormycosis is estimated as affecting 140 people in a
population of one million. Mucormycosis is difficult to treat. It may require antifungal therapy
as well as surgery to remove the infected tissue. Liposomal amphotericin B is the treatment ofchoice for both mucormycosis and COVID-19-related mucormycosis.

In India prevalence of black fungus is estimatedas 140 per million population. The mortality
approx. 50%.
rate is 50%.

Approx. 50% of people infectedwith black fungus will die
Source: Clinical Infectious Diseases, 202132

22

Access to Medicine FoundationC A SE S T U DY 5

Access to cefiderocol via innovative partnership
A partnership initiated by Shionogi is the first step to scale up the global production
and distribution of cefiderocol to meet global demand and provide patients accessto a novel antibiotic that treats multidrug-resistant infections.

Product: Cefiderocol (Fetroja®/
Fetcroja®)
Use: An injectable antibiotic active

A novel antibiotic that treats deadly pathogens
Shionogi, a research-based company based in Japan, produces cefiderocol underthe brand name Fetroja /Fetcroja . This siderophore cephalosporin antibiotic was®

®

first approved by the United States Food and Drug Administration in 2019 and uses
a novel mechanism of action against aerobic Gram-negative bacteria. It is includedin the 2021 WHO Model List of Essential Medicines as a Reserve antibiotic with thepotential to treat antibiotic-­resistant infections such as complicated urinary tract
infections (cUTI), hospital-­acquired bacterial pneumonia and ventilator-associatedbacterial pneumonia (HABP/VABP).35 Specific to cefiderocol is its activity against,
among others, drug-­resistant P. aeruginosa and A. baumannii, causing urinary tract,
intestine, blood and pneumonia infections in patients.36 These two pathogens
belong to the most deadly, drug-resistant pathogens worldwide, responsible for216.600 deaths and associated with more than 700.000 deaths in 2019.1
For smaller companies with limited manufacturing capacity, there are significant
challenges in making novel antibiotics accessible in low-and middle-income countries (LMICs). Shionogi reports high cost of goods and struggles to scale up production. The manufacture of cefiderocol is complex, requiring lyophilization and purification processes. Global partners can bring production costs down and production

against aerobic Gram-negative bacteria
to treat infections with limited treatment
options, including complicated urinary
tract infections (cUTI), hospital-acquired
bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/
VABP).35
Scale: Cefiderocol is active against­carbapenem- and multidrug-resistantbacteria including P. aeruginosa and A.
baumannii, which accounted for morethan 700,000 deaths associated with
antimicrobial resistance (AMR) in 2019globally.1
Company: Shionogi & Co, Ltd
Partner(s): CHAI, GARDPCountry: LMICs

to scale, but technology transfers require thorough preparation. The biggest hurdle
lies in the investment of time and resources to find large contract manufacturingorganisations (CMO) with the capability to master complex, high-volume production and to spur roll-out in LMICs while ensuring appropriate use.
A pioneering model for access through partnership
Shionogi only manufactures in Japan and, unlike large research-based companies,
lacks a footprint or expertise in local markets. Having recognised the challenge
to make its novel antibiotic available in LMICs by itself, the company actively
sought partners to improve access. In July 2021, it announced a Memorandumof Understanding (MoU) with the Global Antibiotic Research and Development
Partnership (GARDP) and the Clinton Health Access Initiative (CHAI) to accelerateaccess to cefiderocol in LMICs.37
Shionogi’s first-in-kind approach for increasing access to antibiotics has catalysed a still-nascent collaboration. GARDP aims to provide affordable and sustainable access, promoting appropriate use and stewardship of antibiotics (ensuring
suitable plans are in place), while CHAI will guide on how to reach patients in needDrug-resistant P. aeruginosa and A.
baumanii are two of the deadliest
pathogens
Together responsible for216.600
deaths and associated with more than

700.000
deaths in 2019

via market-shaping, in-country adoption of the product and programme delivery.38
The next major step will be to form a partnership with a large manufacturer.

Source: the GRAM report1

One way for Shionogi to increase access to cefiderocol is to follow the example of the licensing
and technology transfer agreement Otsuka has made with Viatris to produce and distribute a
generic version of delamanid (Deltyba®) to treat active, multidrug-resistant tuberculosis (MDRTB).39 Where delamanid is procured via the Global Drug Facility (GDF) Stop TB Partnership andhas a high demand, a global collaboration for antibiotics is lacking, which makes global access toaffordable antibiotics even more difficult.

23

Appropriate access to antimicrobials

C A SE S T U DY 6

Access to ceftazidime/avibactam via partnership and patient
assistance programme
Through partnering with a local health-tech company, Pfizer has enabled patientsin Ghana to better afford ceftazidime/avibactam, a much-needed Reserve anti­
biotic to treat multi-drug resistant infections.

Product: Ceftazidime/avibactam(Zavicefta™)
Use: An injectable antibiotic active

Making an on-patent antibiotic affordable in Ghana
There are several steps a company needs to take to make an on-patent productaccessible, including filing for registration, supporting stewardship and generating
return on investment. On top of that, companies need to consider affordability
since patients in low- and middle-income countries (LMICs) typically pay out of
pocket, which often makes novel antibiotics unaffordable for those who need them.
To counteract this problem, Pfizer set up patient assistance programmes withlocal partners in Ghana, including the health tech company mPharma. This partnership led to lower distribution costs, which typically drive up overall costs, as local
distribution in LMICs can be challenging. Together with price discounts provided

against aerobic Gram-negative
bacteria to treat infections with limited
treatment options, including complicated intra-abdominal infections (cIAI),
complicated urinary tract infections(cUTI) and hospital-acquired pneumonia(HAP), including ventilator-associatedpneumonia (VAP).
Scale: In 2019, intra-abdominal
infections alone accounted for around
800,000 deaths associated with anti­

by Pfizer and mPharma, this resulted in 50% patient savings. By further providing

microbial resistance (AMR) globally.1

patients with micro financing up to 60 days, ceftazidime/avibactam has become

Company: Pfizer

more affordable to those who urgently need it. Pfizer plans to implement a similar programme in Kenya in 2022. However, finding reliable, local partners that can
implement such patient assistance programmes can be challenging and therefore alimiting factor for bringing this practice to scale.

Partner(s): mPharma, a Ghana-based
health tech company
Country: Ghana

Pfizer’s pledge to make on-patent medicines and vaccines available at cost in 45 LMICs
Pfizer launched the initiative “An Accord for a Healthier World” in May 2022. With the Accord,
Pfizer aims to provide 23 of its on-patent medicines and vaccines on a not-for-profit basis to
45 LMICs, including all 27 low-income countries (LICs).40 The antibiotic ceftazidime/avibactam
is part of the Accord portfolio and Pfizer announced it will include all future medicines within
the Accord agreement.
Pfizer has committed to partnering with local health officials of participating countries andwill seek further global and local partnerships to improve diagnosis, professional healthcare
education and infrastructure, and supply chain management. Within the initiative, partners andparticipants will also work to identify ways to improve regulatory pathways (such as registration) and procurement processes to reduce the time it takes to make medicines and vaccines
available. Pfizer will pilot the initiative in Ghana, Malawi, Rwanda, Senegal and Uganda, to gather
learnings before rolling out to the remaining 40 countries.

24

Access to Medicine Foundation

D ISCUSSIO N

Collaboration between stakeholders is a key
ingredientThis paper has mapped out the chronic issues that are limiting access to essen-

IN BRIEF

tial antibiotics and antifungals in low- and middle-income countries (LMICs) and▶ Lack of access to antibiotics anddescribed strategies that pharmaceutical companies, governments, procurers andother (local) partners can use to increase appropriate access. The case studies inthis paper have demonstrated how different stakeholders can take action - they are
isolated examples that can become standard practices so that patients everywhere
receive the right treatment at the right time. The following discussion elaborates on
the key strategies to expand access to both off-patent/generic and on-patent antibiotics and antifungals.

antifungals drives AMR, yet there
is a stark lack of access initiatives.
▶ Local manufacturing reduces
underserved regions’ dependency
on fragile supply chains.
▶ Partnerships between different
stakeholders is a key denominatorto spur action.

Supporting local manufacturing and technology transfers in LMICs
Local manufacturing of antibiotics and antifungals in LMICs increases access toessential medicines, while reducing the risks of shortages and stockouts. For
example, in this paper’s first case study, Sanofi responded to local demand and set▶ Clarity on demand for specificproducts can prompt companies
to strengthen supply chains.
▶ Research-based companies canup local production of metronidazole in Nigeria via capacity building and technology

set up early access programmes

transfer. This practice shows that, with an existing infrastructure and reliable local

for novel antibiotics to close thepartners, it is possible for pharmaceutical companies to build local manufacturing

gap between first global launchcapacity for much-needed Access antibiotics. However, unlike Nigeria - home to more

and filing for registration inthan 200 million people24 - most LMICs have smaller populations and lower demand.

specific LMICs.

In these regions, rather than serving one country with one local manufacturing▶ Companies should proactively

plant, building regional manufacturing hubs that serve several countries has greatercommunicate with regulators topotential to meet the threshold of viability, expand limited manufacturing capacity,make registration processes fasterand make a financially sustainable impact in underserved regions.

and more efficient.

Besides pharmaceutical companies, governments can also spur the development of regional manufacturing hubs by promoting intra-continental trade. Tradebetween African countries, for example, accounts for only 15% of the continent’s
total trade, resulting in a high dependency on markets beyond Africa.41 Initiatives
such as the Economic Community of West African States (ECOWAS) Trade
Liberalization Scheme and the Africa Continental Free Trade Agreement seek tounite the typically small and fragmented African markets by addressing challenges
in export, regulatory requirements and logistical issues.
International health organisations such as the World Health Organization (WHO)can also offer solutions. In 2021, WHO initiated the mRNA vaccine technology
transfer hub in South Africa to build capacity for mRNA vaccine production acrossLMICs.42 Six African countries - Egypt, Senegal, Kenya, South Africa, Tunisia andNigeria - of 15 countries in total have emerged as the first recipients of the mRNA
technology transfer.43 Besides local manufacturers and WHO, partners of the initiative include the Medicines Patent Pool (MPP), Access to COVID-19 Tools (ACT)
Accelerator, COVID-19 Vaccines Global Access (COVAX), African Union, and theAfrica Centres for Disease Control and Prevention (Africa CDC). A similar programme needs to be considered to responsibly catalyse regional manufacturing ofessential antibiotics and antifungals in LMICs.
Identifying the right public-health partners
Pharmaceutical companies, international health organisations and governments
can partner to procure essential antibiotics and antifungals or fund and implement
access programmes. A good example is the case study involving the clinical access25

Appropriate access to antimicrobials

programme in South Africa for the antifungal flucytosine. International healthorganisations set up a partnership with a generic medicine manufacturer to ensure
access to flucytosine, even though the medicine had not been not filed for registration in any country in Africa. Viatris responded to the call for action and supplied
the essential antifungal. The partnership was funded by the global community supporting people living with HIV/AIDS, as flucytosine is used to treat HIV-associatedcryptococcal meningitis (CM).
Another example of partnership is the technology transfers Sanofi has set up
since 2008 with local manufacturing partners to produce metronidazole in Nigeria.
In 2019, local manufacturing in this country got a new impulse with a requirement
for pharmaceutical companies by the Nigerian government. Companies that wantto market anti­biotics in Nigeria have to locally manufacture these products, either
through a partnership with a local manufacturer or by setting up local manufacturing plants. While this policy aims for Nigeria to become less dependent on the international anti­biotic supply chain, it can also result in multinational companies exiting
the Nigerian ­market. Therefore, flexibility is warranted and alignment between thegovernment and companies is key to ensure the migration to local manufacturing isrealistic and timely.
In the fragmented market for on-patent antibiotics, partnerships between companies, international health organisations and governments can be a promising way
forward to increase appropriate access to novel antibiotics in LMICs. An example isthe case study where research-based company Shionogi sought out partnerships toreach more patients in LMICs with their on-patent antibiotic cefiderocol. Shionogi
initiated a Memorandum of Understanding (MoU) with Clinton Health Access
Initiative (CHAI) and Global Antibiotic Research and Development Partnership(GARDP) that aims to provide affordable and sustainable access, while also promoting appropriate use.
Another example is Pfizer’s recently launched “Accord for a Healthier World” initiative. With the Accord, Pfizer aims to provide its current and future on-patent medicines and vaccines to 45 low- and lower-middle-income countries on a not-for-profit
basis. Pfizer has committed to partnering with local governments and international
health organisations for implementation. Alongside making medicines rapidly available, the company intends to strengthen the local health systems of participating
countries with public and private partners. Sharing the burden of costs and tasks inthe production and the delivery of supplies is a critical first step towards overcoming
health inequity for the poorest countries in the world.
Finally, the Global Fund to Fight AIDS, Tuberculosis and Malaria and other international health organisations have partnered with companies to address HIV/AIDS,
tuberculosis and malaria. Despite being donor-driven and less sustainable in thelong term, these partnerships were able to consistently implement access andstewardship programmes for essential medicines. Access to antibiotics and antifungals should be defined as a priority on the global health agenda in order to facilitate
similar, effective partnerships. Recently, initial steps were taken to organise a global
partnership specifically for antibiotics called SECURE (see box).

First steps towards a global antibiotic access and stewardship facility
SECURE, an initiative developed by GARDP and WHO, aims to expand access to essential
antibiotics in LMICs by establishing relevant product portfolios of on- and off-patent antibiotics
per participating country, based on public health needs.44 The market-driven and sustainable
portfolios will be financed by development agencies, philanthropic institutions and the LMICs
themselves. The LMICs will be actively involved to ensure appropriate use of the antibiotics thatare provided. A 3 to 4 year-long pilot is expected to start at the end of 2022 to demonstrate thevalue of this novel, global antibiotic access and stewardship facility.

26

Access to Medicine Foundation

Defining local demand to introduce generic medicines
There is a need for global, regional and national efforts to measure and map
demand for essential antibiotics and antifungals, especially for first-line treatments. Lack of clarity on local demand is one of the reasons pharmaceutical­companies do not have the confidence to introduce or reintroduce older, off-­
patent/generic products into LMIC markets. If demand from governments and(pooled) procurement agencies is signalled strongly and clearly, this will trigger
companies to act by appropriately expanding access to essential products in thosecountries. Governments and (pooled) procurement agencies can signal demand in
multiple ways.
Governments can generate information on which antibiotics and antifungals
are being used in their countries and share insights on local resistance patterns
through surveillance of consumption and resistance. This in turn can provide clarityand demonstrate local demand. Once surveillance data has been gathered, demandcan be defined in national policies such as Standard Treatment Guidelines and/or
National Essential Medicines Lists. Companies can use these policies to anticipate
and meet the expected local demand. Furthermore, international health organisations such as CHAI, Médecins Sans Frontières (MSF) and the Pan American HealthOrganization (PAHO) have the potential to expand access to antibiotics and antifungals – more than they are already doing – by consolidating demand for multiple
countries through pooled procurement mechanisms, which can encourage companies to respond by increasing supply.
Once pharmaceutical companies understand demand, the next step is for themto commit to meeting the demand with uninterrupted supply of high-quality andsafe products. To encourage supply security, procurement agencies can include
continuous supply as an important criterium in tenders, in order to ensure diversityof reliable suppliers and reduce dependency on one or few suppliers.
Two case studies in this paper show that signalling demand helps to increase
access to essential products. For example, in the case study involving the antifungal
flucytosine, the Southern African HIV Clinicians Society raised awareness for anunmet medical need and recognised the opportunity for funding, since the productcan be used to treat HIV/AIDS patients. Another example is the case study where
healthcare professionals in India signalled a high unmet medical need for the anti­
biotic colistin to generic medicine manufacturer Cipla.
Making on-patent products available through license agreements and accessprogrammes
A viable way to incentivise research-based companies to ensure access to on-­patent products is to achieve a financially healthy market, whereby companies are­reasonably assured of a sustainable business. However, there are several actions
that companies and governments can take before this happens in order to increase
access to on-patent, essential antibiotics. These include voluntary licensing, accesspartnerships and early access programmes.
As voluntary licensing may not be widely suitable for on-patent antibiotics andantifungals due to low sales volume expectations and restrictive use measures,
license agreements can put heavier focus on other strategic considerations, suchas technology transfer, stewardship, and expansion of production into different­geographical regions. Biotechs or small- and medium-sized enterprises (SMEs)
that are developing new antibiotics are already exploring this approach.16
Research-based companies can set up early access programmes to make not yetor recently registered products available in places with dire need. Improved value
assessment tools for novel antibiotics, such as the Health Technology Assessments(HTA) used by governments and procurement agencies, can further support thelaunch of novel medicines in LMICs. In the meantime, generic medicine manufacturers do not have to wait to introduce essential novel antibiotics to the poorest

27

Appropriate access to antimicrobials

countries via license agreements. Many large research-based pharmaceuticalcompanies, such as GSK, MSD and Pfizer, have pledged not to file and/or enforce
patents in Least Developed Countries (LDCs), taking away the barrier for generic
medicine manufacturers to increase appropriate access. As a result, generic medicine manufacturers have an opportunity to develop, manufacture and market
products such as ceftaroline (Zinforo®), ceftolozane/tazobactam (Zerbaxa®) andceftazidime/avibactam (Zavicefta™) in LDCs while bearing in mind appropriate use.
To date, no such example has been reported.
Harmonising registration across regions
Filing for registration is the first step in providing access to essential antibiotics
and antifungals, whether the products are off- or on-patent. One of the ways thatstakeholders can create favourable conditions for pharmaceutical companies toincrease registration is through harmonisation of regulatory processes. Local regulatory bodies can align the registration processes between countries in the same
region to enable swift access to generic products. On top of that, regulatory bodies and WHO can raise awareness of collaborative registration procedures (CRP),
such as via mutual recognition procedures, among pharmaceutical companies.
Companies can then make use of CRP to file for registration in LMICs, especiallyafter a medicine has already been approved by a stringent regulatory authority suchas the United States Food and Drug Administration or European Medicines Agency.
Companies need to be proactive and enter conversations with regulatory bodies
to identify opportunities for improving the way of working and communicate about
efficiencies in the registration process to speed up procedures. In the case of novel
treatments or new indications for existing treatments, companies can set up early
access programmes to close the access gap between clinical trials and filing for­registration, since it may take years for regulatory bodies to approve a product.
Conclusion
The cases in this paper, in which pharmaceutical companies addressed local­availability to antibiotics and antifungals, show that collaboration and partnerships
between different stakeholders are key denominators to spur action. A lack ofappropriate access to essential antibiotics and antifungals is an urgent and significant
issue in antimicrobial resistance (AMR) as it drives resistance, yet there is a starklack of access initiatives linked to specific products and populations being run by
the pharmaceutical companies manufacturing these medicines.
All stakeholders need to step up and explore every opportunity within theircapabilities to support and accelerate industry efforts, integrating them within theirbroader AMR responses. The recommendations in the next section show what
each stakeholder can do to contribute to expanding appropriate access to essential
antibiotics and antifungals in LMICs, for patented as well as generic products. This
may include using multiple access strategies for the same products (see “How canpharmaceutical companies expand access?” and Appendix), but most importantly,
stakeholders need to work in partnership.

28

Access to Medicine Foundation

Recommendations
Research-based pharmaceuticalcompanies• Ensure that low- and middle-income countries (LMICs) have access to on- andoff-patent antibiotics and antifungals by applying a variety of access strategies
such as registration, technology transfers and voluntary licensing.
• Pursue collaborations with partners to expand access to on- and off-patent­antibiotics and antifungals in LMICs.
• Build regional manufacturing hubs in countries where there is already a local
presence or portfolio matching market opportunity by finding reliable local
partners.
• Commit to not file or enforce patents in Least Developed Countries (LDCs),
low-income countries (LICs) and middle-income countries (MICs).
• Set up early access programmes after completion of successful clinical trials tofill the access gap before registration of products is approved.

Generic medicine manufacturers• Ensure that LMICs have access to generic versions of antibiotics and antifungals,
depending on demand in these countries, by introducing relevant products incase of a high unmet medical need as defined by national health authorities andrelevant national policies such as Standard Treatment Guidelines.
• Enable production of more generic versions of off-patent antibiotics and anti­
fungals by participating in voluntary licensing when originator companies offer
the opportunity.
• Build regional manufacturing hubs in countries where there is already a local
presence or portfolio matching market opportunity by finding reliable local
partners.
• Develop, manufacture and market essential patented antibiotics and anti­fungals
in those countries where the originator company committed to not file orenforce patents.
• Apply for WHO Prequalification where relevant.

Governments

In low- and middle-income countries:• Define demand in the country for specific antibiotics and antifungals by including these products in policies such as Standard Treatment Guidelines and/or
National Essential Medicines Lists.
• Ensure that appropriate use and stewardship guidelines are part of Standard
Treatment Guidelines and that WHO’s Model List of Essential Medicines and
AWaRe classification are used appropriately.
• Set up surveillance systems to monitor the resistance and consumption of antibiotics and antifungals and ensure access to the right diagnostics. If there arefinancial barriers, explore options for investments such as from the World Bankor high-income countries (HICs).
• Financially support and incentivise the creation of local manufacturing hubs for
antibiotics and antifungals, including active pharmaceutical ingredients (APIs).
• Invest in intra-continental trade agreements and IP policies, such as the
Economic Community of West African States (ECOWAS) Trade Liberalization
Scheme and Africa Continental Free Trade Agreement, to streamline trade andlogistics of antibiotics and antifungals for small and fragmented markets.
• Utilise Collaborative Registration Procedures (CRP) where possible.

29

Appropriate access to antimicrobials

In high-income countries:• View antimicrobial resistance (AMR) as a global health security issue.
Governments can take a collaborative, balanced approach between Ministries of
Health, Finance and International Development to address AMR.
• Ensure a viable market for pharmaceutical companies developing new products
by implementing payment models that separate payment from sales volume, forexample through upfront market entry payment or a subscription style model
following the England’s National Health System (NHS).15
Regulatory bodies• Invest in regulatory harmonisation schemes, such as collaborative registration
procedures or mutual recognition procedures, to make it easier, faster andcheaper for pharmaceutical companies to file for registration within multiple
countries at the same time. Raise awareness about these types of schemes sothey can be better utilised by companies.
• In case of high unmet medical needs for specific products, engage with pharmaceutical companies to define and generate the data needed to file forregistration.

Procurement agencies• Consider security of supply as an important criterium in national and pooled­procurement processes on top of the lowest price in tenders. Use innovative
Health Technology Assessments (HTA) to assess the value of antibiotics andantifungals to society, rather than for individual patients.
• Collaborate with other procurement agencies to estimate pooled demand andcommunicate estimates to the pharmaceutical industry.

International health organisations• Partner with local governments and pharmaceutical companies to ensure accessto antibiotics and antifungals in LMICs in case of high unmet medical needs by
procuring medicines and funding or implementing access programmes.
• Build local manufacturing hubs by identifying local partners, including pharmaceutical companies, governments and other international health organisations,suitable for manufacturing and rollout of antibiotics and antifungals in LMICs.
• Raise awareness for WHO’s Prequalification process, so that more pharmaceutical companies submit relevant antibiotics and antifungals for Prequalification,and support WHO’s Expression of Interest process, which requests submissions
from companies when their products have great public health value.

Healthcare professionals• Follow Standard Treatment Guidelines to ensure antibiotics and antifungals areprescribed and used appropriately.
• Help define demand for specific antibiotics and antifungals within your country
so these can be communicated in national healthcare policies.

30

Access to Medicine Foundation

APPE N D IX

Access strategies
Access Strategy

Definition

Context

Company Example

Capacity Building

The company forms partnerships

Lack of capability and training areCompany: Sanofi

with local stakeholders to increasesignificant challenges. Companies

capacity (e.g. by training of staff

that demonstrate best practice often

Since 2008, Sanofi has been involved inor obtaining equipment and otherpartner with others, and/or open

capacity building in Nigeria to locally pro-necessary resources) in order totheir own offices locally. They also

duce the Access antibiotic metronidazole.

strengthen the supply chain.

work with other stakeholders (suchIn 2019, two technology transfers were

as governments and NGOs) to plancompleted that involved upgrading planttransfers of technology to enableproduction to state-of-the-art manufactur-

products to be made sustainably.

ing and Sanofi was issued by the Nigerian
Regulatory Authorities (NAFDAC).

Early Access

An Early Access Programme is a

The transition from Phase III clinical

Programme

pathway allowing patients to accesstrials demonstrating the efficacy of

medicines that are yet unregistered

a medicine to widespread accessin a country. These programmesin routine-care settings can be

typically include medicines forslow and tortuous.30 Early Accessserious or life-threatening diseases

Programmes are also known as com-when there are no other treatment

passionate use and named patient

options available, until marketing

programmes.45

No examples to disclose.

authorisation has been granted.
Company: GSK

Equitable Pricing

A targeted pricing strategy, which

Equitable pricing strategies are

Policyaims at improving access to medi-at the heart of patient-oriented

cines and vaccines for those in needbusiness operations. Such strategies

GSK applies equitable pricing to all its

by taking affordability for individ-

need to be sustainable in the long

off-patent products, devolving pricing

uals and healthcare systems into

term for both the pharmaceuticaldecisions to the company’s regional

account in a manner that is locallycompanies and the patients toGeneral Managers. They can negotiate low

appropriate. This means that prices

ensure maximum patient reachinter-country access prices to secure aare set within the ability of specificacross the income pyramid. In thisbroader reimbursement in public markets

populations to pay, with reference

way, companies can provide per-and by capitalising on excess stock oppor-

to a range of socioeconomic factors.

sonalised, income-tailored support

tunities to sell its products at a discount.

based on intra-country pricing
solutions and economic conditions
by focusing on the needs of local
populations and integrate accessstrategies into the delivery of theirhealth products.
Patient AssistancePatient assistance programmes are

In the case of on-patent medicines

Company: Viatris

Programme

defined as programmes initiatedand vaccines, companies hold theProduct: Pretomanid (Dovprela)by pharmaceutical companies that

key to access. Patient assistance pro-

provide financial assistance or free-grammes are not sustainable in theViatris offers pretomanid (Dovprela) to up

of-charge medicines for a defined

long-term but do take into accountto 40 eligible patients per year in every

patient population with limitedaffordability to help ensure fast

country where it is not registered, available

ability to pay.

access to new medicines in low- andfor free or on par with GDF access pricing.

middle-income countries (LMICs),

Low- and lower-middle-income countries

acting as a shortcut to innovative andwill be offered a price similar to that of theneeded medicines and vaccines.

GDF and Viatris will expand the programme if demand increases.

31

Appropriate access to antimicrobials

Access Strategy

Definition

Context

Company Example

Pooled Procurement

Pooled procurement is the formal

Access strategies for supranationally

Companies: GSK, Pfizer

arrangement where financial andprocured products are generally

Products: Pneumococcal 13-valentnonfinancial resources are com-better structured and applied more

(Prevnar 13®), pneumococcal 10-valent

bined across different purchasing

widely. Pentavalent and pneumo-(Synflorix®)

authorities to create a single

coccal vaccines, as well as the TB

entity for purchasing medicines ormedicines in scope, are procured

Pneumococcal vaccine prices are negoti-

vaccines on behalf of individual pur-through organisations including Gavi,

ated between companies and UNICEF andchasing authorities. Pooled procure-GDF and the Stop TB Partnershipare made available to Gavi countries at ament can be managed through aand distributed to a wide range ofmaximum price of USD 2.90 per dose. GSK

third party such as UNICEF, the Stopeligible countries.

and Pfizer have agreed to freeze prices for

TB Partnership, GDF or PAHO.46

their pneumococcal vaccines (Prevnar 13®
and Synflorix®) in Gavi graduated countries
for up to 10 years after graduation.

Price Caps

A price cap or price ceiling is a

To address affordability more

Company: Pfizer

maximum price that can be charged

efficiently, companies should look

Product: Ceftazidime/avibactam

for a product. A price cap is usuallyat implementing price reductions(Zavicefta™)

negotiated between a government

or price segmentation in more

and a pharmaceutical company tocountries, especially low-income

In 2020, Pfizer implemented a pilot

take affordability into account.

countries.

program, capping the price of ceftazidime/
avibactam (Zavicefta™) to reduce out-ofpocket expenditure for patients.

Product Donations

A short- or long-term donation of

Product donations continue to play

Company: Pfizer

products based on the expressed

an important role in controlling,

Product: Azithromycin (Zithromax®)needs of a country. Donations may

eliminating or eradicating neglected

be made in emergency situations,tropical diseases (NTDs) that

Pfizer is part of the International Trachoma

such as conflict and naturalaffect populations living in low- andInitiative (ITI), established in 1998. In 2020,

disasters, or may be longer-term

middle-income countries. For people

31.1 million treatments of azithromycin

to control, eliminate or eradicate aliving in poverty, donations may be(Zithromax®) were shipped to twelve

neglected tropical disease (NTD).

their only chance of getting accesscountries through the ITI. As of April

to the treatment they need.

2020, nine countries in scope of the AMR
Research Programme have been validatedby WHO as having eliminated trachoma
as a public health problem. More than 95
million people have benefited from Pfizer’s
donation programme.

Public-Private

A public-private partnership (PPP)

Public-private partnerships can be

Companies and products:

Partnershipis a partnership between one orused to expand access to medicines• MDR-TB medicine bedaquiline (Sirturo®),more public organisations andand vaccines by procuring and dis-the private sector to provide a

tributing these products in specificpublic asset or service in whichcountries or regions. These partner-

the private party bears significant

ships can also secure competitive

risk and management responsi-

prices and ensure good stewardshipbility and remuneration is linked

practices.

Johnson & Johnson• MDR-TB medicine delamanid (Deltyba®),
Otsuka and Viatris• M/XDR-TB medicine pretomanid(Dovprela), Viatris

to performance. The Access to

Most TB medicines are procured via the

Medicine Foundation also considers

GDF Stop TB Partnership, which ensuresa partnership between a non-profit

that national TB control programmes haveorganisation and the private sector

uninterrupted access to quality-assured

to be a PPP.

medicines by providing direct procurement
services and securing competitive prices,
contingent on good stewardship practices.

Registration

Filing for registration is a vital first

Registration is an important first

Company: Pfizer

step towards introducing a medical

step to ensure products are madeProduct: Ceftazidime/avibactam

product into a country, as successful

available for sale, especially in coun-(Zavicefta™)

registration means that a producttries with higher levels of disease

is now allowed to be imported andand inequality. Companies can show

Pfizer has filed its Reserve antibiotic

sold. Companies can register theira commitment to enter markets

ceftazidime/avibactam (Zavicefta™) for

products with the national regu-

in need by filing for registration

registration in 20 countries in scope of thelatory authorities of each country

with local regulatory authorities as

AMR Research Programme, including threeby filing dossiers with technical,

widely and rapidly as possible after alow-income countries (Ethiopia, Tanzania,

medical and scientific information.

product is first approved.

and Uganda).

32

Access to Medicine Foundation

Access Strategy

Definition

Context

Company Example

Technology Transfer

A pharmaceutical company

Pharmaceutical companies’

Companies: Otsuka and Viatristransfers knowledge about thedecisions to transfer technology

Product: Delamanid (Deltyba®)

process to make a specific medicine

depends on a variety of factors,

or vaccine to a manufacturing site

such as finding a local partner, local

Otsuka is has initiated a technology trans-

in a country where that product ispolitics and market environment,

fer to Viatris for delamanid (Deltyba®).

needed, along with the technology

political stability or good regula-

The first phase of the technology transfer

necessary to manufacture it.

tory standards. While low-income

was completed in 2020, allowing Viatris tocountries are not always able tomanufacture, package and distribute dela-

meet these conditions, stable andmanid in its own licensed countries. The

industrialised upper-middle-income

second phase of the technology transfer

and lower-middle-income countries

for full API manufacturing is on-going andmay present an opportunity for

was expected to be completed in 2021.

successful technology transfer.47
Tenders

Company: Novartis

A tender is a competitive procure-

Tenders can be an effective tool

ment procedure to supply medi-

for procurers (e.g., governments orcines or vaccines. The tendering

supranational procurement agencies)

Novartis’ tender bidding prices are set

process typically comprises priceto secure a volume of medicines orusing Novartis cost of goods with anand volume requirements and isvaccines at a specific price. Tenderadded minimum acceptable margin ascommonly used in many countries

bidding criteria can include additional

well as historical data and local insights

to encourage competition, particu-

aspects such as supply reliability.

from key accounts/buyers. Local insights

larly in lower-income countries orTenders often enable to drive com-

to define the tender price can take into

international agencies procuring on

petition and ensure the most suitableconsideration the last awarded prices, thebehalf of lower-income countries.46

agreement is secured between thelast awarded companies and the maximum

procurer and the company.

tender price determined by the National
Health Insurance Scheme concerned.

Tiered Pricing Policy

Tiered pricing, also known as

For most vaccines, companies apply

Company: Sanofi

differential pricing, refers to whentiered pricing policies that allow

Product: DTaP HepB IPV Hib (Hexaxim®)

differing classes of buyers arethem to adjust the prices of theircharged different prices for thevaccines to countries’ ability to pay,

Sanofi applies a tiered pricing policy tosame product. In the context ofsetting higher prices in middle- andprice its vaccines, including Hexaxim®. The

vaccines, low- and middle-income

high-income countries and offering

price is defined based on the channel ofcountries can be charged a reduced

lower prices in low-income countries.

distribution and the GNI per capita.

price compared to high-income

In low- and middle-income countries

countries.48

not supported by pooled procurement mechanisms such as Gavi,PAHO or UNICEF, companies still
have a responsibility to ensure thatability to pay is taken into account.49

Voluntary Licensing

A voluntary license is an authorisa-

How large research-based phar-

Companies: Otsuka and Viatristion given by the patent holder tomaceutical companies manage

Product: Delamanid (Deltyba®)a generic medicine manufacturer,

their intellectual property impacts

allowing the manufacturer tothe availability and affordability ofOtsuka has a voluntary licensing agree-

produce the patented medicine or

medicines and vaccines. For example,

ment with Viatris to accelerate access tovaccine, often at a lower cost. The

when rights-holding companies

delamanid in high TB burden countries,

license usually sets quality require-enable generic medicine manufac-

enabling delamanid to be locally manufac-

ments and defines the countries

turers to develop generic versions of

tured in India and resulting in a lower-costin which the licensee can sell thetheir medicines, it can increase theirgeneric version.

product.50

affordability, support supply, foster
competition and ultimately improveaccess. This is achieved through theuse of a non-exclusive voluntary
license – one important approach
among many to making a productaccessible.

API: Active Pharmaceutical Ingredient; GDF: Global Drug Facility; GNI: Gross National Income; MDR-TB:
Multidrug-resistant tuberculosis; M/XDR-TB: Multidrug- and extensively drug-resistant t­ uberculosis;
NGO: non-governmental organization; PAHO: Pan American Health Organization; TB: tuberculosis;
UNICEF: United Nations Children’s Fund; WHO: World Health Organization.

33

Appropriate access to antimicrobials

D E FI N ITI O NS
Access strategy

Broad-spectrum antibiotics

Pharmaceutical companies use access strategies to expand access to

Broad-spectrum antibiotics are antibacterial medicines that are active

their medicines in low- and middle-income countries. An access ­strategy

against a wide range of bacterial types and may be used to treat a wide

includes all activities and processes that pharmaceutical companies under-

range of bacterial infections.

take to secure a price and define a target population, while ensuring accessto the product short- and/or long-term. The strategy may apply to a

Extensively drug-resistant tuberculosis (XDR-TB)

defined set of diseases, products, therapeutic areas or to a subset of their

Extensively drug-resistant tuberculosis is a rare type of multidrug-resist-

portfolio.

ant tuberculosis that is resistant to isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line medicines (i.e.,

Active pharmaceutical ingredient (API)amikacin, kanamycin or capreomycin).

The active pharmaceutical ingredient (API) is the active ­pharmaceuticalcomponent of a medicine that carries out its intended effects. Some

Generic medicine­medicines, such as combination therapies, have multiple active ­ingredients

A medicine that is created to be the same as a known marketed brand-

that target multiple disease pathways and/or symptoms. The inactive

name drug (the originator medicine) in dosage form, strength, route ofingredients of a medicine are referred to as excipients.

administration, quality and performance characteristics, and intended use.
See also Originator medicine.

Antibacterial medicine
Antimicrobial medicine used to treat bacterial infections by directlyGram-negative bacteria­targeting the bacteria that causes the infection or the disease process

Gram-negative bacteria are bacteria that do not retain the crystal violet(as opposed to targeting the symptoms of the infection). Biocides are notstain used in the Gram staining method of bacterial differentiation due toconsidered antibacterial medicines. See also Antibiotics.

their bacterial cell wall.

Antibiotics

Healthcare Professional (HCP)

Equivalent to Antibacterial medicine. The term “antibiotic” is often used

Any specialised worker in any branch of healthcare that provides preven-inconsistently in literature to denote either a drug that targets any typetive, curative or rehabilitative services to the community.

of microorganism in the body or, alternatively, a drug that targets bacteria specifically.

Multi-drug resistant tuberculosis (MDR-TB)
Multi-drug resistant tuberculosis is caused by tuberculosis that is resistant

Antifungal medicine

to treatment with at least isoniazid and rifampin, which are the two most

Antimicrobial medicine used to treat fungal infections by directly targeting

potent tuberculosis medicines.

the fungi that causes the infection (as opposed to targeting the symptomsof the infection or toxins produced by the pathogen).

Narrow-spectrum antibiotics
Narrow-spectrum antibiotics are antibacterial medicines that are active

Antimicrobial resistance (AMR)

against a selected group of bacterial types. Examples include colistin, an

Antimicrobial resistance is the ability of microbes such as bacteria, viruses,

antibacterial that selectively targets gram-negative bacteria, and vancomy-fungi and parasites (protozoa or helminths) to grow in the presence of ancin, an antibacterial that selectively targets gram-positive bacteria.

antimicrobial substance (e.g., a medicine) that would normally kill them orlimit their growth. Resistance is a consequence of evolution via natural or

Off-patent medicine

artificial selection.

A medicine for which the granted patent protection has expired. Patent
protection typically lasts for 20 years and is specific to each country.

Antibacterial resistance
Antibacterial resistance is the ability of bacteria to become resistant toOn-patent/patented medicine

antibacterial medicines through mutational resistance and horizontal gene

A patented or on-patent medicine is a medicine that has received exclu-

transfer. Mutational resistance occurs when bacteria develop mutations insivity rights, allowing the patent holder to prevent or stop others fromgenes that affect the activity of the antibacterial medicine. Horizontal genemaking, using, selling or importing the medicine within the country thattransfer is the acquisition of genetic information by transfer from an organ-

granted the patent. The Antimicrobial Resistance Benchmark research pro-

ism that is not its parent.

gramme determines patent status for its products in scope through a process that combines data from selected regulatory authority websites (e.g.,Appropriate accessthe US FDA) and participating companies.

Improving the availability, affordability and accessibility of antimicrobial
medicines and vaccines while ensuring that these products are being used
responsibly by limiting their overuse and misuse to ensure they stay effective for as long as possible.

34

Access to Medicine Foundation

Originator medicine
The medicine that was first authorised worldwide for marketing, normallyas a patented product, on the basis of its documented efficacy, safety andquality, according to requirements at the time of authorisation. The originator medicine always has a brand name; this name may, however, vary
among countries.
Over-the-counter medicine
A medicine that can be purchased without prescription from a healthcare
professional.
Pull incentive
Pull incentives, in the form of extended exclusivity periods, higher reimbursement or market entry rewards, reward companies for bringing
new drugs to the market through lowering the uncertainty for return on
investment.
Push incentive
Push incentives, in the form of grants, partnerships or tax credits, areemployed to lower the cost of and de-risk research and development of a
new medicine.
Stewardship
A systematic and comprehensive process that aims to ensure that all
aspects of prescription (e.g., drug, dose and duration), dispensing and theuse of antimicrobial medicines are consistent with the available evidence
on how to minimise the emergence of antimicrobial resistance.

35

Appropriate access to antimicrobials

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36

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