Cell and Gene
Therapies
Health system progress in moving fromcutting edge to common practiceCOMMISSIONED BY

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice2

Contents
3

About this report

5

Executive summary

11 Country areas of focus
15 Introduction: What cell and gene therapies have to offer
18 Where CGTs stand and where they might take us
25 How the healthcare ecosystem will need to change
33 The CGT Readiness Scorecard
37 Detailed insights from the scorecard
55 Conclusion: Considerations for policy
57 References

Gilead and Kite are separate entities with an integrated vision for the
future of oncology. GILEAD and the GILEAD logo are trademarks of Gilead
Sciences, Inc. KITE and the KITE logo are trademarks of Kite Pharma, Inc.
© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice3

About this report

Cell and Gene Therapies: Health system
progress in moving from cutting edge
to common practice is an Economist
Impact white paper, commissioned
and funded by Gilead Sciences.
The study reviews the current availability ofcell and gene therapies (CGTs) and estimates
future numbers of therapies that are likely tocome onto the market up to 2031. We thendescribe the challenges which the technology
presents to various healthcare actors
and present a scorecard which examines
how well prepared nine countries are forrolling out CGTs. Further details about themethods and key findings from the horizon
scanning piece and the benchmarking study
are available in the Technical Report.
The report has been commissioned
and funded by Gilead Sciences, Inc.
The findings and views expressed in
the report do not necessarily reflect
the views of Gilead Sciences, Inc or
Kite, a Gilead Company. Economist
Impact bears sole responsibility andfull editorial control for this report.

The Economist Impact research teamconsisted of Anelia Boshnakova, Paul Kielstra,
Alan Lovell, Rosie Martin, and Clare Roche.
We would like to thank the following
individuals (listed alphabetically) who
have contributed their views andinsights for this paper via interviews:•

Dr Gareth Baynam, Medical Director,
Rare Care – Clinical Centre of Expertisefor Rare and Undiagnosed Diseases
at Perth Children’s Hospital•

Dr Michael Dickinson, Associate
Professor and Lead of the Aggressive
Lymphoma disease group within Clinical
Haematology at Peter MacCallum
Cancer Centre and Royal Melbourne
Hospital; Julie Borschmann Research
Fellow, University of Melbourne•

Dr Matthew Frank, Assistant Professorof Medicine in the Division of Bloodand Marrow Transplantation andCellular Therapy, Stanford University•

Sabrina Hanna, Founder,
The Cancer Collaborative© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice•Dr P. Joy Ho, Clinical Director of
Haematology, Haematology Lead in
Immune Effector Cell Therapies, andHead of Myeloma and Thalassemia/
Haemoglobinopathy Units at the RoyalPrince Alfred Hospital in Australia•

Dr Luigi Naldini, Director, San Raffaele
Telethon Institute for Gene Therapy•

Stephen Majors, Directorof Public Affairs, Alliance forRegenerative Medicine (ARM)•

Roudie Shafie, Director, OVID
Health, UK; Member of Secretariat,
Cell & Gene Collective, UK•

Yoshitsugu Shitaka, Vice-Chairpersonof the Forum for Innovative
Regenerative Medicine (FIRM), Japan4

We would also like to thank the following
individuals for taking part in our expert panel:•

Dr Jacqueline Barry, Chief Clinical
Officer and Executive Director of the
Cell and Gene Therapy Catapult•

Dr Michael Dickinson, Associate
Professor and Lead of the Aggressive
Lymphoma disease group within Clinical
Haematology at Peter MacCallum Cancer
Centre and Royal Melbourne Hospital•

Stephen Majors, Directorof Public Affairs, Alliance forRegenerative Medicine (ARM)•

Olivier Negre, PhD, Board memberof the French Society of Gene and Cell
Therapy, Co-President of the Gene andCell Therapy Institute in Paris, memberof the EuroGCT consortium, Head of
R&D for Smart Immune, co-founderand Partner at Biotherapy Partners.

•

Dr William W. L. Wong, Decision
Modeller and Associate Professor at
the School of Pharmacy, Universityof Waterloo and member of
the Ontario Health Technology
Advisory Committee (OHTAC).

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice5

Executive summary

Cell and gene therapies (CGTs) change ourindividual biological blueprints. They mightrewrite an individual’s DNA so that it nolonger codes for a tragic, early demise, or
remove faults which certain cancers exploit
to avoid immune systems. CGTs are noteasy to deploy: they require highly complex
interventions by multidisciplinary teams
who rely on complicated supply chains andwork in specialised facilities. Nor do theywork on every patient. Success, however,is common enough that individuals withpreviously deadly genetic conditions andcancers now have the realistic hope of a cure.

Our research shows that CGTs are likely
to become increasingly mainstream
during the next ten years.
The problem with this potentiallyrevolutionary new tool is that healthsystems do not easily take to revolutions.
CGTs are, in many ways, a whole new
way of delivering medicine. Accordingly,
actors across the health ecosystem—
including regulators, payers, providers, andpolicymakers – will need to move beyond
existing comfort zones. Our research showsthat CGTs are likely to become increasingly
mainstream during the next ten years, andthat stakeholders in healthcare have to act
now in order to prepare for their arrival.
The study’s key findings are:
The first fruits are still limited, but apotentially rich harvest is likely: Available
CGTs are still few: a total of 45 are approvedfor sale in at least one of the world’s leading
pharmaceutical markets. The treatmentson the market are likely just the first signsof a coming wave. Over 2,600 clinical trials
for CGTs were taking place in mid-2021.
Companies are conducting about half ofthese, and their investigations in this field
have more than doubled since 2015. We
project that by 2031 the US alone will have
100 approved CGTs and the European Union
70. As the volume of these therapies grows,
the kinds of conditions they address will
also expand—from largely blood cancers
and genetic rare diseases today to a range
of non-communicable conditions withmultiple causes and solid tumour cancers.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice•Reimbursement decisions: CGTs
present Health Technology Assessment(HTA) bodies and payers with high stakes
choices. The therapies can be very costly:
the list price of the most expensive is
up to $3.5m for a course of treatment.
Because often a single course is needed,
however, the value of these interventions
can still compare favourably to existingtreatments which may require lifelong
interventions. Like regulators, payers
will need to adopt new approaches inorder to make decisions amid uncertainty
concerning how long a CGT might remain
effective. Moreover, the high upfront
cost makes experimentation with new
kinds of payment arrangements—
spread over longer periods andbased on patient outcomes—more
appealing. These, though, have beenchallenging to make work in the past.

•

Healthcare provision: The highly
specialised requirements of CGTs andtheir high costs makes their delivery in alimited number of specialist centres themost viable approach. Health systems
need to develop those facilities, which
will require an ability to interact far
more closely with external stakeholders,
especially manufacturers, than in otherfields of medicine. Moreover, the centres
need to be integrated into health systems
more broadly. This will require extensive
education of primary care and specialist
clinicians, the development of diagnosis
programmes for conditions which CGTs
can now treat, and creation of formalreferral pathways to link up patients who
could benefit with the care now available.

The medical potential of CGTs will
require institutional as much as
scientific innovation: Actors throughout
the health system must address a range
of issues in order to deliver the rapidly
rising number of CGTs to those who could
benefit. The main challenges include:•

Regulation: CGTs do not fall easily
into the existing categories commonlyused by regulatory agencies: some aretreated as drugs, others as devices orprocedures. The kind of data relevant toregulatory decisions differ from thosefor other forms of medical interventions.
CGTs require (for the most part) a single
application, the effects of which should
endure for a very long time. This creates
uncertainty about which endpoints touse for approval. It may take years before
it becomes clear how well a treatment
lasts, or what the optimal initial doseis. Moreover, the number of patients
involved in many CGT trials, especiallythose addressing rare diseases, are small.
All of these factors will require a greateruse of conditional approval and ongoingcollection of real world evidence.

6© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

The CGT Readiness Scorecard measures
the state of progress across the healthcare
environment: Our Scorecard assesses
how well different countries are doing
currently in integrating CGTs into their healthsystems, and therefore how likely they are
to be able to provide these therapies totheir populations in future. The scorecard
looks in detail at six broad areas, or domains:
Policy and Planning; Regulation; HTA and
Reimbursement; Guidance and Pathways;
Infrastructure and Access; and Monitoring

7

and Evaluation. Each domain consists ofseveral individual indicators relevant to theareas in question. We have gathered dataon nine developed countries worldwide forinclusion in the scorecard: Australia, Canada,
France, Germany, Italy, Japan, Spain, the UK,
and the US. Because best practice on CGTs
is still developing, it would be inappropriate
to use the scores to compare country
performance overall. Hence, we have notcalculated aggregate national scores.

Figure 1: The Cell and Gene Therapy Readiness Scorecard
Indicator 5.2> 0.01> 0.03

FranceGermany

Italy

Japan

Spain

UK

USA**

> 0.02> 0.04

Canada*1 (out of 3)
1, 2, 3 (maximum score)

Australia

General0
1 (out of 2), 2 (out of 3)

1.1 National / regional strategy for CGTs

0-3

1

0

2

3

0

2

3

2

1

1.2 Horizon scanning programmes for CGTs

0-2

1

2

2

1

1

2

1

2

1

Score
range
Policy and planning

Regulation
2.1 Guidelines for regulatory approval

0-1

1

1

1

1

1

1

1

1

1

2.2 Dedicated regulatory pathways

0-2

1

2

2

2

2

2

2

2

2

2.3 Standards to address remaining clinical uncertainty

0-1

0

1

1

1

1

1

1

1

1
0

HTA and reimbursement
3.1 Guidelines for HTA of CGTs

0-2

2

2

2

2

0

2

0

2

3.2 Adaptive payment models

0-1

1

1

1

1

1

0

1

1

1

3.3 Role of patient organisations

0-2

2

2

2

2

1

0

2

2

2

4.1 Screening programmes

0-3

0

3

0

2

0

0

0

1

2

4.2 National guidelines/toolkits

0-3

0

1

0

2

1

3

3

2

2

4.3 Formal referral pathways

0-3

0

0

0

0

0

0

0

2

0

Guidance and pathways

Infrastructure and access
5.1 Dedicated budget for delivery of CGTs

0-2

1

1

2

2

2

0

2

2

1

5.2 Specialist patient treatment centres

rate

0.024

0.045

0.046

0.031

0.035

0.023

0.026

0.021

0.044

5.3 Programmes for equitable access

0-1

1

1

1

1

0

0

0

1

0

5.4 Training for healthcare staff

0-1

0

1

0

1

0

1

1

1

1

Monitoring and evaluation
6.1 Patient registries for CGTs

0-1

1

1

1

1

1

1

1

1

1

6.2 Electronic Health Records

0-3

2

1

0

2

2

1

3

1

1

Notes:* As care provision in Canada is delivered at provincial level, the score for indicators 4.1 and 4.2 is based on information relevant for Ontario, which has the largest number of residents.
** The score for the US for some indicators (e.g. 1.1 and 3.2) is based on information relevant for the Centers for Medicare & Medicaid Services (CMS).
Therefore it may not be representative for all health systems and/or payers.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice8

An analysis of the scorecard results
yields the following insights:•

Responses within the healthcare
environment tend to have beenreactive rather than strategic: The
rollout of CGTs to date does not reflectextensive top down policy. Instead,different parts of the health system seemto have responded to the challenges
involved as they have needed to facethem. Accordingly, regulators andpayment bodies have made moreprogress in wrestling with the issues
arising from these therapies, while
health systems tend to be further back.

•New innovative regulatory pathways
are helping CGTs reach conditional
approval, but monitoring of realworld evidence requires more work:
Regulators have made notable progressin the creation of new approval pathways
relevant to CGTs, such as the US Foodand Drug Administration’s Regenerative
Medicine Advanced Therapy (RMAT),
the European Medicines Agency’s
Priority Medicine (PRIME), and Japan’s
SAKIGAKE designations. These combine
assistance with regulatory procedureswith a willingness to consider new kindsof evidence on the road to conditional
approval. The tools to gather real world
evidence after such authorisation,
however, would benefit from more
attention. Patient registries are requiredof CGT producers, but are not necessarily
integrated with healthcare provider
systems. Spain’s VALTERMED is an
excellent example of how data can be
combined from numerous sources to thebenefit of a range of health stakeholders.

•

HTA bodies have been innovative inusing existing evaluation tools, but now
need to go further: Governments havemade progress in determining which of
their existing institutions and procedures
they will use to assess the value of
CGTs, and in making these decisions
transparent. The tools on which HTA’s
have relied, however, are largely thosefor rare disease and oncology because
they have the capacity to cope with manyof cell and gene therapy’s challenges
to date. As the range of conditions
which CGTs address widens, a morecomprehensive approach to assessment
will be necessary. Some countries havebegun to make changes. Canada has
seen regulators as well as a nationaland Quebec-based HTA cooperate forthe first time, and the EU’s new HTA
Regulation will lead to joint assessmentof CGTs by member states from 2025.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice9•

Payers have also focussed on
existing mechanisms rather thaninnovating: The uncertainty in outcomescharacteristic of current CGTs calls out
for some version of adaptive payments
which reward results. Similarly, the highupfront costs of these therapies would
make it desirable to payers to spreadout reimbursement. Both of thesedevelopments are visible in scorecard
countries. For the most part, however,payers have used procedures and funding
arrangements for high cost rare disease
and oncology drugs. Italian and Spanish
payers have gone further, putting in place
staged reimbursement arrangements,
although the maximum length of thesecontracts is currently only one year.

•

Policy is a work in progress with bestpractice still undefined: The strength ofgovernance covering CGTs varies widely
across countries. Some have made recent
progress, such as Germany in its HealthCare Development Act of 2021. It remains
unclear, however, which policies work
best. The scorecard’s policy scores do notseem to correlate with scores in otherdomains. This is partly because the mostextensive policies, which score best, havebeen in place too short a time to havean effect. More important, in so rapidly
developing a field, countries are stilllearning what works best. Flexibility anda willingness to innovate will serve healthpolicymakers best under such conditions.

•

Health systems are developing thenecessary specialist facilities, but
it is unclear how many are enough:Every scorecard country has specialist
centres for the delivery of some kindof cell or gene therapy. For medical
interventions this novel, it is unclear how
many facilities are sufficient. Experts
interviewed in countries which haveamong the highest number of centres
indicate that more will be required.
Patients need to spend extensive time
at facilities, not just for treatment,
recovery and monitoring, but to receive
sometimes extensive support services.

The strength of governancecovering CGTs varies widely
across countries. Some havemade recent progress, suchas Germany in its Health Care
Development Act of 2021.

•

Health systems need to do much
more to integrate CGTs into ordinarycare: While specialist centres exist, themost widespread weakness identified
in the scorecard is a lack in many
countries of systematic diagnosis of
CGT-treatable conditions, as well as
formal pathways for getting identified
patients linked up with such care.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

Five lessons for policymakers•

Healthcare systems must grapple withthe fundamental changes required for
introducing new therapies: Diagnosis
and referral systems for CGTs remain
weak; education of health professionals
needs to expand, and investment inspecialist facilities is currently insufficient.

•

Policy must remain flexible:
Policymakers and stakeholders
need to consider what is working
in other countries and be willing toexperiment with new policy models.

We identify five key insights for
those involved in healthcare:•••This is an issue requiring attention
today, not one that can wait
for tomorrow: Rising numbers of
new CGTs will address conditions
with larger patient populations.
Regulatory agencies must build
on progress and begin working
with healthcare systems to gather
real world data: Comprehensive
data collection is needed tosupport conditional approval,
and differences in rules between
countries should be reduced.

10

These are discussed in greater detail in ourconclusion. Full methods for both the pipeline
projection and the scorecard can be found in
the associated technical report [Add URL].

Payers must prepare to deal withhigh-cost, potentially high-benefit,
therapies in fields beyond oncology
and rare diseases: HTA bodies haveso far determined the value of CGTs byrepurposing existing processes rather
than substantially reshaping them.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice11Country areas of focus

The results of the scorecard can be used todescribe potential areas of focus for eachcountry. We describe here those parts ofthe scorecard that each country performed
relatively poorly in. Note that we have not
run any local workshops or in depth country
research, and therefore these should not be
considered recommendations. We discuss
the findings from the scorecard thematicallyin this white paper. Further details, including
methods, indicator descriptions, anddiscussions of scores by domain, can befound in the technical report.[Add URL]
Australia scores moderately acrossthe scorecard. While the country
scores maximum points in the HTA andreimbursement domain, there are many
areas where improvement is possible.
••

Regulation: While there is dedicatedsupport from regulators (the Therapeutic
Goods Administration) for developers,
there are no expedited approval
pathways for cell and gene therapies.
Similarly, there are no dedicatedprocesses to assess clinical uncertainty
through the regulatory pathway.
Guidance and pathways: Australia does
not score any points in the guidance
and pathways domain. This means that

there are no screening programmes,
national guidelines or referral pathways
that meet our scoring criteria. We note,however, that pilot programmes arebeing considered or underway for someof the conditions covered in our scoring
criteria. For example, the Australian
Capital Territory and New South Wales
both offer spinal muscular atrophy andsevere combined immunodeficiency
screening through pilot programs.
•

Specialist treatment centres: Australia
is in a group of four countries with thelowest rates of specialist treatment
centres. Added to the low rate is the huge
size of Australia, meaning that access tocentres will always remain challenging.

Canada scores well across the scorecard,scoring maximum points in the regulation,
HTA and reimbursement domains, and scoring
well in terms of infrastructure and access.
•National strategy for cell and genetherapies: Canada does not have anational long-term strategy for the
adoption of cell and gene therapies,
although it is currently working
on the development of a national
strategy for rare diseases, which is
expected to be finalised in 2022.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice•

Referral pathways: Canada does nothave any referral pathways that meet
our scoring criteria, although there
are some Province level initiatives. For
example, Cancer Care Ontario provides
a brief outline of the administrative
process for the enrolment of patientfor CAR-T therapies; however, this is
not a formal clinical referral pathway.

•

Electronic health records: Provinces
and territories are responsible fordeveloping their own electronic
information systems, with national
funding and support through Canada
Health Infoway. However, there is nonational strategy for implementing
electronic health records and nonational patient identifier.

France scores well across the scorecard,scoring maximum points in the regulation,
HTA and reimbursement domains, andscoring well in terms of infrastructure andaccess, and policy and planning domains.
•

Guidance and pathways: France does
not score any points in the guidance andpathways domain. This means that there are noscreening programmes, national guidelines
or referral pathways that meet our scoring
criteria. However, we note that informalreferral mechanisms are commonplaceand often efficient. Regional or local
guidelines, protocols or referral pathways
are not reflected in the scorecard.

Further details, including methods, indicator
descriptions, and discussions of scores bydomain, can be found in the technical report.

12•

Training: France does not have training
programs for healthcare professionals
and other staff in addition to thetraining delivered by manufacturers.
However, there are several university
programs that offer diplomas in
Innovative Therapies and Medicines,
including cell and gene therapies.

•

Electronic health records: France iscurrently in the process of establishinga national level integrated electronic
health record. Announced in 2019 as partof the ‘National Health Strategy 2022,’
the health record is still being developedand is not yet fully operational.

Germany scores very well acrossthe scorecard, scoring maximum
points in the regulation, HTA andreimbursement, and performing wellin the infrastructure and access, andmonitoring and evaluation domains.
•

Referral pathways: Germany does
not have any referral pathways thatmeet our scoring criteria. However, wenote that regional or local guidelines,
protocols or referral pathways are
not reflected in the scorecard.

•

Horizon scanning programmes:
The German Institute of Medical
Documentation and Information(DIMDI) focuses its horizon scanning
activities on the detection anddescription of technologies prior toMarket Authorisation. This includes theirweighting relative to other technologies,
and a description of associated orsimilar technologies. However, there
is no dedicated horizon screening
programme for cell and gene therapies.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice13

Japan scores moderately across thescorecard. While the country scores maximum
points in the regulation domain, there aremany areas where improvement is possible.
•

Adaptive payment models: There
are no special reimbursement models
for cell and gene therapies in Japan.
However, as the number of approved
cell and gene therapies are increasing,and becoming one of the drivers ofincreasing national medical expenses,
there are some discussions on introducing
specific pricing schemes. However,there is as yet little evidence of any
consensus emerging on what a new
payment model in Japan could look like.

•Role of patient organisations: There isno involvement of patient organisations in
HTA or reimbursement decisions in Japan.
Patient and public involvement is not wellestablished in Japan. Nevertheless, there
are ongoing initiatives. For example, theJapanese Pharmaceutical Manufacturers
Association established a committee topromote cooperation between patients’groups and member companies.

•

Dedicated budget for delivery of, oraccess to, cell and gene therapies:
There is no dedicated budget for the
adoption of cell and gene therapies.
Neither are there specific programmes
supporting patient access (for example,
support with travel-related expenses
for patients and carers, so that out-ofpocket costs are not a barrier for access).

Italy scores moderately across the scorecard.
While the country scores maximum points
in the regulation domain, there are many
areas where improvement is possible.
•••

National strategy for cell andgene therapies: Italy does not havea national long-term strategy for the
adoption of cell and gene therapies.
Guidelines for HTAs: HTA models in Italy
are not specifically adapted to cell andgene therapies. Italy operates multiple
HTA systems across various regions andbodies, such as the Italian Medicines Agency(AIFA), the National Agency for Regional
Health Services (AGENAS) and the National
Institute of Health (ISS). In September 2020,
AIFA published new draft HTA guidelines.
The new guidelines, which were approvedon 30 December 2020, do not containreferences to cell and gene therapies.
Programmes for equitable accessand training for staff: Italy has not
implemented programmes supporting
patient access (for example, support withtravel-related expenses for patients andcarers, so that out-of-pocket costs are nota barrier for access). Patient associations
do sometimes step in and provide this
support where they can. Also, Italy does
not have training programs for healthcare
professionals and other staff in addition to
the training delivered by manufacturers.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practiceSpain scores well across the scorecard,scoring maximum points in the regulation,and monitoring and evaluation domains.
•••

Guidelines for HTAs: None of the
HTA bodies in Spain have cell and genetherapies guidance, including the HealthTechnology Assessment Agency within
the Carlos III Health Institute, the Spanish
Agency of Medicines and Medical
Products, and the Ministry of Health.
Referral pathways: Spain does
not have any referral pathways thatmeet our scoring criteria. There is,however, a general referral procedure
to centres designated for the use of
CAR-T, through the Health Cohesion
Fund Information System.
Programmes for equitable access:Spain has not implemented programmes
supporting patient access (for example,
support with travel-related expenses
for patients and carers, so that out-ofpocket costs are not a barrier for access).

The UK scores very well across thescorecard, scoring maximum points in
the regulation, HTA and reimbursement,
and infrastructure and access domains.
•

Specialist treatment centres:
The UK has the second lowest rateof specialist treatment centres of thecountries included in our research.

•

Electronic health records: While active
electronic health record systems exist in
the UK, there is no national level integration(e.g., hospital data and primary care data
are not integrated). Similarly, there isno evidence that cell and gene therapy
data are easily accessible for regulatory
or reimbursement decisions, althoughclinical data collected by manufactures
is shared with NICE (when covered bynegotiated managed access agreements).

14

The United States scores moderately wellacross the scorecard. While the country
scores maximum points in the HTA andreimbursement domain, there are someareas where improvement is possible.
•

Guidelines for HTAs: The US does nothave guidelines for Health Technology
Assessment of cell and gene therapies.
The lack of a national HTA organisationor process reflects the decentralised
health insurance system, underwhich each private and public payer
makes its own coverage decisions andconducts its own price negotiations.

•

Referral pathways: The US does
not have any referral pathways
that meet our scoring criteria.

•

Programmes for equitable access: The
US has not implemented programmes
supporting patient access (for example,
support with travel-related expenses
for patients and carers, so that outof-pocket costs are not a barrier
for access). Some health insurancecompanies that provide access to celland gene therapies might have specificprograms for supporting patients, butthese programs are limited in scope.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice15

Introduction: What cell andgene therapies have to offer

Coming to grips with success
The future came early this time. Sabrina Hanna
is founder of the Cancer Collaborative, aCanadian organisation which seeks to bridge
gaps between relevant stakeholders for thatdisease. She remembers her reaction when,around 2016, she was asked to help consider
the health system implications of chimericantigen receptor T-cell (CAR-T) treatment: “I
had heard about it, but thought this is the stuffof the future, decades away. And lo and behold,here we were at this crossroad of how we
implement this.” Her reaction was not unique.
CAR-T is just one of several interventions
falling into the wider category of cell andgene therapies. Stephen Majors—Director of
Public Affairs at the Alliance for Regenerative
Medicine (ARM), a global, multi-stakeholder
advocacy organisation—recalls that even a few
years ago, typical reactions to CGT included“wow, this is kind of science fiction stuff.”“I had heard about it, but thought this is
the stuff of the future, decades away.
And lo and behold, here we were at thiscrossroad of how we implement this.”
Sabrina Hanna, Founder,
The Cancer Collaborative

The amazement has lessened to an extent
among experts. Mr Majors notes that now
some of these “therapies are a fairly establishedpart of the clinical landscape.” But they arestill very new for most patients: Dr Matthew
Frank – Assistant Professor of Medicine in the
Division of Blood and Marrow Transplantation
and Cellular Therapy at Stanford University –reports that “when you explain it to patients,
they find it futuristic, especially when you
say ‘you are becoming a genetically modified
organism.’” Even medical researchers stillsometimes share a sense of excitement at thepossibilities—likely similar to what colleagues
felt decades ago when antibiotics became
available. Dr P. Joy Ho—Clinical Directorof Haematology and Head of the Multiple
Myeloma and Thalassemia/Haemoglobinopathy
Units at the Royal Prince Alfred Hospital inAustralia – describes a recent trial: “it has reallyachieved a very, very deep response, one that
we have never before seen. We’re obviously
very impressed.” Dr Luigi Naldini, Director of
the San Raffaele Telethon Institute for Gene
Therapy in Milan, is even more effusive. He
recalls a trial of a therapy for metachromatic
leukodystrophy, a tragic disease of earlychildhood. “The treatment was a miracle,” hesays. “Even beyond our expectations because
we prevented the development of the disease.
The children are still very healthy, like normal.”© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

A growing number of CGTs are starting
to deliver on the field’s promise of newtreatments and cures for previously intractableconditions. However, even as researchers
become more used to rapid scientificprogress, thorny questions about how tointegrate these advances into health systems
remain: “what are the barriers? what are theopportunities? how do we get there?”
The pressure for answers, though, is growing.
Dr Michael Dickinson—a haematologist at thePeter MacCallum Cancer Centre in Melbourne,
as well as research fellow at the Universityof Melbourne—explains that “not just theincreasing number of cell and gene products,
but also evidence that they surpass the [existing]standard of care will create a stronger call foraccess.” This Economist Impact study considers
how prepared health systems in nine developed
countries—Australia, Canada, France, Germany,
Italy, Japan, Spain, the UK, and the US—are
to take advantage of what CGTs offers.

Defining terms
Cell and gene therapies are the most
rapidly advancing parts of a wider groupof interventions, which also includes tissue
engineering. In the US these are collectively
known most often as “regenerative medicine”
and in Europe as “advanced therapy medicinal
products” (ATMPs). While overlaps and importantsimilarities justify this general categorisation, celland gene therapies are also distinct fields.

16

Gene therapies are interventions which affecta person’s DNA in ways that prevent, treat, oreven cure a disease. Currently, the target
conditions usually arise from a deleterious
genetic mutation or a cancer. The therapy
can involve editing a problematic gene sothat it no longer promotes disease; replacing
it entirely with a healthy version of the gene;
adding new, therapeutic genes that target a
disease or help other medication to fight it;or silencing a gene which is over-expressing
enzymes. The genetic changes are introduced
through a vector—typically, although not
exclusively, a modified virus. Depending on
the treatment, the vector can work directly on
the individual’s body (called in vivo treatment)or on cells taken from the patient (ex vivo).
These modified cells are then reintroduced inways that will propagate the desired genetic
change within the person being treated.
Ex vivo genetic treatments are where geneand cell therapy overlap. Cell therapy involves
the introduction of new cells into the bodywith a clinical purpose. The original cells canoriginate within the patient (autologous) orfrom another source (allogenic). Depending on
the scope of this therapy’s definition, the cells
may not require substantial modification for
the treatment to be included: for example, ata basic level, blood transfusion falls into thiscategory. The most exciting recent cell therapy
developments, however, have come with exvivo manipulation of DNA to create a specificpost-implantation effect. CAR-T is probably
the best known application. Here, cells fromthe immune system are taken from the patient,modified genetically in a lab to recognise acancer affecting that individual, and then reintroduced. The net effect is to train the patient’s
own immune system to fight the cancer directly.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

A powerful but challenging tool to use
The highly simplified descriptions ofgene and cell therapies above belie hugedifficulties in execution. Dr Naldini notesthat some CGT treatments “are completely
novel” and highly complex. Yoshitsugu
Shitaka—Vice-Chairperson of the Forum for
Innovative Regenerative Medicine (FIRM),
a Japanese industry organisation—agrees:“these are very complicated procedures.”
Indeed, more generally, as a recent Gene
Therapy review article put it, “the patient,product, and system journeys for celland gene therapies are fundamentallydifferent than traditional medicines.”1
While in vivo treatments face important
manufacturing challenges, Dr Naldini says they
benefit from “relatively simple administration.”
A successful ex vivo autologous cell therapy
such as CAR-T, on the other hand, is not simply
a matter of knowing which cells to harvest,
how to keep them alive in transport, or themost effective way to re-introduce the cells
without creating an adverse short- or longterm reaction—all extraordinarily complicatedprocesses in themselves. Other extremelycomplex interventions are also needed.

“Gene therapies are generally more effective
the earlier they are administered, before
diseases can do significant damage.”
Stephen Majors, Director of Public Affairs,
Alliance for Regenerative Medicine (ARM)

17

Before giving a patient immune cells witha specific genetic mutation, for example,
clinicians need to ablate the patient’s own
immune system—in effect, coming as close
as possible to turning it off. Otherwise,
the patient’s body might not accept andbenefit from the modified cells. Of course,
between ablation and insertion of the ex vivo
cells, clinicians must rigorously protect thebiologically undefended patient from disease.1
Nor is the science fully mature. Dr Naldini
explains that finding improved vectors andways to reduce immune systems from blocking
CGT treatments “are areas which require
better understanding and improvement.”
Finally, these new therapies challengeestablished norms around how long to manage
patients for. Ideally, CGTs can change a person’s
DNA permanently, providing prevention andcure in place of managed decline and death.
In practice, it remains unproven how long theeffect of any given cell or gene therapy will
last, requiring ongoing specialist follow-up ofpatients who may be far more healthy thanthose who usually need such attention. Similarly,
the instinct of health systems presented witha new, expensive treatment is to use it as alast line of defence. For many CGTs, this may
be inappropriate. As Mr Majors puts it, “genetherapies are generally more effective theearlier they are administered, before diseases
can do significant damage.” Dr Naldini gives
as an example the new treatment he helped
develop for metachromatic leukodystrophy.
It works well for still asymptomatic patients
but can do much less for those with advanced
forms of the disease. In that sense, some CGTs
have more in common with a vaccine than adrug. “Sometimes you need to go against thestandard approach,” concluded Dr Naldini.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice18

Where CGTs stand andwhere they might take us

The current contribution of cell and genetherapies to the medical armamentarium
While CGTs are finally sufficiently numerous
to require consideration of how best to usethem within health systems, their potential has
been apparent for decades. South Korea, forexample, approved a cell therapy, Chondron,in early 2002. The journey of the science frombench to bedside has, however, been anything
but smooth. As early as 1999, the death in the

USA of Jesse Gelsinger, a patient in an earlygene therapy trial, drove home that harnessing
the potential benefits of the underlying
scientific advances would be complicated. The
death of Wei Zexi in 2016, after unregulated
immunotherapy at a hospital in China, rockedthat country’s biotech sector and brought
gene therapy trials there to a near standstill forseveral years.2 Until 2020, South Korea blocked
the development of gene therapies within its
borders, although not cell therapy research.3

Figure 2: Cumulative cell and gene therapy regulatory approval
16
16

South
SouthKorea
Korea

14
14

FDA
FDA
EMA
EMA

12
12
10
10

UK
UK

88
Japan
Japan

66

Australia
Australia
CanadaCanada

44

China
China
India
India

22

Singapore
Singapore
2021
2021

2020
2020

2019
2019

2018
2018

2017
2017

2016
2016

2015
2015

2014
2014

2013
2013

2012
2012

2011
2011

2010
2010

2009
2009

2008
2008

2007
2007

2006
2006

2005
2005

2004
2004

2003
2003

2002
2002

00

Source:© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

Despite these difficulties, researchers haveproduced a range of useful treatments.
Currently, 35 cell and 10 gene therapies haveachieved regulatory approval in at least one ofChina, India, South Korea, or the nine countries
in our study. Output is also accelerating.
Of these 45 CGTs, nearly half (22) received
their first approval in or after 2017.3,4Among this modest but growing number of
CGTs, those available to any given patient vary
markedly by geography. None of South Korea’s
16 licensed cell therapies, for example, havereceived approval anywhere else. Similarly, of thethree CGTs marketed in China, none have gone
through regulatory review in other countries.
The same is true for the two cell therapies
approved in India. Developed countries, incontrast, are moving slowly toward a common
pool of permitted CGTs. Of the 24 approved in
at least one of Australia, Canada, the EU, Japan,
the UK, and the US, 14 are allowed or underconsideration in two or more of these jurisdictions.
Three are available under all six regimes.3,4
The medical fields benefitting from these
CGTs also differ noticeably by country.
South Korea is again the outlier: medication

19

for burns, acne, and knee cartilage disorders
make up over half of approved treatments
there, but only 14% of CGTs elsewhere. Instead,well over half of CGTs approved by the US
Food and Drug Administration (FDA) and theEuropean Medicines Agency (EMA) address
blood-related cancers or rare genetic disorders.
In short, cell and gene therapy is no longera technology of the future. It has begun todeliver, especially over the last five years.
More important, the potential contributionof CGTs looks set to expand significantly.

Portents of a dramatically expanding
and increasingly diverse pipeline
Research on cell and gene therapy has
expanded rapidly. Clinical trials provide
a proxy for overall activity. By the end ofJune 2021, according to the Alliance forRegenerative Medicine (ARM), over 2,600 weretaking place, about evenly divided between
those conducted by commercial firms andones run by academic and governmental
bodies.5 The number of company-conducted
trials has more than doubled since 2015.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

The extent to which this activity will translate into
new therapies, however, is hard to predict. As
with clinical trials in general, most CGT trials will
be unsuccessful, especially as over 90% of current
studies are only phase I or phase II. Moreover,even successful therapies will need time to prove
themselves. Since 2013, in the USA, the averagetime for a CGT to go from the start of a phase I trial
to FDA approval has averaged five years.6 Manyof the drugs in question were for rare diseases oruntreatable cancers, and in such cases regulators
may permit use after completion of only earlystage trials, if results are promising. If a larger
proportion of CGTs address other medical needs,
where full phase III data are necessary for approval,
the average time involved will presumably grow.
The disease focus of CGTs is, indeed, likely toshift over time. Currently, just under two-thirdsof clinical trials listed in the American Society ofGene + Cell Therapy (ASGCT) database are for20

some form of cancer. The rest are spread over awide range of different categories of condition(Figure 3).7 This is consistent with what our expert
interviewees see as the likely targets for suchresearch in the near future. As Dr Ho observes,“in the short term, cancers will still be the biggest
focus. Haematological malignancies are themain cancers where patients are benefiting
because there are increased challenges withsolid malignancies—but people are working
on that.” Meanwhile, the ASGCT figures do notdifferentiate which trial target conditions are rare,
but a high proportion are likely to be, especiallythose in categories where “inherited” and “genetic”
appear in the description. Mr Majors believes that“the next couple of years are shaping up to be big
years for potential approvals of gene therapies
for rare disease. Five new gene therapies forrare diseases are up for approval in the USA andEurope in 2022, and the first CGT for sickle celldisease could be approved as soon as 2023.”

Figure 3: Cell and gene therapy trial categories (ASGCT, analysis Economist Impact)7
CancerCancer

1,992
1,992

Musculoskeletal
Musculoskeletalconditions
conditionsand
anddiseasesdiseases 207
207
Infectious
Infectiousdiseases
diseases

168
168

Blood
Blooddisorders
disorders141
141

Cardiovascular
Cardiovasculardiseasesdiseases

121
121

Neurodegenerative
Neurodegenerativedisorders
disorders

8989

OcularOculardiseasesdiseases

8282

Endocrine
Endocrinedisorders
disorders

6767

Skin
Skindisorders
disorders

6262

Genitourinary
Genitourinarydisorders
disorders

5858

Inherited
Inherited
metabolicmetabolicdisorders
disorders

5454

Respiratory
Respiratorydiseases
diseases

4747

ImmuneImmunemodulation/transplantmodulation/transplant

4545

Inherited
Inherited
immunodeficiencies
immunodeficiencies

4444

Gastrointestinal
Gastrointestinaldisorders
disorders

2828

Autoimmune
Autoimmunedisorders
disorders

2626

Liver
Liver
diseasedisease2020

Genetic
Geneticdisorderdisorder88© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practiceOver the medium-term, however, somereordering of priorities appears likely. Dr
Naldini, explains that “a big challenge that wehave to address in the future is that the field
is moving away from treating rare diseases.
These were sort of the testing ground andvalidated the strategy.” Soon, he adds, morecommon conditions will become the focus ofattention, including solid tumour cancers, heartdisease, and neuro-degenerative conditions—especially senescence. Others agree, and theearly drug pipeline suggests that the shift isalready beginning. Mr Majors says that within
phase I and preclinical studies “more thanhalf the CGTs in development target cancer,
and around 60% of CGT trials are targeting
prevalent diseases. In five to 10 years, you could
start seeing a pretty significant shift in focus.”
The geographic location of research isalso moving (Figure 4). During the quarter
century before 2015, only 2% of CGT trials
took place in China. By 2021, this was 10%.
Meanwhile, multi-country investigations, rare
before 2015, now account for 7% of activity.
Other major players, notably the USA and
UK, increased their number of trials, but
their share of global research dropped.8,9Figure 4: Percentage of gene therapy trials
per country (analysis Economist Impact)8,9
China

US

UK

Switzerland
CanadaGermanyJapan

Netherlands

Other

FranceAustralia

Multi-country

2016
1.42

2.22
2.31

1.11

1.55
1.82

6.92

3.95

9.45

2.44

66.81

2021
0.9
1

“A big challenge that we have to address in the 1.62
future is that the field is moving away fromtreating rare diseases. These were sort of thetesting ground and validated the strategy.”
Dr Luigi Naldini, Director,
San Raffaele Telethon Institute for Gene Therapy

21

7.1
6.1

1.2
1.5

3.5
7.3

57.2
10.1

The imp act of this change is difficult to guess.
To date, China has approved no foreigndeveloped CGT, nor have its products
obtained approval outside its borders. Chinese
researchers may focus on domestic unmet
needs. If, though, they look for treatmentswith potentially global markets, the impact
of CGTs across medicine will rise.
© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice22

Box 1: Projection Snapshot: How many CGTs will be available in 2031?
For each of our study countries, as well as China, India, and South Korea,
Economist Impact has looked at currently available CGTs and projected a
growth rate to 2031 based on, amongst other things, the existing drug pipeline,
institutions supporting CGT research, and budgetary constraints (Figure 5). The
methodology is explained in detail in the technical report.[ADD URL]
Figure 5: Overall estimates of approved cell and gene therapies
100

FDA

80
EMA
South Korea

60

UK
China
40

Japan
Australia
Canada20

India
Singapore
2030

2028

2026

2024

2022

2020

2018

2016

2014

2012

2010

2008

2006

2004

2002

0

Our projection puts the US well out in front by 2031, with 100 approved CGTs. Someway behind comes a second tier of jurisdictions, including the European Union (70approvals), South Korea (65), the UK (56), and China (51). Japan, which has a strong
policy interest in regenerative medicine, is expected to have only 37 approved CGTs
by 2031, while the technologies are projected to see even lower use in Australia(24) and Canada (20). Any growing political pressure in these countries to expedite
approval of therapies which have been cleared by the FDA or EMA might reduce thisgap with the upper tier. These projections are country specific and do not assess
the extent of overlap between jurisdictions. Therefore, we do not present a figure
for the number of unique CGTs which will be available in at least one market.
These figures suggest that the contribution to medicine of cell and gene therapies
will be important, but not dominant. At the projected rate, between 2022 and2031 the FDA will approve 8 or 9 CGTs per year on average. Since 2017, that bodyhas approved between 45 and 60 new drugs annually. Should this trend continue,
CGTs will make up around 15% to 20% of products coming on-stream.
© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice23

Box 2: Three scenarios: from revolution to business as usual

Scenario 1: A medical revolution from accelerating development
and adoption of new therapies
Under this scenario, the number of clinical trials for CGTs continues to grow. New kindsof cell and gene therapies, an increasing ability to leverage the same technology acrossmultiple platforms, and fast-track regulatory systems combine to allow the field to expand
dramatically. Obstacles to allogeneic stem cell therapies, such as graft versus host disease,are overcome, making treatments more accessible to patients than the current costly andtime-consuming autologous therapies.
Already clear signs of readiness to develop and implement these new therapies exist at
national levels. The Japanese health system, for example, is preparing for the logisticalchallenge of CGTs with large-scale construction of medical facilities and substantial publicprivate collaboration to ensure smooth functioning of manufacturing and supply chains.10
The UK government, meanwhile, is expanding its Cell and Gene Therapy Catapult, an
independent centre set up in 2012 to bridge the gap between clinical trials and full-scalecommercialisation of CGTs.11
Similarly, innovation to reduce the money and space needed for complex, expensive
processes is already taking place. To provide one example of this in action, in the past two
years, PCR tests for SARS-CoV-2 have moved from a lengthy three-step process in specialist
laboratories to a simple, one-stage point of care test.

Scenario 2: More hype than substance as CGTs have only modest impact
In this scenario, various factors—including unexpected limitations to the science itself,
difficulties in implementing it, and cost—mean that CGTs fall short of their current promise.
As with any innovation, the eventual success of CGTs is far from certain. For example, while
between March 2018 and March 2019, 188 new cancer trials were launched, nearly half that
number, 92, became inactive.12 Meanwhile, risks of side effects such as Cytokine-release
syndrome (CRS) and CAR-T cell-related encephalopathy syndrome (CRES) remain serious. As
yet unknown long-term side effects from both cell and gene therapies are also possibilities.
To reach its hoped-for potential, a near-term challenge for CGT research will be to overcome
the ongoing impacts of covid-19. At the same time, the willingness—or even ability—ofgovernments to fund research and expensive treatments may diminish. During the
pandemic, many developed countries increased their borrowing to unusually high levels inhistoric terms. Low interest rates increased willingness to do so. Rising inflation, and likely© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice24interest rates, as well as debates over the need for retrenchment, make it unclear at what
point the purse strings will tighten. In this scenario, the economic benefits of treatment
would be minimal, especially when discounted to take account of the years over which theyaccrue. Investment would therefore be unlikely to occur.

Scenario 3: CGTs remain an effective tool for oncology and certain rarediseases, but fails to have a wider impact
In this scenario, those working on specific cancers, especially ones affecting lungs and blood,
continue to find new uses for CGT. Progress against other cancers, however, advances slowly.
At the same time, capacity for broader CGT research contracts as companies shut down orsell off labs focussed on rare diseases before progress occurs on more common conditions.
Issues with rare disease research capacity have already begun to appear. For example,
GlaxoSmithKline sold its rare genetic diseases programme, including Libmeldy andStrimvelis, to Orchard in April 2018 in order to focus its CGT efforts on oncology. Morerecently, in February 2021, Novartis Gene Therapies was disbanded with the closure of alarge plant in Colorado that made Zolgensma for spinal muscular atrophy.
One reason for such a shift is that existing funding mechanisms provide a particular challenge
for rare disease. Early Access Schemes usually provide treatment for free before regulatory
approval. If, though, these are one-off treatments, it is unclear how the company would everreceive reimbursement.
Even where it is possible to charge for a treatment, the market may simply be too
small to be commercially viable. This was the case for Glybera, a gene therapy for
Hyperlipoproteinaemia Type 1. This rare disorder affects one in 250,000 people. That
population proved insufficient to make the treatment viable in Europe. Glybera was thefirst gene therapy approved by the EMA, in October 2012, but just five years later it waswithdrawn for commercial reasons.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice25

How the healthcare ecosystem
will need to change

Scientific advances are only one of therequirements for bringing new medical products
to patients who could use them. Demand
and the ability of the marketplace to use an
innovation matter as much as the possibilityof supply. National disease burdens shaperesearch priorities, and these are far from
immutable, as the arrival of covid-19 shows.
Healthcare combines the capacity for
rapid scientific advances and frustratingly
high institutional aversion to change. This
spells potential trouble for CGT adoption,
which will require regulatory, funding, andhealth systems to reshape substantially
their current ways of operating.

Regulatory approval
Cell and gene therapies do not fall neatly into
existing regulatory categories. Mr Shitaka notes
that, depending on the compound involved andhow it is used, Japanese regulators sometimes
treat a CGT intervention as a pharmaceuticalproduct and sometimes as a device. Dr
Dickinson adds that, in Australia, they mightalso be treated as procedures. Meanwhile, in
Canada, Ms Hanna reports that the first CAR-T
approval was as a device, the next as a drug.
Dealing with such ambiguity, says Dr
Dickinson, “is challenging for traditional
regulatory pathways.” More generally, therange of differences between CGTs and what
has come before mean that, as Mr Majors
puts it, “you can’t just take regulations put
in place for previous iterations of therapy
and apply them to cell and gene therapy.
Regulators and developers are in a learning
stage together now about what make sense.”
Three regulatory challenges give a sense of
the broader complexities involved. First, CGTs
typically require one, or very few applications,but ideally have a lifelong effect. This gives
rise to a body of interlinked regulatory issues.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practiceCompared to traditional therapies, thenecessary safety and efficacy data for CGT
trials are very different, as are the ways in which
they need to be collected. With CGTs, hugeamounts of information about the safety of
the initial procedure flood in quickly, including
the impact of apheresis or lymphodepletion.13
Other relevant safety data, though, might appear
years later, such as long-term immunogenicity
or insertional mutagenesis.14 In Japan, Mr
Shitaka says, CGT cases are legally required
to be followed up for ten years. In Germany,
there is no specific length, but 15 years is therough average.15 As Dr Naldini explains, lengthy
monitoring is needed because “we can expect
some adverse events to surface in the long term.”

Rather than waiting indefinitely, regulators
may have to accept surrogate endpoints andconsider the likelihood that these will correlatewith improvement in long-term quality of life.
Similarly, in judging treatment effectiveness,regulators must decide the appropriate evidence
to seek and for how long to collect it. Even for
CGT trials with very promising initial results,
says Dr Ho, “we don’t know how durable thatis.” Rather than waiting indefinitely, regulators
may have to accept surrogate endpoints, andconsider the likelihood that these will correlatewith improvement in long-term quality of life.
A second set of regulatory issues revolve aroundproblems of sample size. Ideally, a trial would
have two “arms” —large groups who are in all
relevant ways similar except that one receives
the treatment and the other is a control. The
current focus of so many CGTs on rare diseases
makes such an approach extremely difficult,and while researchers have been working
on designing rigorous trial protocols,16 CGT

26

trials are still more likely to be small, singlearm trials. These limitations continue to havea negative impact on approval rates.17
The third major shift is the relative importanceto CGTs of manufacturing, which is often
closely linked to individual patient treatment.
Then FDA Commissioner Scott Gottlieb
said in 2018 that typically regulators spend
80% of time in an approval looking at
clinical data and 20% considering productissues. For CGTs, he reported that those
proportions were roughly reversed, andthat “the more challenging questions relate
to product manufacturing and quality.”18
Addressing these, and other challenges, in theregulation of CGTs remains a work in progress.
So far, most countries have tried to pour thisnew wine into old regulatory wineskins.19 Moreinnovative regulatory agencies, however, arelooking at a range of promising ways forward.
These include: specific CGT regulatory
guidelines; pathways for breakthroughmedications in areas of substantial unmet
need; adaptive approval pathways; flexibility
in accepting innovative clinical trial design;and conditional approvals combined withongoing gathering of real world evidence.14,19-21

Balancing high known costs
and indeterminate value
Regulatory approval does not mean access.
Somebody has to pay for treatments,and for CGTs, the upfront costs can beconsiderable. Among approved treatments in
the United States, list prices range between$373,000 to $2.1m for a full treatment.22
The makers of Libmeldy, a CGT recently
approved by the EMA and UK authorities,
plan to go to market with a list price ofbetween $3m and $3.5m per treatment.23© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practiceCollectively, these kinds of costs can havea dramatic impact. A National Bureau of
Economic Research (NBER) Working Paper
projected that, by 2026, 23 CGT therapies
will have sales of $25.3bn in the US.22 Basedon EIU estimates, that comes to just over
4% of the pharmaceutical market that year.
The figure does not include expenses related
to specialist care and infrastructure needed
to deliver these treatments, nor the cost of
any new CCTs which had yet to enter trials
in 2021. Roudie Shafie, Founder of the Cell &Gene Collective—a UK coalition of biotech

27

and pharmaceutical companies—notes thatsuch high immediate outlays “bring huge
opportunities for patients, but present
enormous challenges for health systems.”
Such costs are already impeding the translationof promising innovations into standard
care. Since 2010, four treatments in South
Korea (20% of CGTs ever approved) havebeen withdrawn from the market, and in theEuropean Union that number is five—more
than a quarter of approved CGTs (Tables 1
and 2). The reasons are largely commercial.

Table 1. Cell and gene therapies withdrawn from EMA regulatory status
Therapy

MechanismIndications

StatusZalmoxis24,25

Geneticallymodified T cells

Haematologicalcancers

Approved August 2016, withdrawn October
2019 by MolMed S.p.A for commercial reasons.

Provenge(sipuleucel-T)26,27

Autologous
mononuclear cells

Prostate cancer

Approved Sep 2013, withdrawn May 2015 byDendreon UK Ltd for commercial reasons.

MACI

Autologous
culturedchondrocytes

Cartilage defects
in the knee

Approved June 2013, suspended November
2014 due to absence of an authorized
manufacturing site, Vericel Denmark
ApS decided not to renew in July 2018.

Glybera28,29

Gene therapy

Hyperlipoproteinaemia
Type 1

Approved October 2012, withdrawn
October 2017 as uniQure cited a lackof demand for the product.

Chondrocelect30,31

Autologous
cartilage

Cartilage diseases

Approved October 2009, withdrawn July
2016 by TiGenix NV for commercial reasons.

Table 2. Cell therapies withdrawn from South Korea3
Therapy

MechanismIndications

StatusLSK Autograft

Autologous skinkeratin cells

Skin burnApproved September 2010,
withdrawn March 2011.

Autostem

Autologous
adipose tissue

Subcutaneous
fat defectApproved February 2010,
withdrawn December 2010.

Hyalograft 3D

Autologous dermal
fibroblasts

Diabetic foot ulcer

Approved Sept 2007, withdrawn
December 2010.

NKM Injection

Acting lymphocytes

Malignant lymphoma

Approved August 2007,
withdrawn December 2010.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

Dr Naldini warns that “we are in that paradoxical
stage where treatments are potentiallyavailable, which are not going to be offered[because of cost]. This is something we have toaddress.” He adds that the shift away from rarediseases to other areas in CGT research is, inpart, driven by such market considerations.
One tempting solution for payers is to pressure
producers to reduce prices. While this may
work for larger pharma companies, in manycases the margins might already be slim.
Elsewhere the room for manoeuvre is evenmore limited. Dr Naldini points out that most
CGTs currently are being developed by small
biotechs. “In some cases, this is their only
product. If they don’t ask for high prices, theymight disappear,” he says. “It’s a complex model.”The problem is not that these treatments
necessarily lack value for money. The
NBER analysis cited above found that thecancer-fighting CGTs which it analysed
would, on average, have a cost per qualityadjusted life year gained of slightly under$50,000. This puts it just better than theintermediate care value range of the US
Institute for Clinical and Economic Review.22“ Cell and gene products have potentiallygood efficacy lasting for years, but haveusually not been fully evaluated. So, with
pay for performance, we may not know what
we are looking for in terms of performance,
what kind or outcomes, and for how long.”
Yoshitsugu Shitaka, Vice-Chairperson,
Forum for Innovative Regenerative Medicine (FIRM), Japan

28

Therefore the obstacle is not necessarily
inherent value for money. For many CGTs
the issue is that, as one 2021 analysis argued,“the current HTA process is inadequate
for evaluating these new therapies.”32
Sometimes, the high initial outlay required mayundercut payers’ willingness even to assess
cost-effectiveness. This, argues Ms Hanna,is short-sighted: “we know that these very
expensive treatments upfront reduce healthcare
costs down the line. I don’t think reimbursers
are really looking at that.” Meanwhile in Japan,
Mr Shitaka reports that although 16 CGTs havebeen approved, only one has gone througha Health Technology Assessment review.
Those officials willing to take a closer look,however, often have under-developed tools
with which to work. When assessing the value
proposition of these treatments, for example,
what should be included in the benefits?
Different national HTA bodies have distinct
policies in this area.33 For CGTs, cost-offsets
are a particularly relevant issue when a single,
albeit high cost, treatment could eliminate theneed for years of current care interventions.
Just as for regulators, payers need to makedecisions when the long term impact of CGTs
remains unproven. Mr Shitaka explains that, if
health systems want to pay based on the value ofresults, “cell and gene products have potentiallygood efficacy lasting for years, but have usually
not been fully evaluated. So, with pay for
performance, we may not know what we arelooking for in terms of performance, what kindor outcomes, and for how long.” On the other
hand, notes Dr Ho, waiting to make a decision
carries its own costs: “you cannot expect atherapy that clearly needs a lot of resources tobe developed if you keep waiting three or four
years to see if the patients have survived.”© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

Various proposals for ways to address these
problems exist. Such ideas usually include
some way of spreading out payments
over a longer period, be it a multi-year oran annuity arrangement. Schemes also
typically include some sharing of risk basedon outcomes. This might involve additional
payments as the effect of a given CGT
shows itself to be more durable, or having
companies provide refunds when treatment
results fall short of expectations.14,20,32-34

29

Amid these difficulties, what Mr Majors saysof the US payer landscape is more generally
applicable. Some, he says, have been working
on new models, but “by and large, thesystem still has a long way to go to be able
to accommodate therapies that may just be
given as a single dose, and may be durable
potentially for much longer than ten years. That
has to be solved if the CGT sector is ultimately
going to change the healthcare landscape.”

Innovation within health systems
These ideas are conceptually appealing.
Nevertheless, how to make them work is notstraightforward. As with regulatory uncertainty,
long term registries and comprehensive
electronic health records are necessaryfor evidence gathering to support sucharrangements. These are expensive. Bestpractice on how to apply outcomes-based
arrangements also remains underdeveloped. An
OECD review found that use of coverage withevidence development (CED) arrangements—in
which patient results are aggregated—have apoor record in reducing uncertainty aroundoutcomes. Pay-for-performance contracts,on the other hand, tend to be expensive andthe results for individual patients are often
not combined to give an overall idea of how
well a treatment performs as a whole.35

A challenge for CGTs is that, as one analysis
put it, they “frequently do not fit naturally into
established healthcare systems.”36 This helps
explain Dr Dickinson’s experience that, after
the approval of the first CAR-T therapies inAustralia, “my colleagues and I noticed that
we were getting far fewer referrals than weshould have for the size of the population.”
Similarly, Dr Frank recalls that, in his California
facility, “we expected many more patients thanwe saw.” The novelty of CGTs will accordingly
necessitate changes within health systems.
These begin with the creation of appropriate
care pathways. The first step, diagnosis,
remains a significant hurdle. Ms Shafiecomments “screening is a critical part of
the journey, without faster updates to© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

screening, patients fail to be identified,even when new pathways are introduced.
Therefore the ultimate value to patients,
families and health systems is not realised.”
Next, clinicians need to get used to referring
patients who might benefit. Dr Ho notes, when
her facility began delivering CAR-T therapy,“one of our big challenges was to educate
the referrer.” She adds that, still, “a lot of
haematologists have never had a patient who
has gone to have” such treatment. Dr Frankalso reports that “it took a lot of education,outreach, and networking to have the broader
community of oncologists understand this wasout there and effective. Understandably, there
is initial scepticism” of something so new.
The issue goes beyond simply advertising
the possibility of care. Dr Dickinson says that
weakness in training medical providers about
when to refer and “where the treatment
is best placed in a patient journey can be
major barriers” to the uptake of CGTs.

“It took a lot of education, outreach,and networking to have the broader
community of oncologists understandthis was out there and effective.
Dr Matthew Frank, Assistant Professor of Medicine, Division of Blood andMarrow Transplantation and Cellular Therapy, Stanford University
The capacity to provide these treatments
at scale also needs to be developed. This
will entail substantial workforce training. Mr
Shitaka reports a shortage of personnel able
to deliver CGTs in certain hospitals in Japan.
In Australia, Dr Dickinson expects “a real[human resources] demand in this space thatwill be difficult to meet quickly.” Similarly,30

in 2019, two leading American clinicians
wrote of “an educational void [which makesit] imperative to augment the practitioners’
literacy, competency and overall proficiency
in new knowledge and specialised skill.”37
Once sufficiently trained, these individuals will
have to work together closely. For decades,
healthcare providers have moved towardcross-specialty, team-based approaches.38
While the transition took extensive effort, Dr
Ho says that now “most tertiary and quaternary
hospitals are very used to multidisciplinary care.”
CGTs, however, will force further deepeningof multidisciplinary across remaining medicalsilos. Patients will also need access to expert
follow up, which might include access to services
such as nutritionist counselling, fertility teams,
or mental health support for patients andcarers. Moreover, notes Dr Frank, “Toxicities
can arise that are challenging,” he adds. “I had
a patient with a seizure more than a monthafter infusing the therapy four hours away inrural California.” He arrived by helicopter.
For such teams to be effective, continues Dr
Ho, the various relevant specialties still need“a huge amount” of additional education.
Moreover, the integration of effort will require
working with new stakeholders. For example,
manufacturers and physicians will have to
get used to coordinating.1 Dr Frank says that
“normally I don’t know my chemotherapy
manufacturers. With CAR-T therapy I know
the teams from all the manufacturing groups
well. I have their cell phone numbers.”
Finding such partners will be difficult for
healthcare systems, nor will it be easy to bringcell modification in house. Manufacturing
for CGTs looks set to remain a high costarea with significant human resource
shortages in the coming years.11,39,40© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice31

require things like point of care manufacturing
and sufficient ICU space to handle theneeds of these innovative treatments.”
Though inevitable and efficient, concentration
in a few centres does bring the ethicalchallenge of equity for those who live far fromtreatment facilities. Ms Hanna explains thatpatients in the Canadian province of British
Columbia face six-hour plane flights to reachthe nearest available centres in her country.
“It’s been a huge issue for us,” she adds.
Where resources are lacking to have facilities
close to patients, health systems will needmoney to take patients to those facilities.

Such assets, though, are typically in short supply
and invariably costly. This has led in Australia,
Dr Ho explains, to “the current model wherecertain hospitals are selected to deliver these
therapies. I don’t see that changing because I
don’t see that a huge amount of infrastructure
can be put into multiple hospitals to each do afew patients.” Her country is not unique. The
experts with whom we discussed the matterall expected that, for the foreseeable future,
CGT would be conducted in specialist centres.

All of the above costs money, and Mr Majors
notes that in order to offer these therapies,
providers “need to be able to get reimbursed
for them.” Given the novelty of CGTs, payers
will have to create new coverage categories.
For example, Mr Majors explains that in 2020,“the Centre for Medicare and Medicaid Services
established a DRG [diagnosis-related group]
code specifically dedicated to CAR-T therapies
for bloodborne diseases, which was expanded in
2021 to include certain other immunotherapies
as well. This enabled healthcare providers
to get reimbursed in a much easier fashion.
That’s a big first step.” Although payment
systems in the US differ from those in othercountries, the issue has wider resonance. Mr
Shitaka explains that, in Japan, fees for medical
procedures are relatively low compared tothose for drugs. Depending on how cell andgene therapy products are classified, this “isanother challenge for their wide usage.”

Ultimately, this need for concentration should inturn require health providers to consider facility
design. Ms Shafie says “if the UK government iscommitted to constructing 40 new hospitals,
they need to be built with cell and genetherapies in mind.” She argues that “this would

Healthcare systems, then, are complex
structures with all parts needing to bebroadly aligned in order to function. The
roll out of CGTs will require far more
substantial adjustments than the additionof one more treatment to the formulary.

Healthcare systems must also develop
specialised infrastructure islands in whichthese multidisciplinary teams can deliver CGT.
The appropriate facilities need the space andtools to provide these treatments, access tocertified manufacturing facilities, systems tomonitor outcomes—all of sufficient quality
to pass rigorous regulatory muster.41© The Economist Group 2022

Cell and Gene Therapies: Health system progressin moving from cutting edge to common practice32

Box 3: A pandemic’s collateral impact
As it has across healthcare, covid-19’s impact has reached the developmentof CGTs. Our interviewees expect that, looking back in five to 10 years,
the pandemic will have been a turning point of some kind in this field.
Where they differ is on the particular changes involved.
The pandemic may be instrumental in accelerating research in the future. It has reshaped
how clinical trials are run, explains Ms Hanna. She notes that, because of covid-19, “a lotof people are looking at different ways of delivering clinical trials so that they’re morepatient-friendly. For example, people are trying to find ways to bring clinical trials to thepatient versus bringing the patient to the clinical trial.” In this way, the pandemic has
accelerated a longer-term trend which should assist drug development in general.42
Meanwhile, the specific technology behind innovative covid-19 vaccines, says
Dr Naldini, may make government funders and regulators “realise the value of
research on areas like genetic modification, gene delivery, and RNA base vectors.
The effort to make the vaccine should also establish a pipeline for more rapid
and robust product development in the area of cell and gene therapy.”
At the other end of the pipeline, however, covid-19 could temporarily slow the approval
process. Mr Majors explains that, for the FDA, the same individuals who work on new
CGTs are also responsible for new covid-19 vaccines. The impact here will likely be
noticeable but limited. The Agency had estimated that it would be approving 10 to 20 new
CGT products annually by 2025. Mr. Majors indicates that FDA leadership has said theprediction is still viable, though the reality may be at the lower end of the prediction.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice33

The CGT Readiness Scorecard

Introducing the scorecard
In order to examine how well prepared healthsystems are for CGTs, Economist Impact hascreated the CGT Readiness Scorecard. It looks
at the current state of progress across six
domains—made up of 17 indicators—in ninemajor economies around the world: Australia,
Canada, France, Germany, Italy, Japan, Spain,
the UK and the US. The higher the scoreon each indicator, the more advanced or
prepared a country is in the relevant field.
Our data are inevitably constrained tomeasures of how well health systems are
doing at present. That said, the scorecard’s
underlying assumption is that countries which
are already further ahead in wrestling with thechallenges of CGT implementation will likely see
a more extensive, sustainable, and equitableroll out of these technologies in future.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

The domains are:••

Policy and planning, including theexistence of funded, formal policies topromote CGTs, as well as the formal
use of horizon scanning to prepare forchange in this rapidly growing field.
Regulation, including whether drug
approval agencies have developed
rules and pathways that deal withthe specific challenges of CGTs.

•

HTA and reimbursement, including theexistence of processes and payment
models adapted to the distinct value
propositions of CGTs, as well as whether
patients are involved in the HTA process.

•Guidance and pathways, including
whether screening, guidelines, andreferral pathways have been introduced
to make use of CGTs which have been
widely approved within these countries.

•

Infrastructure and access, including
the availability of facilities, trained
healthcare staff, budget, and assistancefor non-medical costs to provide
CGTs to all patients in need.

•Monitoring and evaluation, including theavailability of electronic health records(EHRs) and patient registries in order todetermine how well individual patients are
doing over time, as well as the aggregate,
long-term effectiveness of CGTs.

Some indicators are binary, recognising
the existence or not of a desirable asset for
using CGTs. Other metrics are more complex
qualitative assessments. For example, national34

policies for the advancement of CGTs are rated
from 0 points to 3, depending on the scope of
diseases covered and funding availability.
One indicator is quantitative: the number of
specialist patient treatment centres providing
some form of CGT per 100,000 population. (Fora more detailed description of the domains andindicators, see the Technical Report).[Add URL]
Use of the scorecard requires caveats. First, suchan exercise is constrained by the availabilityof internationally comparable data. Someareas were impossible to include because theinformation is not accessible or even existent.
Second, diversity in healthcare governancearrangements complicates meaningfulcomparisons. While the indicators give nationalscores, all of our countries split responsibility
for healthcare policy, funding, and delivery
between national and sub-national levels ofgovernment; in the US, private sector decisions
play a substantial role as well. Which levels ofgovernment do what varies widely by country.
Where it is impossible to get a full national
picture for a specific indicator, the performanceof the largest sub-national entity has served
as a proxy. In the UK, for example, data often
come from the English NHS. In several cases
for Canada, Ontario is used. Although in many
circumstances the only practical solution forscoring fairly, this approach has disadvantages.
Ontario, for example, is further ahead thanmany provinces on CGT-related matters, making
Canada’s scores, in a few cases, higher thana completely representative one might be.
Third, a benchmarking exercise likethe scorecard is impressionistic rather
than precise. The scores are a roughindicator of how countries are doing.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practiceMoreover, while each indicator is likely
to be valuable in the effective roll out of
CGT, we have no way yet to judge theirrelative importance. These treatments
have been available for too short a time.
As a result, this is not an index which provides
overall national scores, or even domain ones.

35

Instead, the only meaningful comparisons
between countries are for results on the same
indicator. More generally, this scorecard,rather than a way to reveal winners andlosers, is meant to start discussions about
existing strengths on which to build, andweaknesses that require attention.

Figure 6: The Cell and Gene Therapy Readiness Scorecard
Indicator 5.2> 0.01> 0.03

FranceGermany

Italy

Japan

Spain

UK

USA**

> 0.02> 0.04

Canada*1 (out of 3)
1, 2, 3 (maximum score)

Australia

General0
1 (out of 2), 2 (out of 3)

1.1 National / regional strategy for CGTs

0-3

1

0

2

3

0

2

3

2

1

1.2 Horizon scanning programmes for CGTs

0-2

1

2

2

1

1

2

1

2

1

Score
range
Policy and planning

Regulation
2.1 Guidelines for regulatory approval

0-1

1

1

1

1

1

1

1

1

1

2.2 Dedicated regulatory pathways

0-2

1

2

2

2

2

2

2

2

2

2.3 Standards to address remaining clinical uncertainty

0-1

0

1

1

1

1

1

1

1

1
0

HTA and reimbursement
3.1 Guidelines for HTA of CGTs

0-2

2

2

2

2

0

2

0

2

3.2 Adaptive payment models

0-1

1

1

1

1

1

0

1

1

1

3.3 Role of patient organisations

0-2

2

2

2

2

1

0

2

2

2

Guidance and pathways
4.1 Screening programmes

0-3

0

3

0

2

0

0

0

1

2

4.2 National guidelines/toolkits

0-3

0

1

0

2

1

3

3

2

2

4.3 Formal referral pathways

0-3

0

0

0

0

0

0

0

2

0

Infrastructure and access
5.1 Dedicated budget for delivery of CGTs

0-2

1

1

2

2

2

0

2

2

1

5.2 Specialist patient treatment centres

rate

0.024

0.045

0.046

0.031

0.035

0.023

0.026

0.021

0.044

5.3 Programmes for equitable access

0-1

1

1

1

1

0

0

0

1

0

5.4 Training for healthcare staff

0-1

0

1

0

1

0

1

1

1

1

Monitoring and evaluation
6.1 Patient registries for CGTs

0-1

1

1

1

1

1

1

1

1

1

6.2 Electronic Health Records

0-3

2

1

0

2

2

1

3

1

1

Notes:* As care provision in Canada is delivered at provincial level, the score for indicators 4.1 and 4.2 is based on information relevant for Ontario, which has the largest number of residents.
** The score for the US for some indicators (e.g. 1.1 and 3.2) is based on information relevant for the Centers for Medicare & Medicaid Services (CMS).
Therefore it may not be representative for all health systems and/or payers.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice36

A look at the overall results
Figure 6 shows the scorecard results bycountry for each indicator. The following
sections examine in detail these outcomes
and their implications for how the healthcare
environment needs to evolve. Before turning
to that more focused analysis, the scorecard asa whole gives rise to several general findings:
Results within domains reflect how
innovation progresses through healthcare:
One of the most striking visual messages fromthe scorecard is the variation in performanceacross domains. All the countries have madeextensive progress on regulation and most on
HTA and reimbursement. Meanwhile, the fullmarks across the board on the patient registries
indicator is directly related to regulatory
advances: regulators typically require that
producers of a CGT maintain such databases
for all individuals who receive their treatments.
The gaps in scorecard results are noticeably
greater in fields related to the provision ofhealthcare. This is particularly obvious in theguidance and pathways domain, but also visible
to an extent in the healthcare infrastructure
indicators. The difference in results in these
domains reflects the tendency of all parts of
the healthcare ecosystem to deal with issues
as they present themselves. As Dr Frank points
out, “the technology [behind CGTs] has beendeveloped over 25 years but, in terms of realclinical impact, it has been five or six years orso” since the first patients began to benefit.
The advent of cell and gene therapy appears
more driven by science and markets thanpolicy: A largely reactive response to CGTs

within the health ecosystem, rather than acoherent, broad effort to induce progress,
is consistent with other scorecard results.
Although a later section discusses in moredetail the link between policy and results,
worth noting here is that performance in thepolicy domain is generally weaker than forregulation or HTA and reimbursement.
Strengths and weaknesses exist in every
country: None of the scorecard states has
comprehensive arrangements in place tomake the most of current and future CGTs.
Eight out of nine score zero on at least one
indicator, and the average is four zeros per
country. The exception is the UK, which always
scores something. Nevertheless, it neverreaches three out of three on any of the fiveindicators with that many points available.
Although perhaps predictable for treatments
which are still this new, it remains important tounderstand just how varied performance is.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice37

Detailed insightsfrom the scorecard

This section draws out lessons from thescorecard results under four broad themes:
regulatory innovation; value and funding; healthcare
pathways and infrastructure; and the link
between policy and broader system change.

All except the last use indicators from morethan one domain. For an indicator by indicatorand domain by domain discussion of theresults, see the Technical Report.[Add URL]

Regulatory Innovation
Figure 7: Regulatory and related scores

USA

UK

Spain

Japan

Italy

1, 2, 3 (maximum score)

Germany

Score
range

Canada1 (out of 2), 2 (out of 3)

France1 (out of 3)

Australia

0Regulation
2.1 Guidelines for regulatory approval

0-1

1

1

1

1

1

1

1

1

1

2.2 Dedicated regulatory pathways

0-2

1

2

2

2

2

2

2

2

2

2.3 Standards to address remaining clinical uncertainty

0-1

0

1

1

1

1

1

1

1

1

Monitoring and evaluation
6.1 Patient registries for CGTs

0-1

1

1

1

1

1

1

1

1

1

6.2 Electronic Health Records

0-3

2

1

0

2

2

1

3

1

1

(i) Progress in addressing thespecific characteristics of CGTs
Our regulatory indicators (Figure 7) show
widespread innovation to address CGT’schallenges. This is not representative of
the global state of progress: as reported
earlier, many countries have seen little
regulatory progress in this area.19

To some extent, the similarity in scores across ourstudy countries is an artefact of common politicalarrangements. The European Medicines Agency
has authority over cell and gene therapy approval
within European Union countries. Even where
it does not act directly, the need for France,
Germany, Italy, and Spain to transcribe relevant
EU directives into domestic law strengthens theuniformity of their scores. Moreover, the UK’s

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practiceregulations in the field were also shaped by the
EU pre-Brexit. Now its Medicines and Healthcare
products Regulatory Agency makes policy anddecisions, and some new initiatives have alreadyappeared. These include the Innovative Licensing
and Access Pathway launched in January 2021.43
Nevertheless, broadly speaking, the UK system
retains much of its historic comparability to thatin the EU. Thus, the results of European countries
in this domain were always likely to be similar.
That they, and the scores from other countries as
well, are so high overall reflect extensive efforts
by regulators to come to terms with CGTs. Mr
Majors believes “regulators, including the FDA andparticularly its Center for Biologics Evaluation
and Research (CBER), have in the past few years
been very focussed on cell and gene therapy.”

Regulators, including the FDA and particularly
its Center for Biologics Evaluation andResearch (CBER), have in the past few years
been very focussed on cell and gene therapy.
Similarly, with respect the data challenges arisingfrom CGTs, in Ms Shafie’s experience, “theindustry feels that regulators have taken a very
pragmatic approach and are looking for solutions.”
Sometimes, it is a question of adopting existingarrangements when assessing CGTs. Canada,
for example, since 1998 has allowed conditional
approval of new treatments in the face of data
uncertainty. Similarly, several of the US pathways
to approval which could help with CGTs havebeen around for some time, including: Priority
Review designation (1992), Accelerated Approval
pathway (1992), Fast Track designation (1997),
and Breakthrough designation (2012).44 Eachhas slightly different requirements and benefits,38

and all are included in the FDA’s list of expedited
programmes for regenerative medicines.
Regulators in our study countries have also put
in place important new tools and changes to give
CGTs the ability to prove themselves effective
and safe. To begin with, each has a form ofguidelines to navigate the inevitable complexitiesof achieving regulatory approval for these
therapies. More important has been innovation
on regulatory pathways. Each jurisdiction has
seen some progress in this direction, although
Australia fails to gain full points because its
expedited pathways are available only for genetherapies not gene-modified cell therapies.
The substance of these programmes is broadly
similar across jurisdictions, but the nuancesvary. For example, the US 21st Century Cures
Act (2016) created the Regenerative Medicine
Advanced Therapy (RMAT) designation. This
expanded on the existing Breakthroughdesignation. The latter already provides rolling
review of trial data as it becomes available or,if applicable, priority review of more complete
results; intensive FDA guidance on development;
and senior management commitment fromthe FDA to support development efforts.
RMAT offers these benefits as well, but differs
in its prerequisites. To qualify as a Breakthroughtherapy requires preliminary evidence of a
substantial improvement to clinically relevant
endpoints—compared to existing treatments—
for a serious condition. RMAT candidates
need to meet the lesser hurdle of early data
demonstrating the potential to address anunmet medical need for treating, curing, orreversing a serious illness. Under this pathway,
products get all of the benefits of a Breakthroughdesignation as well as help in looking atways to meet post-approval conditions.45© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

RMAT quickly became more popular among
applicants than the Breakthrough designation.46
It is not, however, easy to qualify. Between 13
December 2016 and 1 January 2022, only 39% of
candidates were approved to use the pathway(only applications where decisions were madeare included in the calculation by Economist
Impact).47 For those accepted, however, RMAT
“is already bearing fruit,” says Mr Majors, notingthat three out of four regenerative medicines
approved by the FDA in 2021 used it.

RMAT quickly became more
popular among applicants than the
Breakthrough designation. It isnot, however, easy to qualify.
The EMA’s equivalent to RMAT is its Priority
Medicines (PRIME) designation. Also introduced
in 2016, it is not restricted to CGTs but does
require some scientific as well as clinicaladvance. It is open to any product with ademonstrated potential to address an unmet
medical need using therapeutic innovations
which are of major interest for public health.
PRIME builds on the EMA’s existing Accelerated
Assessment status (available since 2005).
A crucial change is that PRIME is available
to academic organisations and small- andmedium-sized enterprises (SMEs). To qualify,
unlike larger companies, applications fromthese smaller bodies do not need initial clinicalevidence of effectiveness. Instead, they canrely on non-clinical data and safety studies.
PRIME’s features include a designated pointof contact with regulators, and regularinteraction with, and advice from, scientificand regulatory experts to help in planningand executing product development.45,48

39

PRIME is even more selective than RMAT, with
only 24% of applicants given this designation.
The EMA does not produce data on how many
CGTs have used the PRIME designation, but
44 out of 98 products granted eligibility up to
January 2022 were in oncology or haematology—
both fields with substantial CGT activity. The
effort to support SMEs and academia moregenerally, however, is a mixed success. Most
successful applications (59%) are from othercategories—presumably larger business—andSME’s are roughly half as likely as these others
to have their applications accepted.49
Both of these pathways, as well as Japan’s
SAKIGAKE designation, are based on a regulatory
willingness to provide extensive support
to those pursuing the early developmentof promising, innovative treatments—even
while the available evidence is more indicative
than conclusive. These will certainly help thetranslations of CGT research into treatments.
Still unclear is how best to put these intentions
into action. Despite the existence of PRIME,
for example, in 2019 the EMA still has thelongest regulatory approval times of any major
agency for biologics and immunomodulators:
440 and 417 days respectively compared
to 239 and 220 for the FDA.50
More experience of what works will also help
address further major challenges with CGT
approval. While interviewed experts are generally
positive about efforts to adjust regulation
to the needs of cell and gene therapies, they
point out that different agencies have distinct
requirements. Accordingly, notes Mr Shitaka,“one hurdle to broad use of certain genetherapies is poorly harmonised regulation.” Ms
Shafie adds that, “even convergence arounddata requirements would be beneficial.”© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice(ii) Monitoring to alleviate uncertainty
Uncertainty regarding safety and efficacy isa characteristic of CGTs. This issue affects
decisions both on approval and reimbursement.
We deal with the issue here because the basic
difficulties for regulators and payers are similar.
All but one of our scorecard countries
score the maximum one point for having atleast some regulatory policy to deal withclinical uncertainty. Australia is again the
exception. That said, its agency conducting
HTA for CGTs, the Medical Services Advisory
Committee, requires companies selling newly
approved therapies to collect efficacy andsafety data for a year. This then feeds intoa review about reimbursement levels.
Typically, jurisdictions try to overcome
uncertainty by requiring the companies
providing CGTs to establish patient registriesof everyone treated. The data whichthese generate can then be accessed by,depending on the rules, regulators, payers,
and clinicians. This accounts for every country
scoring on the patient registry indicator.
Our uniform marks on this indicator, though,mask substantial weaknesses in the arrangementsof some countries. French requirements forpost-approval data collection, for example,
arises largely from EMA rules, not domestic ones.
Moreover, the data gathered there for CGTs
are at the cohort rather than individual level.
In Germany, while CGT producers must create
registries, healthcare providers are not required
to contribute data. In Australia, meanwhile, Dr
Dickinson reports that “the registry is underresourced and closely tied to industry sponsors
which creates issues around the perceptionof impartiality.” Finally, the relevant Canadianregistries are available only to regulators and
HTA agencies, not to healthcare professionals.

40

An alternative approach might be to gather
registry-like information from electronic healthrecords (EHRs). Although some version of EHR
is increasingly common, they remain a work inprogress. In only four of our countries are theserecords nationally integrated – a particularconcern for CGTs when treatment might require
travel to a facility outside of one’s home stateor province. Moreover, EHRs in three of thesefour countries (Australia, Germany, and Italy) are
best seen as patient-controlled data repositoriesof all their relevant healthcare information.
They are not necessarily tools for sharing
information across health systems. Instead, inthese states, patients retain control over which
healthcare provider can see data submitted
by any other provider. While this guarantees alaudable level of patient-centricity and privacy
protection, it impedes collection of aggregate
data for regulatory or HTA decisions.
Amid this uneven performance, Spain provides
an example of best practice. Since 2006, it has
had patient EHRs—the HCDSNS—similar to
the nationally-integrated patient-controlled
data stores described above.51 In addition, in
2019, it put in place the VALTERMED registry
specifically for treatments with high initial costs
and uncertain outcomes, such as CGTs. It collects
data from hospital physicians and pharmacists,
as well as drawing on longitudinal data frompatient EHRs. The resultant records—which
combine the benefits of a hospital registry andthe aggregation of data from EHRs—are available
to relevant healthcare providers, physicians,
officials from autonomous communities (thesub-national divisions in Spain responsible forhealthcare provision), and the national healthministry.52 Such comprehensive information
gathering is a way to protect privacy and create
the aggregate data needed to reduce uncertainty
around how well a given CGT is performing.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice41

Value and funding
Figure 8: HTA and funding-related scores

Score
range

Germany

Italy

Japan

Spain

UK

USA

1, 2, 3 (maximum score)

France1 (out of 2), 2 (out of 3)

Canada1 (out of 3)

Australia

0

3.1 Guidelines for HTA of CGTs

0-2

2

2

2

2

0

2

0

2

0

3.2 Adaptive payment models

0-1

1

1

1

1

1

0

1

1

1

3.3 Role of patient organisations

0-2

2

2

2

2

1

0

2

2

2

HTA and reimbursement

Infrastructure and access
5.1 Dedicated budget for delivery of CGTs

0-2

1

1

2

2

2

0

2

2

1

5.3 Programmes for equitable access

0-1

1

1

1

1

0

0

0

1

0

All experts agree that prices are a key barrier
to the roll out of CGTs. As Dr Dickinson adds,
however, “cost also contains a lot of otheraspects.” So too does the related conceptof value (or benefit for money paid).
Both are more complex than they might seemon the surface. Assessment of each can varywith what precisely is included in calculating
the figures. Moreover, questions of “cost to
whom?”, “value for whom?”, and the relationshipbetween those two “whoms” quickly getcomplicated in healthcare where payers
and patients are rarely the same people.
Even if an expensive intervention turns out tohave compelling value, finding ways to pay for
it is far from straightforward. As the scorecard
results show, many countries have been wrestlingwith these issues. A closer look also reveals awider variety in approaches than is evident fromthe similarity in points awarded (Figure 8).
(i) Assessing value
Existing HTA processes require adaptation inorder to weigh the distinct value propositions of
CGTs. Accordingly, the scorecard’s “Guidelines

for HTA of CGTs” indicator gives one point for
countries having some kind of CGT-specific value
assessment and a second if this addresses theuncertainty in outcomes of these therapies.
Spain and Italy both score zero because their
HTA institutions do not appear to have national
guidance documents addressing specific CGT
challenges. The US also scores zero because no
single HTA body exists, although the independent
Institute for Clinical and Economic Review (ICER)
published in 2019 its Adapted Value Assessment
Methods for High-Impact “Single and ShortTerm Therapies” (SSTs).53 In that sense, one of
the leading HTA organisations in the US does
have CGT-specific guidelines, but this still falls
short of a statutory body having such a tool.
The six countries which gained their full marks fall
into two broad categories. Four of the countries
have simply clarified which existing bodies will
be responsible for CGTs. In Germany, all CGTs
go through the existing HTA procedures for
drugs.54 France’s Action Plan for the Evaluation of
Innovative Medicines, meanwhile, seeks to use
and adapt existing HTA models to deal betterwith CGTs, although it is short on specifics.55
The Australian government, instead of relying© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practiceon its normal HTA bodies, has used the Medical
Services Advisory Committee (MSAC) to consider
CGTs. The latter’s specific role, since its founding
in 1998, has been to advise governments onwhether proposed new services should be
funded. Meanwhile the Japanese have given
consideration of CGTs to two existing specialist
sub-committees of the Central Social Insurance
Medical Council inside the Ministry of Health.
The first, which assesses all new technologies,
has existed since 2005. The second, the Costeffectiveness Evaluation Committee, beganwork in 2017, and has experience collecting
and assessing outcomes information. Although
the strategy in these countries to use existingprocesses and institutions, with limited or nochange where possible, is the easiest to roll out,
it assumes that existing bodies will be able tomeet the novel challenges in assessing CGTs.

42

Canada and the UK, on the other hand, haveseen more extensive changes in HTA processes.
Ms Hanna notes that Canada’s overlapping
federal and provincial jurisdictions in healthresult in “a very complicated [HTA] system.”
The institutions themselves decided thattraditional silos were inappropriate in addressing
the challenges of these novel therapies. As aresult, for CGTs, Health Canada (the regulator),
CADTH (the national HTA agency), and INESSS(Quebec’s provincial HTA agency) have workedon aligning their regulatory and HTA activities.
This allows them to share information andmake more informed, rapid, and co-ordinateddecisions on the potential benefits of given
therapies.56 It is hard to overstate the extent
of this change. Ms Hanna explains that, when
this approach was used initially for CAR-T
assessment, “it was really the first time we’veseen something like this. One of my colleagues
said that it was the first time that Canada has
actually [acted as a single] country” in this field.
The UK’s National Institute for Health and Care
Excellence (NICE) has already been dealing withthe assessment of CGTs for some years. Indeed,
the UK was the first country in Europe to pay
for CAR-T therapy.57 This extensive experience
has informed recent major revisions to its
methods and processes for appraising specialised
technologies, including CGTs. As of February2022, it will: give greater weight to health benefits
for severe conditions; increase use of real world
evidence; give its independent committees
more flexibility where evidence generation isparticularly difficult; and clarify how very rarediseases will be dealt with in its Highly Specialised
Technologies Programme.58 All of these are
directly relevant to payment decisions for CGTs.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

Looking ahead, EU co-ordination will soon
strengthen HTA evaluation in France, Germany,
Italy, and Spain. The European Union’s HTA
Regulation entered into force in 2022. Under it,
relevant agencies of member states will begin to
conduct joint assessments. ATMPs—including
CGTs—will be assessed in this way from 2025.59,60
Member states will still decide whether the value
revealed in the HTA is worth paying for, but atleast within a few years Italy and Spain should
begin to draw even on this scorecard indicator.
The large number of top scores in this section
should not be over-interpreted. They measure theextent to which countries have recognised andbegun to wrestle with the particular challenges
of assessing the long-term value of HTAs. The
scorecard cannot judge how far countries havegone toward best practice because consensus
on one simply does not exist. Hotly contested
issues still include: the calculation of savings;
whether new measures, such as saved young life
equivalents (SAVEs), may be better metrics forassessing value; appropriate discounting rates
for future savings, and the correct incremental
cost-effectiveness ratio cut-off to use for CGTs. In
other words, these are ‘A’s for effort rather thanprizes for having found the perfect formula.20,61-64

The institutions themselves
decided that traditional silos were
inappropriate in addressing thechallenges of these novel therapies.

43(ii) Paying for value I: Mechanisms
The uncertainty around the effectiveness,and therefore the value, of a given CGT makes
full, upfront payment risky. Accordingly,
most countries—including eight out of ninein our scorecard—have put in place adaptive
payment models of some kind. Nor is Japan—
the outlier in this group—likely to remain so.
Mr Shitaka believes that “we need to look ata system to appropriately evaluate the valueof innovation and the uncertainty of thetherapy. In Japan we are discussing this.”
The adaptive payments in the scorecard typicallylink outcomes to reimbursement, but methods
differ. Some involve payments directly related topatient results. This might take the form of, as inAustralia, reimbursement based on how muchpatients benefit from a treatment or, as in certain
German contracts, rebates of upfront paymentsin the event of negative outcomes. France andthe UK, on the other hand, start by agreeing atemporary price for a product until it has time toprove itself. If data gathered during this periodof conditional approval show that the CGT iscost effective, it is funded permanently; if it falls
short, then it is dropped from the formulary.65
This degree of apparent innovation is morestraightforward than it might appear. At thebasic level, these arrangements for CGTs
draw on numerous models developed inrecent years. Many have dealt largely withhigh cost oncology therapies. Italy’s Agenzia
Italiana del Farmaco (AIFA), for example, has
had outcomes-based payments for someproducts—mostly cancer drugs—since 2006.66
Most countries have some orphan drug
arrangement within their HTA processes. These
usually allow for higher levels of uncertainty© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice44

and less extensive evidence before decisions
on reimbursement occur. Some, among them
Scotland’s Ultra-Orphan Drug Risk Sharescheme67 and France’s Autorisations d’Accès
Précoce arrangements, cover the cost of the
medication until evidence of effectiveness canbe gathered.68 Thus, even countries such as
Germany, with little experience of outcomesbased reimbursement,69 have not had toreinvent the wheel on CGT reimbursement.
Should, however, CGTs move as expectedbeyond the fields of oncology and rare diseases,
these ad hoc arrangements will not be enough.
Innovation in reimbursement has begun, but
so far tends to be focussed on spreading out
payments. This is a potentially important way ofaddressing high upfront cost. Both Italy and Spain
have, for the first time, created staged payments.
Nevertheless, whatever the transformative
potential of such deals, their limited duration—
currently full payment is received after just
one year—limits their practical effect.
Longer term payment arrangements, suchas annuities or reimbursement over up
to five years—whether outcomes based
or not—have been much discussed. They
have particularly featured in negotiations
between pharmaceutical companies and
US insurers both public—the Centre for
Medicare and Medicaid Services (CMS)—andprivate—notably Cigna and HarvardPilgrim.
To date, however, no such arrangements havebeen agreed, or at least made public.65(ii) Paying for value II: Budget
The high upfront cost of CGTs means that
dedicated resources are important in providing
sustainable patient access. This can involveearmarked funds or specific budget lines.

Five countries get full marks in the scorecard,
but how they gain them differs. In 2021, Franceand Germany each created specific funds forthese treatments and Italy has had two since
2017: one for oncological innovative medicines
and the other for non-oncological ones. Spain
took a slightly different approach, giving
responsibility for the costs of CGT delivery to
its Health Cohesion Fund in 2018. The UK has
taken another route. Although lacking a specificfund, its extensive efforts to bring CGTs into
mainstream medicine has been well-funded.
Those with lower scores also vary in how they fallshort. The most difficult to assess is, again, the US
because of the large number of distinct payers
in its healthcare system. Almost by definition,
the degree to which CGTs are supported in
the country is fragmented to some extent.
On the other hand, the CMS—which covers
over a third of the population—has shown awillingness to cover CAR-T and is in discussion
on reimbursement of certain gene therapies.65
In the private markets, large insurers, including
Aetna, Anthem, Cigna, and United Healthcare
have launched special gene therapy options
or included certain treatments in their main
coverage.70-73 As ever when discussing the US
market, a lot of people have access to advanced© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

CGTs, but they are not universally available,
especially to the roughly 9% who are uninsured.74
Australia, Japan, and Canada also earn lessthan full marks for distinct reasons. In Canada,
only a limited number of provinces provide
CAR-T therapy. Those living elsewhere need toapply to their governments for out of provincecare. In both Australia and Japan approved
therapies are covered by health systems
in general, but no specific budget for thesetreatments exists. Indeed, in Australia theperennial complications of split constitutional
responsibility in healthcare arise, with the national
government covering the cost of the therapy
itself, but state ones having to decide how muchto set aside for its administration to patients.

The most difficult to assess is, again,
the US because of the large number ofdistinct payers in its healthcare system.
The nature of CGTs also means that patients andtheir carers may require support to both travel
extensive distances and stay far from home inorder to allow post-intervention monitoring.
Those requiring treatment in five of our countries
have access to some such assistance, although it
varies in extent sometimes even within countries.
The high number of insurers within the US
makes it once more impossible to generalise
what might be available. Italy, Japan, and Spain,
meanwhile, appear to lack any programme toprovide such assistance. That said, currently
Japan and Italy have, among scorecard countries,
the highest and third number of facilities toprovide CGTs per thousand square kilometres(see discussion below). In principle, this shouldmean fewer people needing assistance to cover
the costs of being treated far from home.

45(iii) The patient voice
The value of a healthcare intervention is
ultimately in the eye of the beholder. What aprovider might see as a marginal improvement
to an underlying condition, a patient might
consider a huge improvement. As a result, there
is a growing international consensus about
patient-centred healthcare. This includes patient
involvement in treatment decisions but goes
further—to having some involvement in assessing
which therapies offer sufficient value to reimburseand how they are given within the health system.
The scorecard results show that most countries
have made progress in this area. That Japan is the
exception is no surprise. Its doctor-dominatedhealthcare system still retains more of the generalpaternalism which used to be more common
internationally. That said, signs of change exist,
even if not in the areas which the scorecard
measures. In particular, healthcare is delivered at
the prefecture level where a health care council
develops the local health care plan. Under thecountry’s Medical Care Law, these bodies must
include members who represent patients.75
That said, patients exert no formal influenceon national HTA decisions and guidelines.
Other scorecard countries have gone muchfurther and most score full points. This does
not reflect a complete integration of patient
involvement, but ongoing progress toward it.
As Dr Dickinson notes patient involvement “isone thing that Australia does really well.” Thisis the case both in general and on CGT-related
decisions. The country’s MSAC, for example,
involves patients in three ways: encouraging
their participation in online consultations; giving
them formal representation on the committee;
and using in depth information from patients,
carers, and family members in their impact© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practiceassessments for new therapies. Even advanced
arrangements, however, can be imperfect. For
example, how all of this patient input affects
MSAC recommendations lacks transparency.
Looking ahead, the range of challenges in dealing
with CGTs may accelerate efforts to achieve
greater patient centricity. Ms Hanna reports

46

that the process of assessing CAR-T drugs inrecent years in Canada “was the first time thatthe regulators and the reimbursers went topatient groups and asked for input versus thepatient groups going to the reimbursers and theregulators saying we have some inputs. I hope itwill drive more patient engagement in the future.”

Making delivery within health systems effective
Figure 9: Health system-related scores
Indicator 5.2> 0.01> 0.03

Spain

0

3

0

2

0

0

0

1

2

0

1

0

2

1

3

3

2

2

4.3 Formal referral pathways

0-3

0

0

0

0

0

0

0

2

0

5.2 Specialist patient treatment centres

rate

0.024

0.045

0.046

0.031

0.035

0.023

0.026

0.021

0.044

5.4 Training for healthcare staff

0-1

0

1

0

1

0

1

1

1

1

USA

Japan

0-3
0-3

UK

Italy

4.1 Screening programmes
4.2 National guidelines/toolkits

Score
range

FranceGermany> 0.02> 0.04

Canada1 (out of 3)
1, 2, 3 (maximum score)

Australia

General0
1 (out of 2), 2 (out of 3)

Guidance and pathways

Infrastructure and accessIn contrast to the progress seen among
regulators and payers, health systems appear
to be having more trouble coming to grips
with the challenges of CGTs. The difficulties
should not be underestimated. Dr Frank notes
that, although experts and specialists cankeep up, the field “is exploding and there arelots of challenges to deliver this care well.”To help take account of the inherent difficulty ofsuch rapid change, the scorecard intentionally
includes very basic metrics. The most striking
thing about the data is that, even by thesecriteria, healthcare providers have madevery limited progress in establishing thenecessary infrastructure and mechanisms
to deliver CGTs at scale (Figure 9).
(i) How many facilities are enough?
An obvious starting point in assessing healthsystem capacity is measuring how much
CGT it can deliver to the population under
its care. This turns out to be difficult. Typicalmetrics in healthcare studies, such as bed
numbers or clinicians in the field, either do not
apply or comparable data are unavailable.
The scorecard instead counts the number of“specialist patient treatment centres” per capita.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practiceThis term’s expansive definition means that theindicator requires some caution in its use. No
information, for example, is available on thecapacity of these individual centres. The kindof care provided and its quality may also vary.
In Japan, for example, over 4,400 facilities saythat they provide some form of regenerative
medicine.76 Mr Shitaka, however, explains thatthe country has “no framework for facility
certification, which is becoming an important
issue.” Accordingly, for Japan our scorecard
uses the much smaller number of hospitals(29) authorised to provide Kymriah, a CAR-T
treatment for acute lymphoblastic leukaemia.
In general, what goes into the national
figures for this indicator depends on data
availability, ranging from the number of singletreatment facilities—as in Japan—to the totalof those that provide a wider range of CGTs,
such as the Advanced Therapy Treatment
Centres in the UK. The results, if not rigidly
comparable internationally, should give a good
impression of the volume of care available.
Broadly speaking, scorecard countries fall
into three tiers with France, Canada, andthe US virtually tied at the top; Germany
and Italy in the middle; and at the bottom
Spain, Australia, Japan, and the UK.
In assessing these rankings, though, it remains
unclear how many facilities a populationneeds for such a new field. Since so many ofthese centres treat only specific diseases,
even if they met this existing need, others
would be required for a range of further CGTs
both currently and in the near future.
Moreover, although Canada scores highly here,
Ms Hanna points out that the country’s huge area
makes access difficult for those living at a great
distance from the limited number of facilities.

47

A comparison of facilities per capita and per
geographic area is illuminating (Figure 10).
Figure 10: Specialist patient treatment centres
Per 100,000 population>0.03 and <0.04
<0.03
N/A
Per 1,000 square km
0.00>0.01 and <0.03>0.04>0.03 and <0.06>0.06

Per 100,000
population

Per 1,000
square km

Australia

0.024

0.0008Canada0.045

0.0017

France0.046

0.0543Germany

0.031

0.0726

Italy

0.035

0.0695

Japan

0.023

0.0767

Spain

0.026

0.0237UK

0.021

0.0579USA

0.044

0.0147

The results on this second metric fall into thefour tiers, rather than three, and the ranking
has been scrambled markedly. Only Spain
performs similarly across both measures.
Canada, Australia and, to a lesser extent, theUnited States do far worse in the ranking ofgeographic density of facilities than they dofor the number per capita. Japan, on the other
hand, has the most per square kilometre.
Again, though, the question is how much isenough? Mr Shitaka, for one, believes that evenindicator-leading (by density per square km)
Japan needs far more capacity. He explains that“compared to the United States, we are a small
country but to handle cell and gene therapy weshould expand the number of hospitals which canhandle the product.” He thinks this should begin
with creation of centres of excellence spaced
around the country in the east, west, and south.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practiceTherefore, although the scorecard indicatesprogress is being made, experts showed
little confidence that the number and spread
was enough to meet healthcare needs.
(ii) Weakness at the start andmiddle of the patient pathway
The structures which health systems have
put in place to find and assess which patientsmight benefit from a given cell or genetherapy are a widespread area of weakness.
This begins with diagnosis. As a proxy, thescorecard looks at whether neonatal screening
programmes in each country test for betathalassaemia, spinal muscular atrophy (SMA),
and severe combined immunodeficiency(SCID). These conditions were chosenbecause gene or cell therapies have, in recent
years, become available to treat them.
These CGTs work better if administered before
deleterious genetic mutations begin to cause
irreversible damage. Nevertheless, five of
our countries do not screen for any of these
conditions and only Canada gets full markson this indicator. Even the latter requires aslight caveat: because Canadian provinces are
responsible for healthcare, the score reflects
activity in the country’s largest, Ontario.
Some other provinces do not test for SMA.

48

Healthcare systems, then, if they are to takeadvantage of approved CGTs, have insufficient
screening programmes. Some progress istaking place: Italy, for example, has conducted
some successful pilot studies. Nevertheless,the slow rollout in many countries is surprising
as it need not involve extensive change. The
Newborn Screening Ontario programme simply
added these three diseases to the more than
20 others which it checks for using a single
drop of blood taken from a baby’s heel.77
If screening is rare, our scorecard research
could find almost no evidence of formal referral
pathways in the countries covered. Here theproxy measure was the existence of suchtools for three different diseases, again allwith widely approved cell or gene therapies:
refractory or relapsed acute lymphoblastic
leukaemia; refractory or relapsed mantle
cell lymphoma; and retinitis pigmentosa.
No formal referral pathways are available
outside the UK, where NICE has developed
pathways for the first two conditions only.
This does not mean that no work to enhancereferrals takes place. Both Dr Ho and Dr Frank,for example, explain that their facilities, which
provide CAR-T therapies, have had extensive
interaction with oncologists. The latter explains,“we have gone to our referral base to tellthem as much as possible. It requires a lot of
networking, more than is typically needed” for© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practicea new treatment. Similarly in France, although
not through formal procedures, oncology
reference centres coordinate the referral ofcancer patients eligible for CAR-T therapy.
Nor did we check for formal referral
pathways for every condition where a CGT
is available. Nevertheless, their absence forthe designated proxy conditions is anotherworrying sign that health systems are missing
opportunities to make the best use of these
therapies as a group. As Dr Dickinson explains,“referral systems and expected timelines
are crucial, and a referral pathway is very
important, for access to treatment.”
The paucity of pathways puts into context themixed results on national treatment guidelines.
The scorecard measures the existence of such
documents for the same three conditions as
used for referral pathways. The results weremixed: Japan and Spain have national guidelines
for all of them, Australia and France for none.
Again, some exceptional situations make lower
than full marks understandable. As of early
2022, for example, Canada’s provinces werenegotiating a price with the manufacturer for thetreatment for retinitis pigmentosa. Any treatment
guideline would therefore be premature. Overall,our study countries have about half of theguidelines (14 out of 27) that would be possible.

“Guidelines are generally useful, but
not specifically... They are, after all,guidelines. You need expert care. ”
Dr Matthew Frank, Assistant Professor of Medicine, Division of Blood andMarrow Transplantation and Cellular Therapy, Stanford University

49

Why this matters is important. The distinction
which Dr Frank draws—that “guidelines are
generally useful, but not specifically”—is helpful,
if initially enigmatic. He explains that an expert
will not use such documents as a rule book forevery case. “They are, after all, guidelines. You
need expert care. An expert, such as myself,
will not need to read them as we treat patients.”
Indeed, clinicians involved in CGT would alreadyhave the knowledge which guidelines seek todistil, he continues. Even when used as referencematerial, specific national publications are notnecessarily needed for experts. Dr Dickinson
notes that “where a [domestic] guideline doesn’t
exist, an international [one] may be used.” Indeed,
Germany’s two points on this indicator are forits conscious adoption of European Society for
Medical Oncology guidelines in its facilities.
The bigger utility of these documents, and one
where specific national guidelines are valuable,
is for other actors within the health system. Dr
Frank says that they are “critically important
for the referral base, and helpful for payers toknow what is allowed.” Given the lack of referral
pathways, an increase in the number of guidelines
would help fill the knowledge gaps which are
impeding greater use of available CGTs.
Healthcare staff training is another way to address
those gaps. Here, countries got one point for any
evidence of educational opportunities not directly
provided by treatment manufacturers. A third of
those in the scorecard did not reach even that low
bar. Among the others, although valuable efforts
are taking place, it is unclear whether these aresufficient to meet the ongoing need. In Spain andGermany, for example, seminars for professionals
to learn about CAR-T exist, but there are nodata on how many have taken part. In Canada,
several programmes have provided broader
training within the field of CGT. Even with these,
an expert panel in the country in 2020 “identified
a lack of [highly qualified personnel] in Canada
for the ... administration of gene therapies.”78© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

The UK’s Advanced Therapy Treatment
Centre (ATTC) network is taking a morecomprehensive approach. As a first step, thesefacilities, working with the country’s Cell andGene Therapy Catapult, have been examining
current training levels within the healthcare
workforce and what is required to supportdelivery of CGTs. They have also, in partnershipwith Health Education England’s eLearning for
Healthcare, developed content for medical
professionals to increase understanding of thefundamentals and clinical adoption of ATMPs.79

50

Although signs of progress and examplesof good practice exist, then, health systems
in the scorecard countries still need tograsp the nettle of finding and funnelling
the relevant patients toward approved
and funded cell and gene therapies.

Although signs of progress andexamples of good practice exist,
then, health systems in thescorecard countries still needto grasp the nettle of finding
and funnelling the relevant
patients toward approved andfunded cell and gene therapies.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice51

Box 4: New approaches to rare disease diagnosis in a world of cell and gene therapy
A large proportion of current CGTs treat rare diseases. While individually rare, the large
number of these illnesses creates a substantial collective burden: when aggregated,
they are estimated to affect between 3.5% and 5.9% of the world population.80 As
Gareth Baynam—Medical Director of Rare Care at the Perth Children’s Hospital—
explains, “rare diseases are the single biggest health system cost, especially in children.
US data shows that the inpatient hospital costs of rare diseases are 1.5 times allcommon diseases combined in children; and on parity in adults.81 We know from Irish
data that, in high income countries at least, they are the biggest killer of kids.”
Diagnosis of rare diseases is no easy task. Knowledge within the health system of how to
identify a given condition often correlates with its general prevalence. For those with a one in
2,000, let alone a one in a million, deleterious mutation, the result is the so-called “diagnostic
odyssey”. Patients bounce from expert to expert, experiencing one misdiagnosis followed byineffective treatment after another.
But new programmes to support rare disease diagnosis are emerging. They harness two
factors: 1) the use of multidisciplinarily teams to address difficult cases, and 2) the tools madeavailable by the same broad wave of advances in genomics which have helped power CGTs.
The first such programme, often still cited as a model, is the Undiagnosed Disease Program(UDP), founded in 2005 by the US National Institutes of Health. From a single centre in
Baltimore, it has expanded to a country-wide network of clinical sites under the leadershipof a central body and sharing certain core facilities (the Undiagnosed Disease Networkor UDN). Individuals can apply for consideration by the UDN or be recommended bya healthcare provider.82-84 A multidisciplinary team reviews the case history of newly
accepted programme participants. If this does not lead to a diagnosis, patients and in somecases their immediate relatives then undergo a series of tests—including whole genome
sequencing and whole exome sequencing. The case is then considered again in light ofthese test results, and the details of the case are added to the UDN’s store of data.
Health systems in several countries—including Spain85 and Japan86—and sub-national
jurisdictions – notably Western Australia87 and a network of six regional Italian raredisease centres88—have created similar programmes. At their core, all combine someform of multidisciplinary clinical team with advanced genetic testing. It is the latter
which accounts for the lion’s share of progress. Of UDN diagnoses between September
2015 and May 2017, 74% came after whole genome or whole exome sequencing.83© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice52

Currently, the most extensive national network is Japan’s Initiative on Rare andUndiagnosed Disease (IRUD), which is fully integrated into the public health system.
It coordinates 487 clinical centres and hospitals where patients interact with
their treatment teams. Five of these also act as regional analytical centres which
conduct genetic testing for the others. IRUD also has 469 expert participants from
21 clinical specialties to assist the local treatment teams where needed.86
These programmes are still unable to provide a diagnosis for most patients, but they
are a substantial improvement on the past. And data suggests that the programmes
are getting better at making successful diagnoses.83,86,89,90 This use of new institutionalarrangements to exploit scientific advances in genomics not only helps patientswith rare diseases, but health systems as a whole. Dr Baynam suggests that “theincredibly large opportunities for health system savings is critical for health system
sustainability.” Moreover, just as treatment of rare disease was a proving ground forthe science behind CGTs, the ability of clinicians in this field to innovate around how
health systems deploy them can also lead to their much more effective use.

The policy environment
Figure 11: Policy-related scores

Germany

Italy

Japan

Spain

UK

USA

1, 2, 3 (maximum score)

France1 (out of 2), 2 (out of 3)

Canada1 (out of 3)

Australia

0

1.1 National / regional strategy for CGTs

0-3

1

0

2

3

0

2

3

2

1

1.2 Horizon scanning programmes for CGTs

0-2

1

2

2

1

1

2

1

2

1

Score
range
Policy and planning

Our first domain, policy and planning, carries
with it the implicit assumption that strategy andplanning are important to the roll out of CGTs.
It is a reasonable supposition, at least arguingfrom analogy. For some years, evidence that
National Cancer Control Plans lead to better
outcomes at the population level91 has driven
their increasing adoption worldwide. Moreover,cancer control and CGTs have certain similar
characteristics, such as high-cost interventions
and the need for multidisciplinary care.

CGTs, however, are too new a healthcare
tool to have strong evidence for what agood policy might look like. In creating thisindicator, therefore, the scorecard kept
things simple (Figure 11). A strategy for using
cell and gene therapy in at least one clinicalarea, such as oncology or rare disease,scored one point; a more general strategy
which addressed the roll out of CGTs acrossmultiple areas secured two; and a budget
to pay for the strategy gained a third.

© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice

The results, however, make it hard to say
whether policies with even these limited criteria
have much of an impact. Canada, for example,
has no discernible strategy and therefore
scores a zero. Nevertheless, it scores a zerofor only one other indicator. Spain, on theother hand, while achieving full marks on CGT
strategy, gets zero points for four indicators.
This does not necessarily reflect weakness
in Spain’s approach. Important elements of
it—the Precision Medicine Infrastructure
plank of the Science and Technology Plan, andthe Strategic Projects for the Recovery andEconomic Transformation in health—were
launched only in 2021. Similarly, Germany’s
full score on this indicator comes largely fromits Health Care Development Act, which its
legislature approved also in 2021. It will taketime to see the effects of these initiatives.
The UK has one of the oldest stand-alone CGT
strategies, dating back to 2012. Since then,however, strategies from other areas – suchas genomic and precision medicine as well as
industrial strategy—have had an increasing
impact on the field.92,93 In fact, the establishmentof Advanced Therapy Treatment Centres
within the NHS relied on funding from UK

53

Research and Innovation, a non-departmental
government body.94 Even amid this movementaway from an overarching, stand-alone
approach to CGTs, the country still has athriving research ecosystem in the field. Looking
ahead, Ms Shafie believes that, in the current
circumstances, “we don’t need a strategy. We
need an action plan, saying who is going to
do what.” She adds that “The Cell and Gene
Therapy Catapult recently published a fantastic
cross-sector framework that stakeholders
can get behind to help accelerate action.”
The US scores only one point for policy, because
the CMS—the payer arm of its Department
of Health and Human Services—provides
funding for CAR-T treatments. Even withoutcomprehensive governance, however, the US
appears far ahead of other parts of the world
on CGTs on various measures. According to
Economist Impact calculations as of 2021,
57% of gene therapy trials took place in the
country.8 It is difficult to obtain reliable data on
the number of patients treated, or even sales
figures. That said, analyses of market size inrecent years estimate that North America makes
up 50% to 60% of worldwide CGT sales, andthe US alone 77% of those for oncology.95-97© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice54

Like for like comparisons, to the extent thatthey are possible, yield a similar message. Whenlooking exclusively at CAR-T for blood cancers,
the best available estimate is that around 4,000
people received such treatments in the US in
2019.98 In contrast, in 2021, only a little over
1,500 such cases were reported to the European
Bone Marrow Transplant Registry which
covers Western Europe and Israel.99 Although
not conclusive, this information is suggestivethat overall access is greater in the US.

availability, even if it falls short of universal. Mr
Majors describes “a strong effort broadly here in
the US for hospitals to compete with each otherby offering the latest, most impactful healthcaretechnologies. Cell and gene therapies would
be one of those things.” Meanwhile, he adds,
although the health system has a long way to go
in addressing funding challenges, “some private
payers have been particularly progressive about
coming up with new arrangements, which could
include pay for performance or annuity models.”

The US system is rarely held up as a modelof public health provision, but in this case
it is necessary to acknowledge its assets inharnessing a new, rapidly developing technology.
One is its undoubted strength in nurturing
biotechnology research. Second is the opennessof healthcare providers to using these expensive
treatments. Dr Dickinson explains that “asthese products emerge, often the US is the firsttarget market and this will push a demand by
patients globally for access.” Next, market forces
within the system will drive some expansion ofThis is not simply, however, about themarket. The US is not devoid of important
policy strengths in places where theymatter for the new technology. The FDA, in
particular, has been a leader in addressing
ways to safely regulate CGTs without stifling
innovation. Without that, US progress in thisfield would be much more constrained.

National health systems vary, and othercountries can take only limited lessons
from those in any state, especially one asdifferent from most as that of the US.

National health systems vary, and othercountries can take only limited lessons fromthose in any state, especially one as different
from most as that of the US. The broadly
applicable policy lesson from the scorecard isthat, while regulatory, HTA, and health delivery
system innovation are essential to makethe most effective use of CGTs, the kind ofcomprehensive strategy which might be mostuseful remains unclear. Nor, in such a fastmoving field, will the elements of good policy
today likely be the same as that in a few years.

© The Economist Group 2022

Cell and Gene Therapies:
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Conclusion:
Considerations
for policy
Science fiction has become fact one moretime, as advancing medical research on celland gene therapies has delivered cures which
once seemed decades away. Deploying
these treatments within health systems,
however, will not be straightforward. In orderto derive the greatest health benefit from
CGTs at the lowest cost, policymakers andother stakeholders would be wise to keep thefollowing insights from our research in mind:•

This is an issue requiring attention
today, not one that can wait for
tomorrow: Already 45 cell or genetherapies are available in at least one major
pharmaceutical market worldwide. The
global number of trials has accelerated
even amid the disruption of the covid-19
pandemic. By 2031, Economist Impact
projects that the US alone should havearound 100 CGTs with market authorisationand the European Union around 70. These
therapies will form an important minorityof new approvals by regulatory agencies in
the coming decade. Moreover, rather thanrare diseases, these new CGTs will addressconditions with larger patient populations
who will not be content to miss out on
the best treatments available. Institutions
across the healthcare ecosystem needto determine how to address the specificchallenges of these novel therapies quickly.
© The Economist Group 2022

Cell and Gene Therapies:
Health system progress in moving from cutting edge to common practice••Regulatory agencies in the scorecard
countries must build on substantial
progress and begin working withhealthcare systems to gather realworld data: The most substantial
innovations so far in dealing with CGTs
has been by regulators. In particular, thosein the US, EU, and Japan have developed
useful new pathways to deal with theuncertainty over long-term effectiveness
which affects these therapies. Now, officials
in major markets should consider how tomove toward more comprehensive data
gathering by healthcare systems in order tosupport their various forms of conditional
approval more effectively. Meanwhile,
they should consider ways to reduce
differences in rules between countries sothat CGTs found to be safe and effective
can be rolled out faster to more people.
Those making reimbursement
recommendations must prepare to deal
with high-cost, potentially high-benefit,
therapies in fields beyond oncology andrare diseases: HTA bodies in the study
countries have been wrestling actively
with issues around CGTs, in particulardetermining the value of therapies witheffects of uncertain duration. In mostcases, though, they have done so by
repurposing existing processes rather thansubstantially reshaping them. Similarly,
payment arrangements for CGTs have seen
little innovation beyond their inclusion inexisting schemes for orphan or oncology
drugs. These are useful starting points, but
now comes the harder work of finding thebest ways to deal with CGTs in other fields.

56•

Healthcare systems must grapple withsome of the fundamental changes
required for introducing any new
therapy: Across our scorecard countries,
diagnosis and referral systems for CGTs
are still weak or non-existent. Educationof health professionals, especially those
not experts in these treatments, needs toexpand. Formal programs for identifying
patients who could benefit, as well as
pathways for linking them up with providersof the therapies are both pressing needs.
Meanwhile, investment in current specialist
facilities is likely insufficient for what isneeded. This will become an even bigger
problem as the number of CGTs grows.

•

Policy must remain flexible: No
tried and true checklist exists for thewidespread roll out of CGTs. The field is
too novel. Policymakers and stakeholders
need to consider what is working inother countries. More important, theyneed to be willing to experiment withnew models that will be appropriate
in their own healthcare systems.

Perhaps the best general advice is thatstakeholders should seek ways to make thisexciting new technology ordinary, quotidian,even boring. That is the clearest indication that
it is available wherever it can make lives better.

© The Economist Group 2022

Cell and Gene Therapies:
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