Article Pack

Regional Comparisonsof Pharmaceutical
Regulations

November 2023

Introduction

Our articles illuminating differences in performance and regulatory expectations for policy agencies
in different markets set us apart from competitors. They compare regional drug review trends,
approval decisions and regulatory guidance, often in context of how a specific drug or biotech
product fared in different regions.
These insights reduce the complexity of navigating multiple markets and increase prospects for
product marketing authorization.
Find these articles quickly at Pink Sheet’s Regional Comparisons page on our website.

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November 2023

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Contents

Principles-Based vs Prescriptive: How US & EU Compare In Their Approach
To Decentralized Trials

04

EMA And FDA Compared – The Case Of Minoryx’s Leriglitazone

08

How Do Japan’s Clinical Trial eConsent Rules Compare With The EU And US?

11

Gene Therapy HTA: How Do The European, Australian And Canadian Systems Shape Up?

13

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November 2023

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Principles-Based vs Prescriptive:
How US & EU Compare In Their
Approach To Decentralized Trials
Vibha Sharma
24 Jul 2023

Executive Summary

In this regional comparison, regulatory experts at a US-based
decentralized clinical trials (DCT) firm discuss their views on
how the FDA’s draft DCT guideline compares with the pan-EU
recommendation paper on this topic. This first segment of a
two-part article dwells on the thinking behind why US and EU
regulators tend to go down different paths.

Both US and EU regulators recognize theimportant potential benefits and value of
decentralized clinical trials (DCTs) and are
keen to support such studies. Their respective
guidelines on DCTs – issued just five months
apart – are largely similar but have somenotable differences.

DCTs allow some or all trial-related activities
to be centered around participants, typicallyenhanced by health technologies. These trials
gained prominence during the COVID-19
pandemic, when travel and social distancingrelated restrictions made in-person clinicalresearch visits difficult.

The US Food and Drug Administration published
its draft DCT guideline in May, with stakeholder
comments being accepted until 1 August. EU
regulators offered their harmonized perspectiveon the use of decentralized elements in clinical
trials in a final recommendation paper in
December 2022.

While the FDA guideline and the EU paper
both underline the importance of ensuring thatthe use of any decentralized element in a trial
should be “fit for purpose,” they differ in theirlevel of prescriptiveness, says Kevin Potgieter,
vice-president of regulatory affairs at the USbased virtual clinical trials solutions provider
Medable.

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November 2023

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Principles-Based vs Prescriptive: How US & EU
Compare In Their Approach To Decentralized Trials
In its guideline, the FDA has made a purposefulchoice to write in broad strokes, stopping
short of detailing specific ways to execute
decentralized or tech-enabled clinical trials.
This comes as no surprise to Potgieter, who
explained that whenever the FDA deals withsomething new, it tends to allow more freedom
and maneuverability, which enables businesses
to advance innovation faster than they would
have otherwise if the agency were very
prescriptive. (Also see “Decentralized Clinical
Trials Could Affect Validity Of Non-Inferiority
Finding, US FDA Says” – Pink Sheet, 2 May,
2023.)

Kevin Potgieter is Vice-President of Regulatory Affairs at
MedableThis is quite different to how things are donein the EU where, for example, when it comes tocomplying with new requirements such as thoselaid down in the Clinical Trials Regulation or
the Medical Devices Regulation, “it’s very muchabout ‘Here’s how you need to do it’ and ‘Here’s
the prescription that you have to follow’,” noted
Potgieter.

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“It’s a very different approach” between
the two regions in terms of the “levelof prescriptiveness that is expected” todemonstrate compliance with software
requirements to support DCTs – Kevin
Potgieter, Medable
This philosophical difference between the US
and the EU becomes evident in their respective
DCT recommendations, although “to a lesser
degree,” he said.
An example of a prescriptive requirementin the EU recommendation paper is thatwhen it comes to using software to support
DCTs, it now points to the recently-finalized
European Medicines Agency guidelineon the use of computerized systems andelectronic data in clinical trials. This final
guideline contains specific considerations forsoftware development, testing and functional
requirements. (Also see “EMA Finalizes Key
Guideline On Use Of Digital Tech To Capture
Electronic Trial Data” – Pink Sheet, 14 Mar,
2023.)
By contrast, in the US the FDA points to thenew draft guidance on Electronic Systems,
Electronic Records, and Electronic Signaturesin Clinical Investigations, which in turn points
to the overarching Part 11 of the Code ofFederal Regulation (ie, the FDA’s regulationfor electronic documentation and electronic
signatures).
“It’s a very different approach” between
the two regions in terms of the “levelof prescriptiveness that is expected” todemonstrate compliance with software
requirements for electronic informed consent,
electronic patient-reported outcomes(ePRO)/
electronic clinical outcome assessment(eCOA)
and other DCT elements, Potgieter said.

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Principles-Based vs Prescriptive: How US & EU
Compare In Their Approach To Decentralized Trials
The EU DCT recommendation paper places
greater emphasis on aspects like quality
by design – Pamela Tenaerts, Medable.
The FDA’s guideline is more of a “principlesbased” document that encourages stakeholders
to think about “what’s right for the circumstanceof the trial, of the participant” and of thetechnology being used, she added.
In contrast, the EU paper places greater
emphasis on aspects like quality by design
and focusing on critical-to-quality factors
with respect to the trial’s design and giving
importance to the patient’s voice in designing
the DCT, Tenaerts noted. Moreover, given thatall 30 member states in the European Economic

Pamela Tenaerts is Chief Scientific Officer at Medable

DCT Regional Comparison

As global technology solution providers haveto meet the “higher bar” when designing theirsoftware, they follow the EU requirements which
point to very specific deliverables. These “morethan satisfy the US requirement,” but “we don’t
see that explicit requirement in the US side,”
Potgieter explained.

This article is part of a Pink Sheet analysis
of DCT regulation in the EU and US.

Another example of a prescriptive requirementin the EU recommendation paper is its emphasis
on a physical, in-person meeting between
the potential trial participant and the study
investigator during the informed consent
process, although it permits this to be done
remotely in certain circumstances, said Pamela
Tenaerts, chief scientific officer at Medable.
In the paper, EU regulators also explain why
a physical meeting may be more necessary
for some trials, for example those involving
vulnerable populations, and “almost start
directing or giving an indication of how people
should think about it,” Tenaerts noted.

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• Another articles looks at how the EU
and the US compare on the morepractical aspects of running DCTs,
such as presenting information on
decentralized elements in trial dossiers,
dealing with the sponsor-investigator
overlap, and the use of local healthcare providers. (Also see “Different, But
Not Poles Apart: Running Decentralized
Clinical Trials In EU & US” – Pink Sheet,
25 Jul, 2023.)• A companion article to the one provided
here a deeper dive into some aspectsof the US draft guidance. (Also see“FDA’s Decentralized Trial Guidance:
Investigator, Health Care Provider
Demarcation Raises Questions” – Pink
Sheet, 24 Jul, 2023.)

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Principles-Based vs Prescriptive: How US & EU
Compare In Their Approach To Decentralized Trials
Area have a voice, “you see that come out insome of this.” (Also see “EU Aims To Drive
Uptake In Decentralized Clinical Trials With
Harmonized Guide” – Pink Sheet, 15 Dec, 2022.)

Interplay Of Other Guidances
For sponsors planning to undertake DCTs in
the EU or the US, the Medable executives said
they must also look at other documents andlegislation in these regions that may affect the
deployment of decentralized elements.

As such, Tenaerts believes that guidance
documents should not be too specific asthey can get “outdated pretty quickly,” aswas the case with International Council for
Harmonization’s first guideline on good clinicalpractice requirements (E6) issued in 1996. That
happened because “back then, they didn’t think
about electronic systems” or “any of those
things,” she noted.

In the US, for example, there are a series ofguidelines on patient-focused drug development
as well as recommendations on electronic
informed consent (eConsent). Likewise in theEU, additional aspects to consider include theGeneral Data Protection Regulation and the EU
digital signature legislation.

The principles-based approach, Tenaerts
explained, encourages people to “think about
what you’re trying to do and do the right thing”
and this has its benefits because “who knows
what the next thing is that we’re going to beusing in clinical trials.” She noted that guidances
are meant to work for all kinds of situationsand “if you get very specific, you kind of backyourself in a corner.”
Potgieter does not expect the US guideline
to remain a high-level document for long. “Iguarantee, over the years there will be course
correction” when issues crop up that are
essentially the equivalent of a safety or a data
integrity signal, he said. The FDA will find that“sponsors struggle with this thing, so we need toprovide a little bit more [guidance].”
The EU regulators too have indicated that the
DCT recommendation paper would evolve
continuously given the “rapid advances” in thefield of DCTs. The current focus, however, is onreviewing and tracking DCTs to gain experience
before considering the need for any updates
to the paper. (Also see “EU Countries Focus On
National Best Practices For Decentralized Trial
Approvals & Inspections” – Pink Sheet, 23 Jun,
2023.)

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November 2023

Another major document that will impact DCTs
globally is the ICH E6(R3) draft guideline, which
has been updated to explain how GCP principles
can be applied to emerging innovations in trial
design and conduct. (Also see “ICH Consults
On Modernized GCP Principles To Make Clinical
Trials More Efficient” – Pink Sheet, 25 May,
2023.)
Tenaerts believes that the draft E6(R3) includes
elements that are closer to the EU DCT
recommendation paper, which is relatively moreprescriptive. “It will be very interesting to see, as
the harmonization period for ICH E6(R3) comesup, how much … within the FDA guidance will
shift” because the ICH guideline at present is“more EU in spirit”, said Potgieter.
While the ICH harmonization process is
expected to take a long time (the draft E6(R3)
was only issued for stakeholder consultationin May 2023), Potgieter said “where the rubber
meets the road most” will be when sponsors
start submitting applications for investigational
new drugs proposing new studies that include
up to seven to eight different DCT elements
and seeing how the FDA provides feedback. For
example, whether it “gives them a thumbs upor thumbs down, or says, ‘Hey, we need to see
more on this element. How do you control thator mitigate the risk for this, etc’.”

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EMA And FDA Compared – The
Case Of Minoryx’s Leriglitazone
Francesca Bruce
06 Jul 2023

Executive Summary

The EMA offers more flexibility than the US FDA when it comesto missed primary endpoints in certain circumstances, meaning
a potentially quicker route to authorization in the EU.

Spanish biotech firm Minoryx Therapeutics
hopes a newly approved Phase III trial willlead to the US approval of its orphan drug
leriglitazone for X-linked adrenoleukodystrophy(X-ALD) in 2026 at the earliest.

although the timeline could be longer. If thefirst efficacy readout for the study at 18 months
does not show efficacy, there will be a second
readout at a later date, followed by a third ifnecessary.

Meanwhile, the European Medicine Agency’s
review of the drug is well under way, with adecision on marketing authorization expected
at the end of 2023 or the beginning of 2024.
The Pink Sheet took a look at the different
approaches to approval in the two markets andhow missed primary endpoints and a lack ofnatural history data have impacted the route toauthorization.

Key Takeaways

In June, the FDA gave Minoryx the goahead to initiate the Phase III CALYX trial ofleriglitazone for treating X-ALD patients withcerebral adrenoleukodystrophy (cALD). The
study is intended to lead to full approval in 2026,

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November 2023

• The EMA offers a more flexible
approach than the FDA when primary
endpoints are missed for orphan
products where there has been little
natural history data of the disease to
inform trial design.
• The review of leriglitazone is moreadvanced in Europe than in the US.
• Leriglitazone could be offered a
conditional marketing authorization in
the EU.

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EMA And FDA Compared – The CaseOf Minoryx’s Leriglitazone
By contrast, in the EU, a review of thecompany’s marketing authorization applicationby the EMA’s committee for human medicinal
products (CHMP) began in September 2022. The
process is ongoing and the company is waiting
for the next round of comments from thecommittee, said Marc Martinell, CEO of Minoryx,
in an interview with the Pink Sheet. He expects
an EU decision on authorization at the end of2023, or the beginning of 2024 if the CHMP
has any “unforeseen requirements”. CALYX will
have little bearing on the decision as the EU
submission is based on the results of an earlier
trial.
Endpoints“There have always been some importantdifferences in the development on both sides of
the Atlantic and in the way the FDA and EMA
have seen the product and what they have beenrequesting,” said Martinell.
One notable difference has been the EMA’s
flexibility with regard to missed primary
endpoints for a treatment for a rare disease
with little natural history data available toinform trial design.
“When you move into the zone of results witha missed primary endpoint, that is when the
differences between regulators become more
pronounced… In Europe you may have more ofa global picture perspective… whereas in the US,
you are more tied by the primary endpoints,”
Martinell commented.
In the EU, the marketing authorization
application for leriglitazone is based on the
Phase II/III ADVANCE trial, a two-year double
blind placebo controlled study that aimed
to evaluate the efficacy of leriglitazone on
the progression of adrenomyeloneuropathy(AMN) in male patients, determined by a motor
function test. The study missed its primary
endpoint in the overall population, which was achange from baseline in the 6-minute walk test.

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November 2023

The Disease
X-ALD is an orphan neurodegenerative
disease with a global incidence ofapproximately 6.2/100,000 live births andwhich is characterized by demyelinating
brain lesions. The lesions rapidly progress
and lead to acute neurological decline
and death. They also produce severe
symptoms, including loss of voluntary
movements, inability to swallow, loss ofcommunication, cortical blindness andtotal incontinence and death, with amean survival of three to four years.
Adrenomyeloneuropathy (AMN) andcerebral adrenoleukodystrophy (cALD)
are the most common phenotypes.
AMN, the chronic form of the disease,affects patients at adulthood and ischaracterized by progressive spastic
paraparesis, sensory dysfunction andincontinence. AMN patients are also atrisk of developing progressive cerebral
lesions. cALD mostly affects males, andonset is typically between the age of fourand eight. If untreated cALD progresses
quickly and leads to permanent disability
and death within two to four years.

Despite missing the primary endpoint, the study
did yield “important results in other endpoints,”
said Martinell. It showed that leriglitazone
reduced the progression of cerebral lesions
and incidence of cALD and the progressionof myelopathy symptoms, including balance
deterioration.
“The reason why we missed the primary
endpoint was essentially because of the lack of
the proper understanding of the natural historyof this disease,” Martinell observed. “When wewere starting, very little was known about X-ALD

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EMA And FDA Compared – The CaseOf Minoryx’s Leriglitazone
and particularly AMN, the chronic component of
the disease affecting the spinal cord. This was
the target population under the study.”“The EMA recognized this sometime ago when
we were discussing the study design,” he said,
adding that there were discussions on how topresent the data in a pre-submission meeting.
Now there is more natural history data available
and a better understanding about the diseaseprogression. “There is a phase of disease when
patients progress a lot on that endpoint anda phase where they do not,” Martinell noted.
Analysis of patients in the early phase of thedisease versus those in later stage disease
showed that there is an important effect on theearly stage group with regard to the primary
endpoint. According to Martinell, the company
has been able to set this out to the EMA. “This is
the kind of consideration we describe in the file.”
Meanwhile, in the US the company had
anticipated that another trial would benecessary. The FDA wanted a larger sample sizeof patients and a study with primary endpoints
that definitively showed clinical benefit, said
Martinell. The FDA-approved CALYX Phase
III trial is designed to satisfy these requests
and is enrolling 40 male X-ALD patients with
progressive cALD defined by the presenceof gadolinium-enhancing brain lesions. The
primary endpoint of the placebo controlled trial
is time to death or bedridden with permanentventilatory support.
CMA vs Accelerated Approval
Another important difference between the tworegulatory systems is that in the EU there is thepossibility of receiving conditional marketing
authorization (CMA). “You don’t have theequivalent in the US. You have accelerated
approval. That can change things and be why
you may end up in different situations on bothsides [of the Atlantic].”10

November 2023

In the EU products are eligible for a CMA if
they are intended to treat or prevent a seriously
debilitating or life threatening disease. They
must serve an unmet need and have a positive
benefit-risk profile. When a CMA has been
granted, the authorization holder must fulfill
certain obligations, such as completing ongoingstudies, starting new studies or collecting
additional data to confirm the medicine’s
positive benefit-risk profile. Martinell did not ruleout the possibility of a conditional marketing
authorization for leriglitazone in the EU.
In the US, the accelerated approval pathway
allows for earlier authorization of drugs
that fulfill an unmet need and treat serious
conditions based on a surrogate endpoint.
Companies are then expected to conduct
further studies to confirm the expected clinicalbenefit.
CALYX is intended to lead to full approvalstraightaway as the primary endpoint is on
survival, said Martinell, though he acknowledged
the accelerated approval pathway could be apossibility if primary endpoints are not hit.
PIP
A third difference between the two markets is
the requirement that in the EU the company
must produce a pediatric investigation plan
(PIP) detailing clinical studies to be conductedin children, unless a waiver is granted.
As part of its EMA-approved PIP, Minoryx is
conducting the NEXUS study in 20 boys between
two and 12 years old with cALD with brain
lesions with or without gadolinium enhancement.
The primary endpoint is the proportion ofpatients with clinically and radiologicallyarrested disease at week 96. Interim results
included in the EU filing for leriglitazone showthat all evaluable patients were clinically stablewith radiologically demonstrated disease arrest
or lesion growth stabilization after 24 weeks.

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How Do Japan’s Clinical Trial
eConsent Rules Compare With
The EU And US?
Eliza Slawther
10 Aug 2023

Executive Summary

A newly translated guidance document from Japan’s drug anddevice regulator outlines the points that clinical trial sponsors
should consider when using electronic methods to collectinformed consent from participants.

Sponsors of clinical trials in Japan can use
electronic methods to explain and obtain
informed consent from participants (eConsent),
as long as communication is provided “atthe same level as a conventional face-toface setting,” according to guidance from thePharmaceuticals and Medical Devices Agency.

the efficiency of clinical trials. Although it
highlights some circumstances where using
more traditional, physical methods of explaining
and obtaining trial participant consent might beappropriate, the guidance broadly supports theuse of digital tools during this process.

In a document that was translated into English
this month following the March publication of
the original Japanese language version, thePMDA outlines considerations for companies
that are looking to use eConsent in the clinical
trial process.

eConsent refers to using remote communication
mechanisms such as digital documents orvideo calls to provide potential clinical trial
participants with the information they need tomake a decision on whether to participate in the
study, and to collect their consent, for instancethrough the use of electronic signatures.

The PMDA notes in its guidance that theuptake of eConsent technology has improved

Japan’s guidance is similar to the approachtaken by the US Food and Drug Administration,

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November 2023

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How Do Japan’s Clinical Trial eConsent
Rules Compare With The EU And US?
which encourages sponsors to consider theindividual circumstances of a trial and theparticipant during the consent process. (Alsosee “Principles-Based vs Prescriptive: How US &EU Compare In Their Approach To Decentralized
Trials” – Pink Sheet, 24 Jul, 2023.).
By contrast, EU guidelines on using electronic
tools during clinical trials emphasize theimportance of conducting physical meetings
where possible during the consent process,but say that eConsent methods are permitted“where this can be justified and is allowed
nationally and if approved by an ethics
committee.”Sponsors conducting clinical trials in Japan
should evaluate the “appropriateness” of using
eConsent methods during the clinical trial design
process and put forward an eConsent procedure
for review by the institutional review board, thePMDA says, although the document does notstate that sponsors must justify the decision touse eConsent instead of physical meetings.
There are some cases where sponsors must
consider whether eConsent is suitable, thePMDA notes, such as where participants areunable or unwilling to use digital consent tools.
Face-to-face meetings should be offered as analternative in these situations.

The production of a global database that
describes country-level requirements foreConsent is one key aim of an ongoing EU
initiative launched to boost the uptake of thistechnology in Europe, where its use is currently
limited.

Sponsors also need to account for individual
variations in digital literacy or accessibility whensetting up eConsent IT systems, and ensure thatparticipants are offered training or additional
information so they can operate systems
appropriately.

The project, run by the EU Forum for Good
Clinical Practice, also aims to address
challenges such as a lack of harmonization
around eConsent terminologies and unclear
regulatory, ethics and privacy requirements(Also see “EU Multistakeholder Project Aims To
Give eConsent The ‘Place It Deserves’” – Pink
Sheet, 6 Jun, 2023.).

The PMDA document also provides information
and advice around verifying participants’
identities, the use of video and phone calls,
requirements for electronic signatures, and the
secure storage of eConsent records.

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November 2023

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Gene Therapy HTA: How Do
The European, Australian And
Canadian Systems Shape Up?
Eliza Slawther
25 Sep 2023

Executive Summary

A report comparing the health technology assessment methods
used in nine European countries, Australia and Canada foundthat England has the most favorable reimbursement landscapefor gene therapies – but outlined several areas for improvement
across the board.

There are six main actions that healthtechnology assessment organizations should
implement to capture the value of genetherapies, according to researchers from the
UK’s Office for Health Economics (OHE). Yet,the organization suggested in a recent report,
wide variations in the HTA methods used withindifferent countries demonstrate the importanceof continued changes to HTA methodologies
and evidence generation to enable the potential
benefits of gene therapies to be realized.
Some of its recommended actions include
the development of standards for the use of13

November 2023

real-world evidence and surrogate endpoints
in HTAs, the inclusion of patient-reported
outcomes and the use of data collected ininternational registries.
In a report published earlier this month, theOHE compared the extent to which 11 different
countries have achieved these actions, andfound that England was the highest performer,
having implemented five out of the six
recommended. Switzerland, on the opposite endof the scale, appeared to have carried out the
fewest number of actions recommended by the
researchers (see table).

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Gene Therapy HTA: How Do The European,
Australian And Canadian Systems Shape Up?

England’s HTA body, NICE, was found to havefully achieved all but one of these recommended
actions. The only one it had not met was theinclusion of outcome or other value-based
arrangement in its methods, which the report
said NICE “partly achieved”.
The countries included in the report wereAustralia, Canada, Denmark, France, England,
Germany, Italy, the Netherlands, Spain, Sweden
and Switzerland. The report looked at how well,

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November 2023

if at all, the HTA organization for each country
met each of the six recommendations, andconsidered the reimbursement status of nine
gene therapies.
Sian Besley, lead author of the report and an
economist at the OHE, told the Pink Sheetthat many additional value elements fromwhat’s known as Lakdawalla’s value flower“are not considered in current HTA methods”.
Also known as the International Society for

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Gene Therapy HTA: How Do The European,
Australian And Canadian Systems Shape Up?
Pharmacoeconomics and Outcomes Research(ISPOR) value flower, this model includes
12 potentially underappreciated or ignored
elements of value in conventional drug HTAs
such as equity, disease severity, and adherenceimproving factors.
For example, she said “the value of hope – which
may be very relevant for many gene therapies” –is not always considered.
However, Besley explained that the key
takeaway from the report is that for the
fourth recommendation, which related tocapturing benefits beyond the clinical efficacy
of a medicine, “value elements are often notconsistently and transparently considered
across technologies.”

In Italy, staged payments linked to individual
patient outcomes were in place for two genetherapies, but the report noted that there had
been a recent decline in the use of outcomebased payments in Italy “in favor of confidential
price discounts.”

There has been a growing consensus in recent
years that traditional HTA methods are suited

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November 2023

Often, these therapies come with price tags
that far exceed $1m per patient. CSL Behring’s
hemophilia B gene therapy Hemgenix(etranacogene dezaparvovec), for example,
has a list price of $3.5m, and was recently
provisionally turned down for reimbursementin England, although negotiations are ongoing.
(Also see “England: CSL Undeterred By Draft
NICE Rejection Of Its £2.6m Hemophilia B Gene
Therapy” – Pink Sheet, 2 Aug, 2023.).
Country Comparisons
Most of the countries included in the reportachieved the first recommendation of using HTA
methods that recognize the lifetime benefits
offered by a therapy. However, Australia andSpain only partially achieved this metric, while
Switzerland did not achieve it at all.

Italy’s Agenzia Italiana del Farmaco (AIFA),
which is the country’s medicines regulator
as well as its pricing and HTA authority, wasthe only one found to fully achieve the fourth
recommendation – “many outcomes-basedand economic risk-sharing agreements havebeen implemented, making use of their wellestablished registries,” the report said.

“The recommendations are not specific tothe HTA of gene therapies and should beconsistently applied across HTA of othertreatments,” the report said. “However, due tothe combination of challenges presented by
the HTA of gene therapies, if implemented, therecommendations are likely to have a larger
impact on the assessment of gene therapies.”

more towards chronic therapies, rather thannovel gene therapies that are intended to be acure, or at least provide long-term symptomatic
relief for individuals with genetic diseases. (Alsosee “Advanced Therapies: Payment Revolution
Must Accompany Industrial Revolution In
Europe” – Pink Sheet, 12 Aug, 2022.).

Switzerland scored lowest overall in terms ofmeeting the six recommendations. It did not
fully achieve any of them, and only partiallyachieved two, which were including outcome
or other value-based arrangements andexpanding data collection through registries andinternational collaboration.
Besley explained that the large variations
between HTA bodies were “not surprising”
given that some were more established thanothers. “The key benefit of our analysis lies inuncovering where these variations may impact
the HTA of gene therapies,” she said.
“Many of our recommendations focus on
ensuring that methods to improve theappropriateness of HTA for gene therapies areclear and transparently implemented. This is

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Gene Therapy HTA: How Do The European,
Australian And Canadian Systems Shape Up?
not always the case, and efforts are needed toembed the principles explicitly into publishednational HTA methods and guidelines,” shecontinued.
Further research is also needed to assess thebarriers that are preventing countries from
implementing the OHE recommendations,Besley said, which would then be followed by
an exploration of how these barriers could beovercome.
NICE Moving To ‘Modular Approach’
The report reflected favorably on England’s
NICE, and praised its highly specialized
technologies (HSTs) program, which it said wasan example of extra value being recognized forvery rare technologies beyond the number ofquality-adjusted life years (QALYs) gained.
“The HST pathway offers a more pragmatic
approach to dealing with uncertainty,” theOHE report said. NICE’s real-world evidence
framework was also found to be “the mostcomprehensive guideline for the inclusion of
RWE in HTA.”
A spokesperson for NICE said that the HTA
body recognized the high potential andtransformative health benefits of innovativetechnologies such as gene therapies, “andthe importance of robust health technology
assessments to secure rapid, evidence-based
patient access and value for money.”

Orchard Therapeutics, the manufacturer ofLibmeldy (atidarsagene autotemcel), an exvivo gene therapy used to treat children withmetachromatic leukodystrophy, told the Pink
Sheet that the patient perspective had been
incorporated into the NICE HTA process in its
experience.
“That’s really important in terms of being able
to fill in some of the evidence gaps, which
you cannot inform [just] by using [trial] data,”
Francis Pang, senior vice president for global
market access at Orchard, told the Pink Sheet ina recent interview.
Libmeldy was reimbursed in England in February2022, after a new pricing agreement wasreached following an initial rejection from NICE.
(Also see “Libmeldy: ‘Significant Discount’ For
World’s Most Expensive Drug Secures English
Funding” – Pink Sheet, 4 Feb, 2022.).
During the interview, which will be published infull later this month, Pang also discussed theaccess challenges involved in getting innovative,
advanced therapy medicinal products (ATMPs)
such as Libmeldy to patients across the globe,
and explained how HTA processes can beadapted to meet the needs of gene therapies.

“It’s great to see the OHE recognize NICE’s
assessments are based on processes andmethods that are fit-for-purpose even whenaddressing these more complex treatments,” thespokesperson said.

EU Joint HTA Impact
The upcoming EU-wide joint clinicalassessments (JCAs) introduced by the EU
regulation on HTA could see some of thevariations in the methods used by EU member
states to assess gene therapies removed, giventhat JCAs will be conducted at an EU level
rather than nationally. The outcomes of JCAs
will not, however, be legally binding for national
reimbursement and pricing decisions.

“NICE will ensure its manual remains cuttingedge by moving to a modular approach for
any future updates, allowing us to update
our processes and methods in an agile andresponsive way,” the spokesperson added.

Paolo Morgese, head of public affairs, Europe,at the Alliance For Regenerative Medicine(ARM), told the Pink Sheet that the OHE report“draws conclusions similar to recent ARM
research.”

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Gene Therapy HTA: How Do The European,
Australian And Canadian Systems Shape Up?
“While at varying degrees, several national
HTA bodies are adapting their methodologies
to fit the unique nature of ATMPs,” he said,
adding that the pan-European JCAs due totake effect in 2025 “should be inspired by
HTA modernization in countries like the UK,
Germany, France, Italy, and Sweden.”
The ARM has previously discussed its concerns
about the upcoming joint HTA assessments,
although it has broadly supported the legislationin principle given the potential for EU-level
JCAs to reduce the administrative burden
on companies seeking reimbursement foradvanced therapies. (Also see “Direction Of
Travel Of EU HTA Regulation Is ‘Disappointing’
For Advanced Therapies” – Pink Sheet, 6 Dec,
2022.).
HTA bodies are not the only organizations thathave struggled in recent years to assess thevalue of gene therapies. Regulators acrossthe globe also face ongoing challenges in
deciding whether a gene therapy is likely to bebeneficial in the long term, given that the data
are not available until patients treated withgene therapies have lived for many years. (Alsosee “Gene Therapy: Years After Accelerated
Approval, Will US FDA Still Be Asking ‘Does It
Work?’” – Pink Sheet, 20 Feb, 2023.).

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November 2023

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