Orphan and Ultra-Orphan Technologies:
European and Australian Payer Perceptions
Susan L Hogue,1 Andrew P Brogan,1 Eleanor L Croft2
1
RTI Health Solutions, Research Triangle Park, NC, United States;
BACKGROUND
– Australia: In 1997, established a legal framework for orphan
drug designation, with waiver of application and evaluation
fees, and no annual registration fees.1
– European Union (EU): In 1999, adopted regulation providing 10 years
market exclusivity, protocol assistance, and fee reductions.2 Since
then, there have been 2,100+ orphan designations requested,
1,400+ orphan designations received, and 100+ marketing
authorizations spanning several therapy areas (Figure 1).3
Kalydeco (Ivacaftor)
Soliris (Eculizumab)
• In 2012, the European Medicines Agency (EMA) approved
ivacaftor for the treatment of patients with cystic fibrosis with the
G551D mutation in the CFTR gene that codes for the cystic
fibrosis transmembrane conductance regulator protein. In 2013,
the Therapeutic Goods Administration (TGA) issued regulatory
approval in Australia for ivacaftor.5
– In the cystic fibrosis population, 4% to 5% have the G551D
mutation in the CFTR gene. Ivacaftor is the first drug to treat
the underlying molecular defect in cystic fibrosis. Ivacaftor is a
high-profile case due to the high cost of the drug, which is
approximately $300,000 per patient per year.
• The EMA approved eculizumab for the treatment of paroxysmal
nocturnal hemoglobinuria (PNH) in 2007 and atypical hemolytic
uremic syndrome (aHUS) in 2011. The TGA approved eculizumab
for PNH in 2009.
– Eculizumab is a humanized monoclonal antibody (mAb) that
targets and inhibits complement component 5 (C5), a latestage component of the complement system.
HTA and Access
OBJECTIVE
• Orphan and ultra-orphan technologies have an increasing impact
on health care spending; thus, we sought to gain insights from the
RTI Health Solutions Payer Advisory Panel on these technologies.
Figure 1.Distribution of EU Marketing Authorization Applications
Across Therapeutic Areas
M 1%
L onco 40%
R 4%
Number of conditions: 81
(including extension of indications/variations)
V 4%
A Alimentary tract and metabolism
J 3%
C Cardiovascular system
H Systemic hormonal
J Antiinfectives for systemic use
L Immunology
M Musculo-skeletal system
N Nervous system
•France
– ASMR (Improvement of Medical Benefit Assessment) score of
2 (1 is highest score). Mutation testing required and approved
if meets mutation requirements. Clawbacks in place in France
if orphan drug exceeds a revenue threshold. Threshold for all
indications combined.
R Respiratory system
B 8%
H 3%
L immuno 4%
V Various
Source European Medicines Agency, 2015.3
METHODS
•Germany
– Available with no restrictions.
• We conducted in-depth, qualitative, one-on-one interviews with
health economics professors, health technology assessment
(HTA) and/or payer advisors representing Australia and the EU-5.
•Italy
– Managed/paid for at the hospital level in most cases. No
risk-sharing agreement because not oncology.
•Spain
– Available but a large hospital pharmacy group has strongly
recommended against use of the therapy because there is not
enough evidence to support use. Limited use in practice in
Spain because of high price.
RESULTS
Review Process for Orphan Indication Therapies
• Evidence requirements and expectations for therapies with
orphan indications can differ from those without in the EU-5:
– France: Cost-effectiveness model is not required if the revenue
for the therapy is expected to be less than €20 million annually.
– Germany: Full dossier with a Federal Joint Committee (G-BA)approved comparator is not required if the revenue is less than
€50 million over a rolling 12-month period.
– Italy: Experimental stage with risk-sharing agreement could be
available for therapy with an orphan indication.
– Spain: Special considerations may impact price comparisons if
no previous treatment is available for the orphan indication.
– United Kingdom (UK)
• National Institute for Health and Care Excellence (NICE):
Additional flexibility on cost per quality-adjusted life-year (QALY)
is available if qualifications for certain unmet needs, disease
burden, and lack of alternative treatments are met.
• Scottish Medicines Consortium (SMC): If regular HTA review is not
favorable, manufacturer can request an additional review
focusing on the patient and clinician perspective rather than
economics. If favorable, the SMC has greater flexibility on cost
per QALY.
• In Australia, the HTA committee can consider some additional tradeoffs (other than cost per QALY) as defined by the “rule of rescue.”4
HTA and Payer Challenges for Orphan Indication
Therapies
• Lack of comparators, treatment patterns, or standard of care
Additional Feedback From Payer Advisors
• Clinical aspects remain a top priority; manufacturers should
design and implement the most powerful trials, or sets of trials,
possible.
Quality of evidence could be a problem, leads to low ASMR rating…
need ASMR better than or equal to 3 if expensive hospital drug and
can be difficult to achieve if poor quality evidence. Budget impact
will impact management, and clawbacks. – France Payer Advisor
• Be aware of risk-sharing requirements/expectations (e.g.,
Australia), revenue thresholds that have additional requirements
(e.g., Germany) and clawbacks (e.g., France).
Manufacturers should keep risk-sharing schemes in mind as part of
the package when they price a drug in Australia because may not
get a better price after risk-sharing scheme is assigned. Risk-sharing
scheme should be part of market forecasting in Australia.
– Australia Payer Advisor
• Clearly define the unmet need and disease burden.
There is a level at which the committee will not comprise…can’t be
really bad at the usual buckets…need to meet minimum thresholds
on clinical efficacy, clinical effectiveness and economic assessment
(maybe < 500K GBP / QALY) then be compelling on some other
point that matters to the committee... patient impact, patient story,
etc. – UK Payer Advisor
• Consider early consultation with stakeholders at appropriate
levels.
• Limited clinical evidence from small clinical trials with which to
make informed decisions
• High cost of therapies with an orphan indication
Consider consultation with G-BA before clinical program starts (to
input on trial design) or before submitting dossier (to identify
appropriate comparator etc.) – Germany Payer Advisor
• Extremely high cost per QALY makes typical economic analysis
inappropriate
The power of knowledge.
The value of understanding.
•UK
– England (~320 eligible patients):
• Cost per QALY originally estimated to be between £335,000
– Scotland (~70 eligible patients):
• Rejected by SMC. Subsequently funded by new government
fund for orphan drugs.
L Antineoplastic
A 18%
• Australia (~250 eligible patients):
– Pharmaceutical Benefits Advisory Committee (PBAC) deferred
initial decision because of cost. Government then allocated
Pharmaceutical Benefits Scheme (PBS) funding on pay-forperformance basis through the Life Savings Drug Program that
recommended use because ivacaftor met rule-of-rescue
exceptions. Rule of rescue is applied on a case-by-case basis.
Indication expansion can impact TGA regulatory orphan
designation.
and £1,274,000. Discounted price remains confidential; however,
cost per QALY was reduced to between £285,000 and
£1,077,000 (~15% reduction). Specialized Commissioning Group
subsequently agreed to fund Kalydeco.
B Haematology
C 8%
RTI Health Solutions, Manchester, United Kingdom
CASE STUDIES: Orphan Therapies That Have Confounded HTA Agencies and Payers in the EU and Australia
• Recognizing the importance of incentivizing orphan drug
development, regulatory agencies around the world have
established orphan designations.1
N 7%
2
– PNH is a rare, progressive, and sometimes life-threatening
disease characterized by excessive destruction of red blood
cells and excessive blood clotting.6
– aHUS is a life-threatening, ultra-rare genetic disease; patients
experience uncontrolled complement activation that causes
abnormal blood clots to form in small blood vessels
throughout the body, leading to kidney failure and damage to
other vital organs.7
HTA and Access
• Australia (~70 patients):
– Initially rejected by PBAC for inclusion on life-saving drug
program (unacceptable cost-effectiveness was one reason).
PBAC approved the drug with payment for performance and
government allocated PBS funding for eculizumab.
•UK
– England (~200 eligible patients):
• NICE asked manufacturer to justify price by providing
information on research and development costs. NICE later
approved based on conditional coordination through expert
center that required monitoring the number of aHUS patients,
development of a protocol for starting/stopping treatment, and a
research program that evaluates when to stop treatment or
adjust dosage. Budget impact is uncertain but will be
considerable.
–Scotland
• Not recommended twice by SMC. Local health boards can
approve and pay for use on a case-by-case basis.
•Germany
– Eculizumab was available in Germany before Act on the
Reform of the Market for Medicinal Products (AMNOG) and is
not subject to its price and access restrictions.
•Italy
– Managed/paid for at the hospital level in most cases and no
risk-sharing agreement because not oncology.
•Spain
– Regional differences in terms of access and payment. Strong
protocol in support of eculizumab use in Valencia for patients
that meet inclusion criteria. Authority above physician level
required, with significant variability at the hospital level where
eculizumab is dispensed on a case-by-case basis.
• Manufacturers should be prepared to justify high-priced drugs.
There is not a blank check. Questions are going to be increasingly
asked about justification for price. More and more resistance in the
future. - UK Payer Advisor
• Manufacturers should consider early value assessment of orphan
therapies in the pipeline.
Not just for orphan...Manufacturers should apply an early costeffectiveness analysis as a weed out mechanism for drugs that won’t
meet cost-effectiveness thresholds. If it is going to fail then fail fast.
- Australia Payer Advisor
CONCLUSIONS
• Payers are seeking more value-based information to better inform
decision making in the evaluation of new orphan and ultra-orphan
technologies.
• Benefits of new technologies may not be captured in traditional
cost per QALY; thus, reducing uncertainty and bridging the clinical
evidence with other robust data will be critical.
• Rising costs of orphan and ultra-orphan technologies will have
more impact on market access in the future; over time there will
be increasing resistance to high prices.
REFERENCES
Please see handout for complete reference list.
* Ms. Croft was an employee of RTI Health Solutions when this work was conducted.
Presented at: ISPOR 18th Annual European Congress, November 7-11, 2015, Milan, Italy