Access Campaign
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2016 ACCESS TO CARE: EURORDIS POSITION ON COMPASSIONATE USE
EURORDIS European Organisation for Rare Diseases 01/08/2016
EURORDIS Position on Compassionate Use (draft 3)
Executive summary .................................................................................................. 4 Policy proposals............................................................................................................... 4 Recommendations to patients’ organisations .............................................................. 5 Recommendations to industry........................................................................................ 5 Recommendations to Member States ........................................................................... 6 Recommendations to European Authorities.................................................................. 6
Introduction ............................................................................................................... 7 What is compassionate use, and why is it much needed.................................... 8 Legal definition of Compassionate Use Programmes in the EU (CUP)......................... 8 Ethical considerations ..................................................................................................... 9 Differences between named patient basis and cohort programmes ........................ 9 Evidence needed to initiate a CUP ................................................................................ 9 Product availability........................................................................................................ 10
EURORDIS views on CUPs in the sense of the European Legislation ..................... 11 Usefulness of compassionate use programmes ................................................. 11 Recommendations ................................................................................................. 11 Recommendations to industry...................................................................................... 11 Recommendations to European and National Authorities ........................................ 13 Recommendations to Patients’ organisations and healthcare professionals .......... 14
Free or paid for CUPs?............................................................................................ 15 The Right-to-Try laws in the USA ............................................................................ 16 Way forward ............................................................................................................ 16 Conclusion .............................................................................................................. 18 Annexes .................................................................................................................. 19 EURORDIS survey on Compassionate Use Programmes for orphan medicines .......... 19 Where to find information on compassionate use programmes (public domain)? 25
Works Cited ............................................................................................................. 26 Glossary................................................................................................................... 28 Credits, acknowledgements and funding ........................................................... 31
1501 SeptemberAugust 2016
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EURORDIS Position on Compassionate Use (draft 3)
EURORDIS Position on Compassionate Use Compassionate use is an early access to promising new medicines. Compassionate use programmes can save lives. A position by E URORDIS In this document: -
An introduction EURORDIS political position on compassionate use Recommendations to developers of medicines Recommendations to European and national regulators Recommendations to Patients’ Organisations and advocates The results of a survey conducted by EURORDIS on CUPs in rare diseases Where to find information on compassionate use (public domain) All sources of information contained in this document; A glossary of all terms used in this document.
About EURORDIS The European Organisation for Rare Diseases (EURORDIS) represents more than 750 rare disease organisations in 58 different countries, covering more than 4,000 rare diseases. It is therefore the voice of the 30 million patients affected by rare diseases throughout Europe. EURORDIS is a non-governmental patient-driven alliance of patient organisations and individuals active in the field of rare diseases, dedicated to improving the quality of life of all people living with rare diseases in Europe. It is supported by its members and by the French Muscular Dystrophy Association (AFM), the European Commission, and corporate foundations and the health industry. EURORDIS was founded in 1997. Further details concerning EURORDIS and rare diseases are available at: http://www.eurordis.org
1501 SeptemberAugust 2016
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EURORDIS Position on Compassionate Use (draft 32) known on its toxicity, and the patient and
Executive summary
his/her doctor have agreed on this option.
Considering that
the authorisation of a medicine, with a higher
according to where they live, and huge
degree of uncertainty on the efficacy and
inequalities prevail in terms of timely access
safety, and with no guarantee that the
to new medicines. It is the case after a
medicine will be actually authorised
However not all countries benefit from an
case before, at a stage where it is not yet a
efficient scheme for compassionate use, and
medicine but an investigational product that
a time delay of more than three years may
is
exist in Europe between patients benefiting
subject
of
clinical trials.
Investigational products may offer the best hope of treatment and relief to those without established effective options. Compassionate use is supported by ethical imperative to alleviate this unfairness.
Patients and their representatives no longer ignore when a product enters first-in-men studies, or proofof-concept trials, or
confirmatory
trials. Even before public registries of
A compassionate use is a programme prior to
Even in Europe, patients are discriminated
medicine has been authorised, it is also the
4
from
a
compassionate
use
treatment,
depending on where they live.
Each investigation of a new product raises hopes, but there is danger to false hope, and this hope should be guided. Pre-authorisation access needs to be balanced with realistic expectations. Having a mechanism to gain early access is crucial, but the process must be steered by research and trial data to the greatest degree possible.
Premature communication about "promising"
clinical trials existed, patients could explore
results after a test on a single animal model
scientific journals and understood when a
or just a few patients is detrimental to all, as
new product development had started.
the views presented are not balanced. There
The time needed to develop a medicine
is often too much hype and too little data.
varies, but in average lasts for five to seven years, usually followed by the regulatory process and its legal timeframe, and finally pricing and reimbursement negotiations.
Not
all
patients
have
the
time
to
EURORDIS is making proposals to remedy the situation.
Policy proposals EURORDIS proposes one of the following options:
contemplate this relatively long process: their
1. Promote the French ATU system, probably as
disease worsens, they lose their body function
the most efficient compassionate use scheme
one
so that every Member State adopts it;
after
the
simultaneously
other, to
they this
die.
And
ineluctable
deterioration, they can hear “promising
2. or adopt an EU Regulation which would
results” coming in the news, in real time. No
confer a greater role in the organisation of CUPs
other situation than this one can be a source
upon the EMA;
of greater despair in a patient’s life: dying and being aware a possible medicine is approaching the market.
3. and/or apply the Directive on Patients’ Rights in Cross-Border Healthcare to include compassionate use as part of the care basket so that patients can benefit from these
Society has a response to compassionate use of a medicine.
this
despair:
treatments wherever they live in the EU; 4. Generalise the Medicines Adaptive
A compassionate use programme is a
Pathways to Patients, where the EU regulator
possibility
may authorise a medicine at an early stage and
for
patients
of
receiving
a
treatment at a stage where efficacy is not
in a limited group of patients that are in high
yet demonstrated, and not everything is
need for the product, keeping in mind that post-
EURORDIS Position on Compassionate Use (draft3 2)
conducted afterwards. This is in the spirit of the
Should compassionate use programmes be paid for?
compassionate-use programme as defined by
A system where all CUPs should be for free or on the
the EU legislation, but with a different regulatory
contrary paid for, at the discretion of the company,
angle. This can only work if payers are part of
would be hardly sustainable.
authorisation confirmatory studies need to be
the initiative as they will need to accept to pay for a medicine with high uncertainties in term of efficacy or safety at that point; 5. Amend the EMA guidelines for compassionate use, the role of the EMA could be reinforced with or without legal changes to the pharmaceutical legislation
A possibility could be to consider the financial situation of the company before accepting a paid for programme, and to agree on a pay-back if the product is finally not authorised, or at a lower price if it is not as valuable as initially estimated.
Recommendations to patients’ organisations
Group of patients or named patient basis?
the importance of compassionate use programmes;
Group of patients or cohort In the first case, a group of eligible patients who
product starts (or clinical trials for a
(indication, population) and when the programme is
repurposing of a known medicine), and
authorised clinicians do not need to request an
engage discussions with the developer at
authorisation for each patient. The programme is
an early stage to agree on if and when a
then run and supervised by the developer with an
compassionate use programme could be
approved protocol.
relevant, and for which patients
This type of compassionate use is the one provided
for in the EU Regulation, however few Member States have adopted national rules to implement this type of programme.
On a named patient basis on the contrary, clinicians need to request an authorisation for each patient. Typically, this is when the number of requests is expected to be low, as it is time consuming both for the regulatory
for
authorities.
Patient organisations, clinicians should consult each other about all practical aspects of the compassionate use programme.
Recommendations to industry
Named patient basis
and
Patients’ organisations should be aware when the clinical development of a new
could benefit from the compassionate use is defined
clinician
Patients’ organisations should be aware of
the
Inequalities in accessing compassionate use medicines were presented to the European Medicines Agency back in 1998. These inequalities undermine the success of the European legislation on pharmaceuticals.
Discuss the relevance and timing of a compassionate use with patients’ advocates and doctors early in the development of a medicine; Define inclusion criteria for the compassionate use with patients and clinicians; Set up clear rules between compassionate-use and clinical trials.
No
Explain the plans for the initiation of a
protocol is needed, and the product can be used to treat different conditions.
CUP country by country,
Accept information on compassionate-
Most if not all Member States have a frame for
use programmes cannot be considered
compassionate use programmes on a named
as confidential;
patient basis.
Collect information from the compassionate-use programme, in particular toxicity data and special populations;
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EURORDIS Position on Compassionate Use (draft3 2)
Plan an adequate supply of the product,
compassionate basis (typically open-label
and in case of an important increase in the
trials with no comparison arm).
number of requests consult with patients and doctors on how to slow down the programme. If tensions occur, the responsibility lies with the company and a company should not ask patients or doctors to make decisions; And avoid:
Interrupting the programme in an abrupt manner, rather discuss the programme-end modalities with patients, doctors and regulators in the first place;
Presenting the programme to clinicians as a gift to high inclusion rates in clinical trials;
Mixing compassionate-use programmes with humanitarian or financial support programmes.
photo 1: Jocelyn, living with Autoimmune lymphoproliferative syndrome
Recommendations to Member States
National authorities should improve transparency of compassionate use programmes they authorise, so that clinicians and patients are aware of which programmes are run in which countries and how to join them;
Member States should create a compassionate use programme Facilitation Group in order to exchange information and build upon common experiences to set up harmonised procedures and create a network which can facilitate future changes in the legislation;
Member States should respect article 83 of Regulation (EC) Nº 726/2004 and notify the EMA of compassionate-use programmes that they authorise.
Recommendations to European Authorities
The European Commission could compare different national schemes for compassionate-use programmes available in the EU;
The EMA could explore how to make a better use of the European register of clinical trials to identify clinical trials which purpose is to provide a medicine on a
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EURORDIS Position on Compassionate Use (draft3 2)
Introduction Back in 1988, people infected with the HIV virus advocated for earlier access to anti-HIV products,
Authorisation scheme (A.T.U). Thanks to this scheme, 11,000 patients could be treated either with indinavir or ritonavir starting March 1996, and when
given the time needed for their development.
both products received marketing authorisation
In the US, patients were marching to the F.D.A
the hospitalisation rate for 1,000 AIDS patients had
asking for accelerated evaluation of new
already declined by 38% compared to early 1996.
medicines, and for a “parallel track” for all those
In mid-1997, hospitalisation rates for AIDS patients
who did not have a chance to enrol in clinical trials.
had dropped by 56%, and mortality by 14%.
In France, discussions between patients’
This represented an estimated 582 deaths avoided,
organisations and health authorities around the
as 17,676 HIV individuals had reached the AIDS
concept developed by French Doctors on “Octroi
stage in 1996, with a 50% mortality risk at 6 months,
humanitaire/octroi compassionnel”, namely
of whom 11,000 could enter the compassionate use
humanitarian access and compassionate access
programmes.
had also started.
later in September and October 1996 respectively,
This example illustrates the public health benefit of
Very soon after these discussions, compassionate
compassionate use programmes: in March 1996,
use authorisations were granted, both for anti-HIV
ritonavir and indinavir had not been evaluated for
products and for experimental treatments against
marketing authorisation, a marketing authorisation
the opportunistic diseases that can occur in HIV-
had not even been submitted in the EU, and yet,
infected individuals.
based on presumed efficacy reported in a scientific
After the initial marketing authorisation of Retrovir® (zidovudine-AZT) in 1986 in the US and 1987 in European countries, other antiretroviral have
conference in January 1996, regulatory agencies and developers agreed to initiate the compassionate use programme urgently.
systematically been the subject of an international
This programme benefited the patients, by reducing
compassionate use programme, see figure 1.
the immediate risk of death for 11,000 of them in
Figure 1
France, the developer, by collecting important safety information complementary to the evidence gained from clinical trials, and the health care system, as the cost of the compassionate use programme was far overweight by the savings in terms of direct hospitalisation costs and lives saved. However again, in many other countries, patients had to wait sometimes an additional year after the marketing authorisation to benefit from these lifesaving treatments: in the UK, the newly created National Institute for Clinical Excellence (NICE) was explaining that cost-effectiveness studies were
In particular, patients who exhausted all other treatments could almost continuously benefit from a new antiretroviral as sequential developments were starting. In 1996, highly active antiretroviral became also available in compassionate use programmes. One example is France, with the Temporary Use
necessary before the NHS could provide these treatments. In September 1996, patients organised a press conference to advocate for access to highly active antiretroviral therapies. In Italy, some 1,000 patients could benefit from the French ATU by consulting doctors at the Hôpital de l’Archet in Nice, but other Italian patients had often to wait until 1997 to be treated.
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EURORDIS Position on Compassionate Use (draft 32)
What is compassionate use, and why is it much needed
analyse the annual reports provided by the sponsors of the orphan designations that inform on their development status).
A treatment, when there is none: Compassionate use is a treatment. It is not
These R&D efforts generate huge expectations in the
an experiment with an investigational
concerned patients’ communities. From the above
product. The intention is to treat the patient,
mentioned data, the precise number of different
hoping he/she can benefit of a positive
product/indication pairs cannot be estimated, but
effect.
certainly a few hundred products are being
Before the medicine is authorised: This
investigated. To complete with EMA data on how
treatment is provided when the product is
many different IMPs are being investigated for rare
not yet authorised.
diseases (email sent 10/08/2016).
For patients who cannot wait for the end of the development: this is the concept, not all patients can afford to wait until a product development is completed, regulators have agreed to authorise it and healthcare systems have agreed to cover it or to reimburse it.
8
It is a societal response to patients in a desperate need of a last option before passing away or deteriorating severely.
Patients with rare diseases are candidates for
The
(COMP)
at
the
association
of
Pharmaceutical
regularly publishes reports and list of medicines in development, and in 2016 it estimates there are more than 560 medicines in development for rare diseases (PhRMA, 2016).
Legal definition of Compassionate Use Programmes in the EU (CUP) Regulation (EC) Nº 726/2004 article 83.2 defines such programmes: Running a Compassionate Use Programme (CUP) consists in making a medicinal product
designated as orphan by the Committee of Orphan Products
based
Research and Manufacturers of America (PhRMA)
compassionate use programmes. Medicines that are Medicinal
US
available for compassionate reasons to a
European
group of patients with a chronically or seriously
Medicines Agency are indicated for life-threatening
debilitating disease or whose disease is
or severely debilitating conditions, and in most cases
considered to be life-threatening, and who
few treatment option exist.
cannot
be
treated
satisfactorily
by
an
authorised medicinal product.
It is difficult to know exactly how many different products for rare diseases are being developed at
The medicinal product concerned must either
present. As of 11 July 2016, 997 phase III and 1,347
be the subject of an application for a
phase II clinical trials are in progress in the EU/EEA to
marketing
or
must
be
undergoing clinical trials.
explore the efficacy of medicines in rare diseases (European Register of Clinical Trials).
authorisation
Again, the EU definition applies to programmes for
Another important figure is the number of orphan
groups or cohorts of patients, not to named patient
medicinal product designations: 1,654 of which 132
basis programmes.
already translated into a marketing authorisation
For
(this represents 122 different products), as of May
organised, different conditions need to be satisfied:
2016. Not all designated orphan medicinal products
1. Eligible patients: A group of patients who
are the subject of clinical trials, and the precise number is not publicly disclosed (only the EMA could
1
This does not apply to named-patients programmes
compassionate
use
programmes
to
be
could benefit from the programme1 has to
EURORDIS Position on Compassionate Use (draft3 2) be defined: indication of the CUP, inclusion
Clinical trial participants
and exclusion criteria.
For
addition to the supply needed for the trials
who were receiving the experimental product, and to those who were on the placebo or comparator.
authorities need to agree on the
The Helsinki Declaration as revised by the World
programme and to organise it, often on
Medical Association in 2008 states that “(33) at the
clinicians’ request. Providing the
conclusion of the study, patients entered into the
investigational product for compassionate
study are entitled to share any benefits that result
use should not interfere with the initiation,
from
conduct, or completion of clinical trials to
identified as beneficial in the study or to other
support marketing authorisation
appropriate care or benefits" (WMA, 2008). And
it, for example, access to interventions
also:
(14)
The
access
describe
Application should have been submitted, or
subjects to interventions identified
clinical trials should be in progress (no
as beneficial in the study or access to other
prerequisite of having obtained a marketing
appropriate care or benefits”.
presumed.
post-study
should
arrangements
EU). At this stage, efficacy can only be
for
protocol
obtained soon: A Marketing Authorisation
authorisation in another jurisdiction than the
by
study
Differences between named patient basis and cohort programmes Named patient basis
Programme for a group
Requested by a clinician
Requested by the company
One request per patient, to be renewed
One request for a group of patients, usually for 1 year
Full responsibility of the clinician
The clinician and the regulatory authority
Safety and efficacy of the product are presumed
Safety and efficacy are highly presumed SPC, patient leaflet, labelling available
principle is the equal access to a
Often compassionate situations at a very early stage of the product development
compassionate product for all patients in
No protocol
need. Criteria such as the social position of a
No data collection
person, or his/her affiliation to a patient
No reporting
Company reports to the authority
organisation, or his/her shareholding in the
Many drugs, few patients
Few drugs, many patients
Ethical considerations General principles ethical
recommendations
exist
on
compassionate use. The French Comité Consultatif National d’Ethique published opinions of general interest (CCNE, 1997): Equal access: An indisputable ethical
company cannot serve as a reason to privilege him/her in accessing the product;
Follow up of patients and data collection according to a protocol
Commitment to submit a marketing authorisation application
Transparency: clear operating procedures to ensure transparency in the programme are needed, both for the patients and the public in general. Some drifts on the allocation of treatments were, rightly or wrongly, criticised (such as geographical inequality);
ethical
access to treatment. This applies both to participants
4. A marketing authorisation likely to be
participants,
make the product available for the CUP in 3. No interference with trials: National
trials
recommendations also exist regarding post-trial
2. Available supply: The developer needs to
Few
clinical
9
Evidence needed to initiate a CUP Regulation
EC 141/2000 OMP states “Patients
suffering from rare conditions should be entitled to the same quality of treatment as other patients”. The information on efficacy/safety is part of the quality of
Clear definition of the beneficiaries: it should
our medicines and the more information patients
be based on scientific and medical criteria.
and doctors have, the better the quality of the
15 August September 2016
EURORDIS Position on Compassionate Use (draft3 2) medicine. This is the reason why we need clear and complete data on benefit/risks, and as much information as possible should be generated before the marketing authorisation. If generating a satisfying level of evidence takes too long, the developer has the option of creating a
Full efficacy and safety evaluation can only take place at the time of the benefit/risk evaluation for a marketing authorisation application. For a compassionate use, real evidence cannot be requested, efficacy can only be presumed.
compassionate use programme (CUP) for those who cannot afford waiting. The CUP inclusion criteria
In other Member States on the contrary, risks and
should mirror the exclusion criteria of clinical trials.
benefits need to be fully evaluated: In Belgium for
The greater the uncertainty, the more the patients
example, compassionate use is only intended for
can be disappointed or harmed.
products already authorised but not yet available as
Regarding the evidence on which a CUP can be
the price has not been agreed and the decision to
authorised, different Member States require different
reimburse them has not been taken. This national rule
evidence on the benefits. The French regulatory
is contradictory to the EU Regulation.
scheme for CUPs, called A.T.U (Temporary Use Authorisation) requires “efficacy and safety to be highly
presumed,
knowledge
according
available2”,
to
which
the literally
scientific means
“accepted without verification or proof”. Harm or the absence of efficacy would of course prevent a CUP. In Germany, efficacy needs to be also “assumed”,
Product availability For the initial phases of development, only small quantities of the compound are needed. When results come in (proof-of-concept studies), the developer decides to conduct confirmatory trials for which higher quantities are needed. At that time, often referred to as the Go/No Go decision, scaling
and not fully established: “evidence and grounds for
up of the production is decided, which sometimes
the assumption that the medicinal product is safe
requires the construction of a new manufacturing
and effective for the envisaged (compassionate)
site or bioreactor and/or the reorganisation of the
use (Bfarm, 2010)”.
manufacturing process. Arrangements for the scaling
The European Medicines Agency guidelines (EMA, 2007) explain: In terms of efficacy, the assumptions for compassionate use may be based on mature randomised phase III trials (e.g. in case of parallel assessment of compassionate use and application for marketing authorisation).
up of the production may be more or less difficult, but in any case they need to be validated by regulatory authorities (for commercial batches), and need to comply with Good Manufacturing Practices (ISPE, 2016). The time needed for this to be completed should never be under-estimated. There is often a time gap between the decision to launch large-scale production and the moment new batches can be used in patients or clinical trial
However acceptable assumptions may rely on
participants.
promising early data observed in exploratory trials (e.g. uncontrolled phase II trials).
2
In French: « leur efficacité et leur sécurité d'emploi sont fortement présumées en l'état des connaissances scientifiques »
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EURORDIS Position on Compassionate Use (draft 32)
11
The
Figure 2: Product supply increases in a discontinuous manner, firstly prioritising clinical trials, then preparing for the market launch. The line represents the probability that the product reaches the market, with ups and downs depending on various events all along the development.
EURORDIS views on CUPs in the sense of the European Legislation3
advantages are: 1. For clinicians an opportunity to learn to use
A CUP use programme should be largely
new medicines in other patients than the
inclusive (reason why it is preferred to
ones enrolled in clinical trials (usually with
named-patient basis programmes)
comorbidities,
The CUP inclusion criteria should mirror the
concomitant therapies);
different
ages,
or
2. For the developer of the medicine an
exclusion criteria of the clinical trials
or
A positive benefit/risk ratio should be
opportunity
presumed, not fully demonstrated
specialists
Equity:
investigators and to shorten the delay on
–
build
networking
with
than
the
trial
other
3. For the regulators, a better knowledge about
to non-members (no advantage for the
the
best informed)
compassionate
If extremely limited supply: random
collected and evaluated).
draw to enrol patients
clinical
market access;
Members of patients’ organisations should not be advantaged compared
–
to
medicine
(when use
data
from
programme
the are
Recommendations
Usefulness of compassionate use programmes
Recommendations to industry
In a workshop organised by EURORDIS on 21 November
and organisation of CUPs can recommend industry
2011 (Eurordis Round Table of Companies, 2011), 82
to:
Patients’ advocates who are working on the design
participants from industry, the European Medicines Agency and Members States reviewed the societal
a) Discuss the relevance and timing of a
benefits of compassionate use, beyond facilitating
compassionate use with patients’
access to new medicines.
advocates and doctors early in the development of a medicine;
Again, these provisions do not apply to named-patient basis compassionate use 3
EURORDIS Position on Compassionate Use (draft3 2) b) Define inclusion criteria for the compassionate use with patients’
use programme. Available supply should be
representatives and clinicians;
prioritised to complete the clinical trials and
c) Explain the plans for the initiation of a CUP country by country, d) Accept information on compassionate-use
authorisation, rather discuss the programmeend modalities with patients’
compassionate-use programme, in
representatives, doctors and regulators in
particular toxicity data and special
the first place; n) Interrupting the programme when a positive
Update the programme according to
opinion is obtained, but rather continue
demand and avoid excluding patients on
providing the product to patients who were
grounds such as patients who are
enrolled earlier until the price and
considered potentially unreliable;
reimbursement decision and in some case
departments within the company: medical
inclusions can be closed during that phase; o) Presenting the programme to clinicians as a
affairs, clinical development, regulatory,
gift to high inclusion rates in clinical trials;
pharmacovigilance, finance and supply
p) Mixing compassionate-use programmes with
chain; h) Produce clear guidelines for the safe use and administration of the product, Plan an adequate supply of the product,
humanitarian or financial support programmes.
When supply is limited and cannot satisfy the
and in case of an important increase in the
demand
number of requests consult with patients’
When there is a very limited supply of the
representatives and doctors on how to slow
compassionate use medicine, ethics committees
down the programme. If tensions occur, the
already published their opinion in the 90s (in the
responsibility lies with the company and a
context of HIV/AIDS when the demand exceeded
company should not ask patients or doctors
the supply; only 250 treatment doses were available
to make decisions;
for 20,000 patients in France in February/March
Allocate adequate resources to establish
1996), the National AIDS Council’s advice was to
and run the programme, including
select patients via a random process. "Since
processes for handling and vetting requests,
patients will be selected randomly by computer,
mechanisms to review eligibility of patients
there will be no conscious or unconscious emotional
and reporting of adverse events;
preference or pressure. Drawing lots will relieve
k) Industry should continue dialogue with
doctors of the responsibility of choice and preserve
European and national authorities on how to
patients' trust in their attending physicians. Lots will
improve the situation and on setting up
be drawn each time supplementary drug doses are
clear rules between compassionate-use and
made available, with the aim of including all
development programmes.
eligible patients.”
And avoid: l)
manner in the eventuality of a negative
confidential;
g) Involve and coordinate different
j)
m) Interrupting the programme in an abrupt CHMP opinion on the marketing
populations;
i)
the largest compassionate use programme;
programmes cannot be considered as e) Collect information from the
f)
who can be enrolled in the compassionate-
Stockpiling supply to prepare market access to the detriment of the number of patients
The National Ethics Council (CCNE) had a similar opinion: “A draw at local level could be organised as an ultimate possibility, in cases where the rational
15 August September 2016
12
EURORDIS Position on Compassionate Use (draft3 2) elements of decision does not suffice to reach a
random selection of the patients, under the
decision”.
strict responsibility of the company.
None of these opinions explained who should
clinician really wants to enrol a patient in a
organise the draw. Local hospitals? National
programme, he or she will make sure the
authorities? The sponsor of the clinical trials/
documents are filed in in a way that
developer of the product? The clinical research
corresponds to the programme inclusion
organisation? The view of prominent patients’ advocates is that
Medical criteria are not the solution: when a
criteria
The company ad hoc ethics committee
the pharmaceutical company that is responsible for
usually receive requests as they come in,
the communication on "promising results" in its press
and patients are enrolled on a first come
releases or at scientific conferences is therefore
first served basis, which favours the always
responsible for monitoring the consequences of this
best informed
communication, including the impact on the
And above all, setting up these committees
requests for compassionate use; society should
is a solution for the company to reject the
accept no body other than the company to
responsibility on others, with an
operate the random process of selecting new
appearance of a concern for ethics, but in
patients to be enrolled in the CUP.
fact with no guarantee of a fair and equitable procedure
Should the company set up its own ethics committee? Some companies appoint an ad hoc ethics committee that reviews requests and decide which
Recommendations to European and National Authorities
National authorities should consult patients’
patients can enter the programme. This approach is
organisations and clinicians when deciding
raising major issues:
on the criteria and conditions for the
compassionate use programmes on their
Transparency: members of these ethics committees are appointed by the company, but the arrangements are
territories
a compassionate use programme, the
unknown. The criteria they use are unclear:
CHMP should consult with
if the programme has been authorised by
patients’representatives and clinicians. This
regulatory authorities, then why to set up
could be best done within the PRIME
this committee? Clinicians should be in a position to enrol their patients without the intervention of a third party.
initiative (EMA, 2016)
compassionate-use programmes available
where regulators did not define the eligible very clear on how many patients can be
in the EU;
The EMA could explore how to make a better use of the European register of
treated and again the company should
clinical trials to identify clinical trials which
take its responsibilities: or there is enough
purpose is to provide a medicine on a
product for all patients, and no triage is
compassionate basis (typically open-label
needed, or there isn’t enough product, and then the less unethical approach is a
The European Commission could compare different national schemes for
For named patient basis programmes, population, then the company should be
Similarly, when requested for an opinion on
trials with no comparison arm);
National authorities should improve transparency of compassionate use
15 August September 2016
13
EURORDIS Position on Compassionate Use (draft3 2) programmes they authorise, so that
authorise, in the appropriate
clinicians and patients are aware of which
European languages
programmes are run in which countries and how to join them
Member States should create a compassionate use programme Facilitation Group in order to exchange information and build upon common experiences to set up harmonised procedures and create a network which can facilitate future changes in the legislation;
Member States should respect article 83 of Regulation (EC) Nº 726/2004 and notify the EMA of compassionate-use programmes that they authorise. EURORDIS takes note of the need for explanation by Member States as the interpretation may differ on the definition of compassionate use, as regards to whether it addresses named patient programmes or cohorts. However, Regulation (EC) No 726/2004 is very clear as Article 83.2 states that “For the purposes of this Article, ‘compassionate use’ shall mean making a medicinal product belonging to the categories referred to in Article 3(1) and (2) available for compassionate reasons to a group of patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who
Recommendations to Patients’ organisations and healthcare professionals a) Patients’ organisations should be aware of the importance of compassionate use programmes; b) Patients’ organisations should be aware when the clinical development of a new product starts (or clinical trials for a repurposing of a known medicine), and engage discussions with the developer at an early stage to agree on if and when a compassionate use programme could be relevant, and for which patients c) Patient organisations, clinicians should consult each other about all practical aspects of the compassionate use programme: inclusion criteria, number of eligible patients, rules to ensure fair access to the programme (information, clinical sites where the programme is run…), follow-up (collection of data on safety, efficacy…) etc. But despite all the efforts to accelerate the process, both on the company side and on the regulatory side, when the compassionate use programme starts, there are always patients for whom it will be too late.
cannot be treated satisfactorily by an authorised medicinal product”. Therefore, named patient programmes are not addressed by the Regulation and EURORDIS does not see the need for further explanation here. The minimum patients would expect is that: a. Member States comply with Article 83.3 and notify the EMA of their programmes, as they are ethically and legally obliged to do b. Member States and the EMA create a public catalogue of the compassionate programmes they
15 August September 2016
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EURORDIS Position on Compassionate Use (draft3 2)
Specific situations in rare diseases
marketing authorisation (NLD): this would represent
Gene therapy
distortion.
unfair competition and would introduce market
Gene therapy trials typically enrol few patients (around 50 in average, EUDRACT). For the benefit/risk evaluation, gene therapy products (belonging to the Advanced Therapy Medicinal Products) do not benefit from a large set of patient data, and yet uncertainties on safety are a major concern for these products before they can be authorised. At the end of early trials, when promising results are shown, patients legitimately can request access on a compassionate use basis. But as gene therapy is
For small enterprises, the cost of running a CUP could limit its size, or even the capacity to start one, if the company could not generate revenues from it.
If paid for Some may argue this is against the spirit of the European Pharmaceutical Regulation and Transparency Directive according to which a medicine cannot be commercialised if not authorised.
a compassionate basis, as the market would vanish
On the other hand, the possibility to generate revenues is an attractive factor for developers to decide a compassionate use programme. Historically, CUPs always started earlier, sometimes much earlier, in countries where the developer could charge for, to the benefit of the patients.
by the time the product is authorised.
If for free in some and paid for in others
one time shot (maybe to be renewed after a certain number of years, 5, 1, 20, to be determined case by case by post-marketing monitoring), the developer cannot afford to offer the gene therapy product on
For gene therapy products, no Member State authorises their use on a compassionate basis, to encourage the conduct of clinical trials with high quality data collection instead. Therefore, proposals are:
introducing inequities in accessing a treatment on a compassionate basis, as patients living in countries where the product can be charged for will always access the product earlier compared to products where the company cannot charge for, or even
To enrol larger numbers of subjects in gene therapy trials
The current practice varies largely by country,
If a compassionate use programme is to be launched: the developer could receive payment
when
and if the product
is
needs to pay (e.g. fees to ethics committees). A simple rule such as 1) or 2) below would not represent an efficient solution: 1. In all Member States all CUP should be free
authorised and deemed of therapeutic value
Free or paid for CUPs?
of charge 2. In all Member States all CUP should be paid for
Compassionate use programmes can be free of
Solution number 1 would be detrimental to the
charge (the company offers the treatment at no
attractiveness of CUPs in Europe: industry could
cost), or paid for. In addition to the treatment, other
simply
costs are to be budgeted (prescription visits, exams,
downwards) and solution 2 could represent a high
sometimes hospitalisation with/without surgery or
financial burden, making it complex for all Member
injection…).
States.
refuse
to
start
them
(levelling
CUPs
If for free Some might consider running a CUP for free as a marketing strategy, equivalent to a promotional campaign to “invade” the market prior to the
15 August September 2016
15
EURORDIS Position on Compassionate Use (draft3 2) Possible solutions: criteria depending on the financial condition of the company, and risk sharing agreement
Paid-for CUPs could be restricted to CUPs run by small and medium size enterprises only (as defined by EMA) that might have objective financial difficulties in running them
Exceptions for SMEs that pay high dividends to share-holders or which financial situation indicates the company has the financial resources to bear the cost of a CUP: could not charge for, or only “minimally”
If other products exist for the condition: given the uncertainties on the efficacy/safety of a medicine used on a compassionate basis, its cost could be limited to half the average cost of other products (including off-label use) based on the defined daily dose (DDD) (WHO Collaborating Centre for Drug Statistics Methodology, 2009), and after the marketing authorisation, if the market price is lower than the price for the ATU, then the marketing authorisation holder could reimburse the difference
If there are no other treatments available for price referencing, then the company could charge for the treatment. If the product is
distributors, visit the prescribers etc.), all is already in place and dales start more or less immediately.
And if the product is finally not as valuable as initially thought, a pay-back system for the difference between the compassionate use price and the market price once authorised could be created, with a minimum and a cap.
The Right-to-Try laws in the USA EURORDIS shares the opinion that "Right-to-try" laws may in fact degrade patient autonomy (NeveloffDubler, 2016). "Right-to-try is a sham," she said. "It's an empty promise which delivers nothing, and patients who want to try a substance that's in the middle of a phase I trial have no basis on which to choose that [substance] and the company has no basis on which to grant it," she said. One of the core ethical principles
of
compassionate
use
must
be
benefit a patient, and "right-to-try" circumvents some of the protections that ensure that validity.
Way forward Solutions to abolish these disparities are simple to theorise but little progress has been observed in the last ten years. Possible actions for next steps to make progress are: 1. Promote the French ATU, probably the most
could reimburse part of the expenses
efficient compassionate use scheme so that
Even when the programme is for free, there
every Member State adopts;
initiative a compassionate use programme quite early, which may represent a more powerful incentive than the revenues it can
2. Adopt an EU Regulation which would confer a greater role in the organisation of CUPs upon the EMA;
generate: by implementing the programme
3. Apply the Directive on Patients’ Rights in
the company installs its product on the
Cross-Border Healthcare to include
market and when a price is finally agreed
compassionate use as part of the care basket
upon and the reimbursement decided, then
so that patients can benefit from these
revenues come in very rapidly, there is not
treatments wherever they live in the EU,
time lost due to the time needed to place the product on the market (work with hospital pharmacists, negotiate with
a
scientifically valid basis for believing a treatment will
finally not authorised, then the company
is a huge incentive for the company to
16
4. Generalise the Medicines Adaptive Pathways to Patients to more medicines, where the EU regulator may authorise a medicine at
15 August September 2016
EURORDIS Position on Compassionate Use (draft3 2) an early stage and in a limited group of patients
The role of the EMA could be reinforced with or
that are in high need for the product, keeping in
without legal changes to the pharmaceutical
mind that post-authorisation confirmatory
legislation:
studies need to be conducted afterwards. This is in the spirit of the compassionate-use
Article 83.4 of Regulation (EC) No 726/2004 states:
programme as defined by the EU legislation, but
“When
with a different regulatory angle. This can only
Committee for Medicinal Products for Human Use,
work if payers are part of the initiative as they
after consulting the manufacturer or the applicant,
will need to accept to pay for a medicine that is
may adopt opinions on the conditions for use, the
highly uncertain at that point.
conditions for distribution and the patients targeted.”
5. Amend the EMA guidelines on
In its guidelines (EMA, 2007), the EMA acknowledges
compassionate
use
is
envisaged,
the
compassionate use
that the conditions for distribution are not defined
In its Communication on Rare Diseases
in
(European Commission, 2008), the European
interprets them as whether or not the medicinal
Commission proposed the EMA to review its
product is subject to medical prescription, or
guidelines on compassionate use
whether it is subject to special or restricted medical
programmes with the objective of ensuring
prescription. It excludes the possibility to address
“A better system for the provision of
conditions for distribution, the strategy for supplying
medicines to rare diseases patients before
the medicinal product in the Member States (e.g.
approval and/or reimbursement (so-called
quantity of product, choice of MS).
the
pharmaceutical
legislation. It therefore
compassionate use) of new drugs”. Yet, the Commission has not yet invited the
This is very unfortunate, as this self-restricted role
EMA to revise their existing guidelines.
leaves many issues related to compassionate use programmes unaddressed, with loopholes and
Many aspects need to be improved:
There are important differences between Member States policies (authorisation of the CUP, documentation required, assessment time, validity, follow up, reporting…)
Liability risks need to be clarified
Transparency of the programmes needs to be improved so that clinicians and patients receive timely information
unguided aspects. There is a distribution of roles between Member States who implement the compassionate use programmes on their territories, and the EMA. With the current distribution of roles, and given the selfrestricted role EMA has, the following aspects are not regulated, neither at the national nor at the European level: •
Anticipation of the programme during
Interference with the marketing
early scientific advice, and discussion
authorisation procedure and whether or
with the developer on the relevance and
not the data collected in a programme
feasibility of a compassionate use before
can be part of the dossier submitted to
clinical trials start, and the respective
regulatory authorities
inclusion/exclusion criteria for the clinical
Supply and logistics, information and
trials
language
programme;
Pressure on supply under compassionate
•
and
the
compassionate
use
Estimates on how many patients could
use
benefit from the compassionate use in
Free of charge or paid for programmes
the EU;
15 August September 2016
17
EURORDIS Position on Compassionate Use (draft3 2) •
•
Criteria to progressively enlarge the
authorised and implemented. For these patients,
number of patients when more product
who are aware that a new product is being
becomes available;
developed somewhere and who are willing to
Pacing
down
measures
when
the
take a higher risk with a not-fully tested product,
demand for compassionate use exceeds
society does not currently propose any solution.
the available supply, and measures to
In such situations, some argue there is no role for
ensure a fair and equitable distribution of
regulators to intervene; it is up to the patient and
available stock among Member States
the doctor to decide. This debate is quite similar to the debate on end-of-life and euthanasia,
Conclusion
when the decision can lie with the patient and
Unfortunately, even with the best compassionate
his/her doctor who are not required to fill in a
use scheme adopted everywhere, there will
form for a named-patient decision. Some refer to
always be patients who will reach an irreversible
this stage, as ultra-compassionate use, which is
disease stage or who may pass away the day
again dependent by the availability of the supply
before
for compassionate use.
the
compassionate
programme
is
15 August September 2016
18
EURORDIS Position on Compassionate Use (draft3 2) programmes. Sixty-four holders of a marketing
Annexes EURORDIS survey on Compassionate Use Programmes for orphan medicines
authorisation for an orphan medicinal product were contacted (covering 2008-2011). Responses were obtained from 17 companies on 19 products. Valid
Survey description
data were obtained for 9 programmes in 42
In 2011, EURORDIS completed a retrospective survey to
European countries. Products and indications are
developers of orphan medicinal products, to learn
shown in Table 2.
from their experience in running compassionate use Table 1: Compassionate Use Programmes, Eurordis survey to Marketing Authorisation
Product
Indication
Mozobil® (Genzyme)
Treatment to mobilise progenitor cells prior to stem cell transplantation
vandetanib (AstraZeneca)
Medullary thyroid carcinoma
inolimomab (Eusa Pharma)
Graft versus host disease
Kuvan® (Merck Serono)
Hyper-Phenyl-Alaninaemia in adults and paediatric patients
Carbaglu® (Orphan Europe)
NAGS deficiency, isovaleric, methylmalonic or propionic acidaemia
Yondelis® (Pharma Mar)
Soft Tissue Sarcoma
decitabine Johnson)
Myelo-Dysplasic Syndrome
(Johnson &
Vpriv® (Shire Pharmaceuticals)
Gaucher type 1
Xyrem® (UCB)
Narcolepsy
Different
companies
practices
The same applied to the termination of the
regarding when to start a CUP in relation to the
programme, which continued for different periods of
Orphan Drug designation, the completion of trials
time after a marketing authorisation had been
recruitment,
granted. The European Regulation (EC) Nº 726/2004
and
the
had
different
marketing
authorisation
application.
article 83-8 states:
Where a compassionate use programme has been set up, the applicant shall ensure that patients taking part also have access to the new medicinal product during the period between authorisation and placing on the market. Examples of compassionate use programmes
CUP started to enrol patients five months later. The
In this first example below (Mozobil®), the trials to be
CUP continued for more than a year after the
submitted
marketing authorisation, filling the gap between
to
authorities
for
the
marketing
authorisation (so-called pivotal trials) completed
authorisation
enrolment 38 months after the designation and the
decision.
and
reimbursement/coverage
15 August September 2016
19
EURORDIS Position on Compassionate Use (draft 32)
Figure 3: CUP for Mozobil® to prepare stem cell transplantation
For Xyrem®, the CUP started before the end of the recruitment in clinical trials and this did not prevent the trials from completing their objectives (below).
Figure 4: CUP for Xyrem® to treat narcolepsy
In this third example (Kuvan®), the CUP started well after the end of the trials’ enrolment, and shortly before the marketing authorisation.
Figure 5: CUP for Kuvan® to treat phenylketonuria
20
EURORDIS Position on Compassionate Use (draft 32) In this fourth example (Vpriv®), the CUP started even before the orphan drug designation, and shortly before the marketing authorisation submission.
Figure 6: CUP for Vpriv® to treat Gaucher type 1
For Yondelis®, the CUP started well ahead of the designation and of the end of trials’ recruitment, but ended shortly before the marketing authorisation.
Figure 7: CUP for Yondelis® to treat soft tissue sarcoma
More recently, a new product was investigated to treat Batten’s disease. When the first 9 patients in the phase I/II trial received treatment for more than six months, a press release was launched by the developer on “promising results, with 6 children who were stabilised” (BioMarin, 12 January 2015). These results were
communicated without anticipation of the parents’ reaction worldwide, who immediately asked for compassionate use for their own children. Battens’ disease characterised by a rapid loss of all cognitive functions once symptoms have started to occur.
Figure 8: no CUP for Cerliponase-alpha (BMN 190) to treat Batten's disease
21
EURORDIS Position on Compassionate Use (draft 32)
More than a year after this early communication, no compassionate use has started, and is not likely to start before 2Q3Q/2016. For most children who had been
expecting treatment since January 2015, this will be too late and the course of the disease will inevitably destroy the brain.
Timelines summary Product
CUP started
MAA* submission
CUP started
Mozobil®
15/05/2008
5/06/2008
21 days before submission
Xyrem®
01/07/2004
11/03/2004
112 days after submission
Kuvan®
01/09/2008
30/10/2007
307 days after submission
Vpriv®
01/10/2009
30/10/2009
29 days before submission
Yondelis®
30/06/2000
27/07/2006
2,218 days before submission
BMN 190
Pending
Pending
548 days after early press release on positive results
Table 2 *: Marketing Authorisation Application
MS disparities organising efficient compassionate use programmes With 9 products and 42 countries, a maximum of 378 programmes could have been conducted if all countries in our surveys had authorised a compassionate use programme for each one of the 9 products. However, only 74 programmes were run, with marked differences among countries as shown in table 3 below: EU/EEA Number of unable to programme Number of able to run programmes Number of able to run programmes Number of able to run programmes Number of able to run programmes Total Table 3
Non EU/EEA
countries run any
1
9
countries 1 or 2
21
2
countries 3 to 4
4
1
countries 5 to 6
3
0
countries 7 to 9
1
0
30
12
Of the 30 EU/EEA Member States, the vast majority (21), could only organise a compassionate use for 1 or 2 products of the 9 surveyed. Only one was successful in conducting a programme for all 9 products (France). After France, the other Member States that run CUPs for more than half of the products were The Netherlands (5), Germany (5) and Spain (5).
22
EURORDIS Position on Compassionate Use23 (draft3 2)
Figure 9
Difficulties for industry when undergoing compassionate use programmes4 Companies have no legal obligation to offer access to experimental treatments, are often uncertain how to respond to requests, and may be uncomfortable in determining how to respond fairly to requests from the wellconnected or those using social media campaigns (Caplan, 2016). These
difficulties
should
not
be
underestimated:
Differences in the local legislation across countries caused products to be available earlier in some Member States than in others The sites where the CUPs are run cannot be selected: any request needs to be honoured, for any patient that meets the criteria In emergency situations, administrative constraints are difficult to manage; even in countries with sophisticated CUP schemes, emergency situations remain difficult to respond to.
Administrative obstacles and lack of experience for some countries Differences in the local legislation across Member States can cause the product to be available earlier in some than in others solely based on the difference in speed of obtaining the local approval for the programme. Labelling in local language information or obligation to use the commercial batches and not the pilot batches prepared for the clinical trials are examples of variations across Member States. Lengthy and protracted negotiations on price and subsequently on reimbursement
4
EURORDIS has listed information available on the contact points in national competent authorities:
differences between MS are problematic from a budget impact on company’s side: the exact duration of the compassionate use programme can hardly be estimated. The programme has a cost for the company, and does not always generate revenues. The programme may deprive the Member States from a “real incentive” to conclude the pricing and reimbursement decision, given that the patients receive the treatment (when programme for free). In general, the sites cannot be selected: any request needs to be honoured, for any patient that meets the criteria for use of the product. One approach could be to restrict the compassionate use programme to Centres of Expertise for Rare Diseases, however the concept of Centre of Expertise not established in all Member States.
Developer’s variable experience with compassionate use Often, the company that develops the investigational product considers that the product has not reached yet a stage where a CUP may be envisioned. This could be solved by early scientific advice with regulators and external experts, for example in the frame of the EMA PRIME initiative (EMA, 2016). Scientific advice can be requested at any time, to discuss and anticipate these aspects. Many recently createdyoung pharmaceutical companies are confronted for the first time to compassionate use requests and do not necessarily have the inhouse resources to deal with many different and complex national procedures. This is again a reason to advocate for a more elaborated European scheme. The embarrass of many companies when requested for a compassionate use is obvious when they respond negatively, objecting
http://www.eurordis.org/content/links-nationalauthorities-websites
15 August September 2016
EURORDIS Position on Compassionate Use24 (draft3 2)
that the programmes will be discussed once efficacy has been demonstrated, which usually means towards the end of the phase III / confirmatory trials and not at the end of the phase II/ proof of concept trials. Requests come sometimes from very prominent people and they can get around the official legal way, but this is obviously not possible for the rest of mortals, this is then an ethical issue to handle as well
Scientific and medical difficulties It is not always possible to distinguish two populations of patients: one eligible to clinical trials, and one who is not. When no distinction can be proposed, there is a risk that patients who are in a clinical trial leave the trial to benefit from the product in the compassionate use programme (in particular
when the clinical trial is comparative and the comparator is a placebo or no treatment). This is one more reason to ask for scientific advice to enlarge the discussion on the eligible population to the clinical trial and to the compassionate use programme with regulators, clinicians, patients’ representatives. The prospective collection of data in a structured way is not possible, unless a huge effort to standardise the data is made before the programme starts. Different sites may use different lab tests, imaging devices or health status scales, and this would make the aggregated results difficult to analyse.
15 August September 2016
EURORDIS Position on Compassionate Use (draft 32)
Where to find information on compassionate use programmes (public domain)? Web site of the Heads of Medicines Agencies (HMA)
European Medicines Agency On this page, you can find information on the role of the agency, on how Member States can request an opinion to the EMA for a given compassionate use, and a register of such EMA opinions already given.
HMA is a coordination of national regulatory authorities. They share common projects, among which the improvement of the transparency of their activities.
http://www.ema.europa.eu/ema/index.jsp? curl=pages/regulation/general/general_con tent_000293.jsp&mid=WC0b01ac05809f843c
Recently the HMAs published a list that contains information on compassionate use in many but not all Member States:
There are also links to an Answers & Questions document on the on the compassionate use of medicines in the European Union (here) and guidelines (here).
http://www.hma.eu/fileadmin/dateien/HMA _joint/02-
For any query to the EMA on this matter, use
_HMA_Strategy_Annual_Reports/08_HMA_Pu blications/2016_05_HMA_Compassionate_us e_program.pdf
this email address:
[email protected]
It is positive a step forward towards more transparency on compassionate use programmes, which supports the need of developers of pharmaceuticals, clinicians and patients to have access to detailed information on how these programmes can be run in each Member State.
Compassionate use programmes are not clinical trials, however in Member States that do not have a regulatory scheme for compassionate use, open label trials can serve to provide a product available on a compassionate basis. Use keywords such as “compassionate” or “open label” to find them. The site URL is: https://www.clinicaltrialsregister.eu
However, this does not respond to all of the information needs. Patients and clinicians would welcome information on specific authorised compassionate use programmes with the aim of ensuring fairness and equity in accessing these programmes designed for unmet needs in life-threatening diseases.
European Register of Clinical Trials
For example, when entering the work “compassionate use” in the search area, 101 such programmes for adults and 238 for children can be found in August 2016:
25
EURORDIS Position on Compassionate Use (draft 32)
Works Cited Bfarm. (2010, 7 16). Ordinance on the placing on the market of unauthorised medicinal products for compassionate use . Retrieved 02 23, 2016, from Bfarm: http://www.bfarm.de/SharedDocs/Downloads/EN/Drugs/licensing/clinicalTrial s/compUse/AMHV_en.pdf;jsessionid=AA68EBDB6CC0C788A1AD8DEED2AABD8 D.1_cid340?__blob=publicationFile&v=3 Biomarin. (2014). Annual report 2014. Retrieved December 14, 2016, from Biomarin: http://files.shareholder.com/downloads/ABEA3W276N/1046929727x0x864649/7AD65B7C-7EF2-4EDB-91B779D0B1773888/2014_Annual_Report.pdf Biomarin. (2016). Cerliponase Alfa (BMN 190) for CLN2 disease. Retrieved December 14, 2016, from Biomarin corporate website: http://www.biomarin.com/products/pipeline/cerliponase-alfa-bmn-190-tpp1for-cln2-disease/ Biomarin. (2016). Cerliponase Alfa (BMN 190) for CLN2 disease. Retrieved February 22, 2016, from www.biomarin.coml: http://www.biomarin.com/products/pipeline/cerliponase-alfa-bmn-190-tpp1for-cln2-disease/ Caplan. (2016, March 8). The Ethical Challenges of Compassionate Use. JAMA, pp. 979-980. CCNE. (1997, March 7). Comité Consultatif National d'Ethique. Retrieved from http://www.ccne-ethique.fr: http://www.ccneethique.fr/sites/default/files/publications/avis048.pdf EMA. (2007, July 19). COMPASSIONATE USE OF MEDICINAL PRODUCTS. Retrieved December 15, 2015, from EMA main site: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_ procedural_guideline/2009/10/WC500004075.pdf EMA. (2016). PRIME: priority medicines. Retrieved from www.ema.europa.eu: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/g eneral_content_000660.jsp&mid=WC0b01ac05809f8439 Eurordis Round Table of Companies. (2011, November 21). 15th Workshop, Paris: “Compassionate Access to Rare Disease Therapies”. Retrieved from www.eurordis.org: http://www.eurordis.org/publication/15th-workshop-ertc ISPE. (2016). Good Manufacturing Practice (GMP) Resources. Retrieved February 23, 2016, from http://www.ispe.org: http://www.ispe.org/gmp-resources
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EURORDIS Position on Compassionate Use27 (draft3 2)
Neveloff-Dubler. (2016). Pre-Approval Access: Can Compassion, Business, and Medicine Coexist? Retrieved from Academy eBriefings: www.nyas.org/CompassionateUse-eB WMA. (2008). World Medical Assocation. Retrieved from http://www.wma.net: http://www.wma.net/en/30publications/10policies/b3/17c.pdf
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EURORDIS Position on Compassionate Use (draft 32)
Glossary ACCESS (ACCESSIBILITY) The patient's ability to obtain medical care and a measure of the proportion of a population that reaches appropriate health services. The ease of access is determined by such components as the availability of medical services and their acceptability to the patient, the location of health care facilities, transportation, hours of operation and cost of care. Barriers to access can be financial (insufficient monetary resources), geographic (distance to providers), organisational (lack of available providers) and sociological (e.g., discrimination, language barriers). Efforts to improve access often focus on providing/improving health coverage. [Source: WHO. A Glossary of Terms for Community Health Care and Services for Older Persons] ACCESS WITH EVIDENCE DEVELOPMENT (AED) Initiative in which a payer provides temporary or interim funding for a particular technology or service to facilitate the collection of information needed to reduce specific uncertainties around a coverage decision. [Source: Stafinski T, McCabe C, Menon D: Funding the unfundable – mechanisms for managing uncertainty in decisions on the introduction o new and innovative technologies into healthcare systems. Pharmacoeconomics 2010; 28:11342.] See also: managed entry agreements AFFORDABILITY The extent to which medicines and further health care products are available to the people who need them at a price they / their health system can pay. [Source: adapted from WHO. A model quality assurance system for procurement agencies] AUTHORISED MEDICINAL PRODUCT As used in Article 83 (2), means a product authorised nationally (national,
decentralised or mutual recognition procedures) or by the Community (Centralised Procedure), in the MS(s) where compassionate use is envisaged. BRAND NAME (INNOVATOR`S NAME, PROPRIETARY PRODUCT NAME, MEDICINE SPECIALITY PRODUCT NAME, MEDICINAL SPECIALITY PRODUCT NAME) Name given for marketing purposes to any ready-prepared medicine placed on the market under a special name and in a special pack. A brand name may be a protected trademark. BUDGET IMPACT A budget is an estimate of revenue and expenditure for a specified period. Budget impact refers to the total costs that pharmaceutical reimbursement and use entail with respect to one part of the health care system, pharmaceutical care, or to the entire health care system, taking into account the possible reallocation of resources across budgets or sectors of the health care system. CHRONICALLY OR SERIOUSLY DEBILITATING DISEASE OR WHOSE DISEASE IS CONSIDERED TO BE LIFE THREATENING The severity of the disease, i.e., its chronically or seriously debilitating, or lifethreatening nature needs to be justified, based on objective and quantifiable medical or epidemiologic data. Whereas a life-threatening condition is relatively easily recognisable, definitions of what conditions are chronic and seriously debilitating should consider aspects as regards the condition is associated with morbidity that has substantial impact on patients’ day-today functioning and will progress if left untreated. Typical examples are cancer, HIV/AIDS, neurodegenerative disorders and auto-immune diseases. Chronic or serious debilitation or fatal outcome should be a prevalent feature of the target disease.
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EURORDIS Position on Compassionate Use29 (draft3 2)
COMPANY Should be understood as meaning “the manufacturer or the applicant” as referred to in paragraph 4 of Article 83 of Regulation (EC) No 726/2004 and denotes the person responsible for providing the scientific file to the CHMP for assessment of the compassionate use of a medicinal product under article 83 of the Regulation. This person is either “a marketing authorisation applicant” if a centralised marketing authorisation is being submitted, or “a manufacturer” if the medicinal product concerned is not the subject of an application for a centralised marketing authorisation. CONDITIONS FOR DISTRIBUTION Are not defined in the pharmaceutical legislation and are therefore understood as the conditions or restrictions regarding the supply and use of the medicinal product, as provided for in Article 9(4)(b) and Article 14(10) of Regulation (EC) No 726/2004. The conditions specify whether or not the medicinal product is subject to medical prescription, or whether it is subject to special or restricted medical prescription. The conditions for distribution do not cover the strategy for supplying the medicinal product in the MSs (e.g. quantity of product, choice of MSs). CONDITIONS FOR USE Are recommendations for health professionals on how to administer and to use the medicinal product safely and effectively. These recommendations include relevant information on the clinical, pharmacological, pharmaceutical properties of the medicinal product and on the conditions for patient monitoring. CO-PAYMENT Insured patient’s contribution towards the cost of a medical service covered by the insurer. Can be expressed as a percentage of the total cost of the service or as a fixed amount. [Source: OECD –
Pharmaceutical Pricing Policies in a Global Market] See also: out-of pocket payments COMMUNITY PHARMACY Health care facility dispensing medicines (POM and OTC, reimbursable and nonreimbursable medicines) to out-patients. Pharmacies are subject to pharmacy legislation (e.g. national legislation regarding establishment and ownership of pharmacies). In many countries, community pharmacies are private facilities, but public pharmacies (i.e. in public ownership) also exist. Pharmaceutical provision for inpatients is provided for by hospital pharmacies or pharmaceutical depots; in some cases hospital pharmacies also act as community pharmacies. [Source: adapted from PPRI Glossary] See also: hospital pharmacy GOOD MANUFACTURING PRACTICES (ISPE, 2016) Is a system for ensuring that products are consistently produced and controlled according to quality standards. It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product. GROUP OF PATIENTS Can be interpreted as any set (i.e. more than one) of individual patients that would benefit from a treatment for a specific condition. The terms “cohort”, “collective use”, “patient group prescription” or “special treatment programme” used in some MSs, in accordance with national legislations, may correspond with this concept. The possibility of using an unauthorised medicinal product for compassionate use on a named patient basis (Article 5 of Directive 2001/83/EC) does not fall under the scope of Article 83. HEALTH TECHNOLOGY ASSESSMENT (HTA) Health technology is the application of scientific knowledge in health care and prevention. Health technology assessment
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EURORDIS Position on Compassionate Use30 (draft3 2)
(HTA) is a multidisciplinary process that summarises information about the medical, social, economic and ethical issues related to the use of a health technology in a systematic, transparent, unbiased, robust manner. Its aim is to inform the formulation of safe, effective, health policies that are patient focused and seek to achieve best value. [Source: EUnetHTA] HOSPITAL-ONLY MEDICINES (HOM) Medicines that may only be administered in hospitals [Source: PPRI Glossary]
environment.) [Source: Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use] TRANSPARENCY DIRECTIVE Directive 89/105/EEC (of 21 December 1988) relates to the transparency of measures regulating the pricing of medicines for human use and their inclusion in the scope of national third party payers. [Source: PPRI Glossary]
PATIENTS TARGETED Is the restricted population (including age groups), as identified by the CHMP, that would benefit from the treatment for compassionate use. PATIENTS WHO CANNOT BE TREATED SATISFACTORILY As used in Article 83 (2), means patients left without treatment options or patients whose disease does not respond or relapses to available treatments, or for whom the treatments are contraindicated or inadequate. Whether patients can be treated satisfactorily or not, will be assessed by the CHMP based on the review of diagnostic, preventive or therapeutic medicinal products authorised, and on the justifications as to why the medicinal products reviewed are not considered satisfactory for the treatment of the patients’ disease. PAY-BACK A financial mechanism that requires manufacturers to refund a part of their revenue to a payer (i.e. third party payer) if sales exceed a previously determined or agreed target-budget. RISK-BENEFIT BALANCE An evaluation of the positive therapeutic effects of the medicinal product in relation to its risks (any risk relating to the quality, safety or efficacy of the medicinal product as regards patients' health or public health and any risk of undesirable effects on the
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EURORDIS Position on Compassionate Use (draft 32)
Credits, acknowledgements and funding EURORDIS would like to thank all staff and volunteers who developed this position Volunteers of the DITA task force Members of the Drug Information, Transparency and Access Task force (DITA) who contributed to this position:
Alba Ancochea, Federation Organisations Rare Diseases (FEDER), Spain Claudie Baleydier, Friedreich Ataxia, France Davor Duboka, National organisation for Rare Diseases, Serbia Fridrik Fridriksson, Gudrun´s Rett Syndrome Research Trust, Iceland Marleen Kaatee, Primary Sclerosing Cholangitis, The Netherlands Juan Fuertes, Primary Pulmonary Hypertension, SPA Ellen van Veldhuizen, Addison Disease Org., NLD Rainald von Gizycki, Pro Retina, GER Danijela Szili, Rett synd., HUN Luc Matthyssen, Pulmonary Hypertension, BelgiumEL Sigurður Jóhannesson, Alternating HemoplagiaHemiplegia of Childhood, IcelandCE Isabel Fernandez, FEDER, SPA Lise Murphy, Marfan syndrome, SwedenWE Inge Schwersenz, Neuromuscular SMA, GermanyER Leire Solis, IPOPI, Portugal Claudia Sproedt, cystinosis, Germany Vesna Stojmirova, Life with Challenges, FYROM Thomas Sannié, Association for Haemophilia, FRA Oliver Timmis, Alkaptonuria Society, United KingdomGBR Christine Lavery, Muco-polysaccharidosis Society, GBR Dragomir Slavev, Thalassemia org., BLG Richard West, Behcet Society, GBR Tatiana Foltanova, Slovakian Alliance for RD Rob Camp, EURORDIS, SPA
Other volunteers and contributors
Pauline Evers, NFK, Dutch Federal Organisation of Cancer Patients Zachary Fitzpatrick, master of science in immunology at UPMC and Institut Pasteur Arielle North, North Consulting
Staff
François Houÿez, EURORDIS, Paris
Rob Camp, EURORDIS, SPA
Copyright EURORDIS Access Campaign 2016©
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EURORDIS Position on Compassionate Use32 (draft3 2)
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EURORDIS Position on Compassionate Use33 (draft3 2)
New in this version:
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National and European authorities should consult with patients and clinicians when deciding a new compassionate use programme Details on where the EMA’s role could be improved (changes in the EU legislation not necessarily required) and in “way forward”, a reminder to the EC to invite the EMA to revise its guidelines on CUP Updated list of DITA task force members Specific cases in rare diseases: gene therapy products Estimates of medicine sin development for rare diseases from the PhRMA added Opinions of the DITA task force members are added, in particular on ad hoc ethics committees set up by the company
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