Regulatory Hot-Topics

Earlier Access to Medicines – Early Access to
Medicines Scheme and Adaptive Licensing pilot
PSI Conference
Dr Daniel O’Connor May 2014
The views expressed do not necessarily reflect the official
position of the MHRA
Earlier Access to medicines
– A key challenge confronting Regulators is earlier patient access to innovative
medicines, particularly in areas of unmet medical need
– Ultimately there is often a fine balance between ‘denying’ patients potentially
useful drugs and approving products for which the drug development is
considered as immature
– However, it is recognised that with greater medical needs e.g. life threatening
conditions with no adequate treatments, it is acceptable to make decisions
based on a greater degree of uncertainty in the data
• ‘Evidence versus access’ balance
Earlier Access to Medicines
– Recently two initiatives were launched to try and address some of the
pressing patient access issues:
European initiative, adaptive licensing, an emerging concept of
‘staggered marketing authorisation approval’, using existing regulatory tools
•This more ‘systems approach’ involving more stakeholders, has also been
called ‘Medicines Adaptive Pathways to Patients’
•A UK initiative, Early Access to Medicines Scheme, which aims to give
access to medicines that do not yet have a marketing authorisation but meet
an unmet medical need
Early Access to Medicines Scheme
EAMS Milestones
Ministerial Industry Strategy Group
The Prime Minister’s Strategy for UK Life Sciences
• Early Access to Medicines Scheme Consultation
• Expert group on the innovation in the regulation of healthcare
Early Access to Medicines Scheme consultation response
Early Access to Medicines Scheme launch
• Step I: the Promising Innovative Medicine (PIM) Designation
• Step II: the EAMS Scientific Opinion
Ministerial Industry
Strategy Group (MISG)
– The MISG brings together government and the research-based pharmaceutical
industry to promote a strong and profitable UK-based pharmaceutical industry
– In 2008, a proposal for an Early Access to Medicines Scheme was developed
as part of a series of events established by the MISG
– The Regulatory Working Group forum considered there was support from all
stakeholders that earlier access to medicines could bring benefits to patients
– The Working Group developed a framework for the EAMS
– Acknowledging that whilst access to such medicines will – at least in most
cases – be at the end of the formal development stage, the scheme could still
provide potentially life-saving treatments around one year earlier than at
Ministerial Industry Strategy
Group (MISG)
The following eligibility criteria were proposed by the group:
• Medicines that will treat, diagnose or prevent life threatening, or seriously
debilitating conditions without adequate treatment options;
• Data will be required that indicates that the benefit: risk profile of the
medicine is positive and that it is likely to offer advantages over any
existing treatment options
• The scheme would be limited to medicines representing a significant
advance in treatment in an area of unmet need
• The scheme will be available for medicines that have completed Phase
III trials but in exceptional circumstances an earlier authorisation may be
possible (based on Phase II data) if information available merits it
Strategy for UK Life
Sciences – EAMS Public Consultation
– In December 2011 the Prime Minister announced a new Strategy for UK Life
– The publication detailed actions aimed at maintaining the UK’s world-class
reputation in life sciences, improving patient health and acting as a catalyst
for economic growth
– One of these commitments was that the MHRA will bring forward for
consultation proposals for a new ‘Early Access Scheme’
– The Strategy sets out the guiding principles for the Scheme as:
• ‘eligible products will be determined by a scientific opinion that the likely
clinical benefits outweigh the risks identified to date where there is high
unmet need; NHS funding for product must be cost effective; the UK
economy should benefit from the scheme’
Strategy for UK Life
Sciences – EAMS Public Consultation
– The MHRA and Department Health launched a joint public consultation from
13 July to 5 October 2012
– The consultation introduced the scheme based on the work of the MISG
– There were 26 questions in the following areas:
• Should a scheme be established
• Scope
• Number of products
• Stage of development
• Patient treatment if medicine fails to be granted a licence
• Information requirements
• Monitoring and surveillance
• Questions on funding
• Macroeconomic gains to the UK
• Fees
• Other questions
EAMS Consultation
– 52 responses were received and the Government’s response to the
consultation was published in March 2014
– Overall, there was overwhelming support for a scheme
– The Government considered that the EAMS:
• Addresses a public health need to improve access to important
innovative medicines for patients with life threatening or seriously
debilitating conditions without adequate treatment options
• Demonstrates a commitment from the UK to pharmaceutical innovation,
through the Promising Innovative Medicine designation and earlier
patient uptake of new innovative medicines in the health service
Strategy for UK Life
Sciences – UK Expert Group
The Expert Group on innovation in the regulation of healthcare was established
in June 2012 following the Prime Minister’s Life Sciences Strategy
– A group of experts drawn from government, regulators, the NHS, industry
and the academic and third sector communities will meet quarterly to
discuss healthcare regulation issues, including the development of new
initiatives and innovations…
– The group considered maximising the impact of, and learning from, the
Early Access Scheme consultation
– The Expert Group published a report in September 2013
– In the report, the group welcomed the proposal for a UK Early Access to
Medicines Scheme and endorsed the draft Government response to the
– The group advised that the scheme should be launched as soon as crossGovernment agreement was obtained
Strategy for UK Life
Sciences – UK Expert Group
The expert group also considered the regulatory flexibilities available in the USA
and EU and noted that the two regulatory systems offered substantively similar
However, one difference was the FDA’s “breakthrough designation” that gave
strong signals to investors on promising products
The expert group considered that much interest has been generated by the
FDA's breakthrough designation, where promising new medicinal products are
designated based on preliminary clinical evidence
The Expert Group recommended that the Government consider the possibility of
adopting a designation that would send signals to investors (as does the US
breakthrough designation), perhaps in the context of the proposed UK Early
Access scheme
Early Access to Medicines Launch
EAMS Overview
– The MHRA launched the scheme on the 7th of April with a dedicated EAMS
webpage, coordinator and guidance
– The scheme aims to give patients with life threatening or seriously
debilitating conditions access to medicines that do not yet have a marketing
authorisation when there is a clear unmet medical need
– The scheme is voluntary and the opinion from MHRA does not replace the
normal licensing procedures for medicines
– Primarily aimed at medicines that have completed Phase III trials, but may
be applied to completed Phase II trials in exceptional circumstances
– There is no set limit on the numbers of products entering the scheme
provided they fulfil the criteria of the scheme
EAMS Overview
–MHRA is responsible for the scientific aspects of the scheme and the scientific
opinion will be provided after a two-step evaluation process:
– Step I, the Promising Innovative Medicine (PIM) designation
» The designation is an early indication that a medicinal product
is a promising candidate for the EAMS
– Step II, the Early Access to Medicines Scientific Opinion
» The scientific opinion will describe the benefits and risks of the
medicine and will support the prescriber and patient to make a
decision on using the medicine before its licence is approved
Step I PIM Designation
– A Promising Innovative Medicine Designation is an early indication that a
medicinal product is a promising candidate for the EAMS
– A designation is a prerequisite to enter the EAMS scientific opinion
assessment (step II)
– The designation will be issued after an MHRA scientific meeting on the basis
of non-clinical and clinical data available on the product, in a defined disease
– Applicants may apply when data from early stages of clinical development
indicates that the medicinal product fulfills the designation criteria
– the product is likely to demonstrate significant benefit for patients in
life-threatening or seriously debilitating conditions
Step I
Step II
awarded on the
basis of Phase I/II
awarded on the
basis of Phase II
Early Access to
Medicines presubmission
review for
Early Access to
Medicines presubmission
Joint ‘PIM’ designation and
Early Access to Medicines
pre-submission meeting, on
the basis of Phase III data
(exceptionally Phase II)
review for
PIM - How to apply
– Applicants seeking a PIM designation should read the available guidance and
complete the PIM designation template in full, indicating how the product
fulfills the criteria for designation
– The Application template includes:
• Administrative and product specific information
• Brief details of current pharmaceutical development
• Criteria 1: Details of the condition and details of the high unmet need
• Criteria 2: The medicinal product is likely to offer major advantage over
methods currently used in the UK
• Criteria 3; The potential adverse effects of the medicinal product are likely
to be outweighed by the benefits, allowing for the reasonable expectation
of a positive benefit/risk balance
– For the joint PIM designation/ pre-submission meeting, both a PIM
designation application template and a pre-submission meeting template
should be submitted at the time of the request
‘Post PIM’ Designation
Following designation, the applicant is expected to complete a clinical
development programme within a reasonable time period, in order to
continue with an application for an EAMS scientific opinion
Designation holders will also be encourage to utilise the MHRA’s
support services including:
• The MHRA Innovation Office that helps organisations
navigate the regulatory framework
• Scientific advice, including:
• Scientific advice for specific scientific issues
• Broader scope meetings on less specific topics
• Joint scientific advice meetings with NICE, regarding clinical
study design that will be used to satisfy regulatory and NICE
Step II – Scientific Opinion
– The scientific opinion will describe the benefits and risks of the medicine and
will support the prescriber and patient to make a decision on using the
medicine before its licence is approved
– To enter step II, the Applicant must hold a PIM designation, complete the
pre-submission template and attend (either in person or via teleconference)
a pre-submission meeting
– The aim of the pre-submission meeting is to ensure that the suitability criteria
for the scheme are likely to be met and to discuss the format of the data to
be submitted to support the benefit/risk opinion
– After the pre-submission meeting, the MHRA will make a recommendation
as to whether the product is considered a suitable candidate for step II of the
– However, it is ultimately the decision of the Applicant whether to proceed
with an application
Pre-Submission Template
– The pre-submission template should include:
• Proposed indication and brief descriptions of the following:
• Summary of quality and non-clinical development programme to date
• Justification of eligibility for scheme
– Life-threatening or seriously debilitating condition in patients with a
high unmet medical need
– Data available to support a positive benefit risk balance and major
advantage over methods currently used in the UK
• Summary of proposal for on-going collection of safety and efficacy data
• Description of format of proposed EAMS dossier
• Description of on-going clinical studies and recruiting countries
Entry into Step II
– Data format requirements are in line with established regulatory guidance
(CTD) and/ or option to submit non-CTD data
– The EAMS dossier should be submitted in electronic format by the date
specified and agreed after the pre-submission meeting
– Late or invalid dossiers will not be able to enter the scheme on the preferred
date as the timetables are set to coincide with our expert committee
– The assessment timetable is fast and flexible, 75 (90) days vs. 150 or 210
days in the EMA centralised procedure (minus clock stops), with options:
• Lengthen clock stops if required
• Close before Day 75 if all issues are resolved
Day 75 Timetable
Day 90 Timetable
Days 0-45
MHRA assessment & consultation with CHM/EAG, list of outstanding issues
communicated to Applicant, with provisional Benefit: Risk (B:R) opinion
Preliminary positive opinion
(Minor issues outstanding)
15 day clock stop
Days 46-75:
Final B:R
positive on
or before
Day 75
Days 46-75:
decision now
revert to
Day 90
Day 90
Preliminary negative opinion
(Major issues outstanding)
30 day clock stop*
Days 46-90:
Final B:R decision made on
or before Day 90
– positive or negative
*in exceptional circumstances, the Applicant can request additional 30 days (30+30)
The Scientific Opinion
– The scientific opinion will describe the benefits and risks of the medicine,
based on information submitted to the MHRA by the Applicant in a public
assessment report (PAR)
– The PAR will be made available on the MHRA’s website to assist clinicians
and patients in making treatment decisions
– More detailed product information will be provided in the EAMS Treatment
Protocol, which will detail the conditions for use, ensuring safe and
efficacious use of the product
– The scientific opinion will be valid for one year, renewable if necessary and
– Negative opinions will not be published
The Scientific Opinion PAR
What is [insert product name]?
What is [insert product name] used to treat/diagnoses/prevent?
How is [insert product name] used?
How does [insert product name] work?
How has [insert product name] been studied?
What are the benefits and risks of [insert product name]?
– Benefits
– Risks
Why has [insert product name] been given a positive Early Access to Medicine
Scientific opinion?
What are the uncertainties?
Are there on-going clinical studies?
What measures are in place to monitor and manage risks?
Periodic Update
During the opinion year, it is expected that the scientific opinion holder will
provide regular updates
The frequency and scope of these updates will be agreed before the issue of a
positive scientific opinion but updates are likely be expected every 3 months and
describe safety and usage of the product under the scheme, along with any
safety and efficacy data from newly-completed clinical trials
MHRA will amend the PAR and treatment protocol as necessary
Where relevant, quality, safety and efficacy data generated during the EAMS
opinion should be submitted at appropriate time points during the marketing
authorisation application
EAMS Summary
Open for applications since 7th April 2014
• Aim to give patients with life threatening or seriously debilitating conditions
access to medicines that do not yet have a marketing authorisation when
there is a clear unmet medical need
• The MHRA is responsible for the scientific aspects of the scheme and the
scientific opinion will be provided after a two-step evaluation process
Detailed guidance and templates can be found on the EAMS webpage
Support through the EAMS coordinator, to provide help and assistance regarding
any aspect of the scheme
New scheme – New processes - MHRA plan to collection information from
applicants on their experiences of the scheme (using an electronic survey)
Adaptive Licensing
Marketing Authorisation
– Medicinal products for human use may only be
placed on the market in the EU if a marketing
authorisation has been issued by the Community
or by a competent authority of a member state
– For a medicine to be licensed, a marketing
authorisation application must be submitted to a
national competent authority or the European
Medicines Agency (EMA)
Centralised Procedure
– Regulation (EC) No 726/2004 lays down a centralised procedure for the
authorisation of medicinal products:
• Single application and evaluation
• Single authorisation granted by the EC
– The types of product which fall within the mandatory scope of the
centralised procedure include:
• Medicinal products derived from biotechnology e.g. those derived from
recombinant DNA technology or monoclonal antibody methods
• New Active Substances in the treatment of AIDS, cancer,
neurodegenerative disorders, diabetes, autoimmune diseases and other
immune dysfunctions and viral diseases
• Orphan medicinal products
• Optional scope e.g. products that constitute a significant therapeutic,
scientific or technical innovation
Centralised Procedure
– Administered by the European Medicines Agency (EMA)
– The Committee for Medicinal Products for Human Use (CHMP) of the
EMA is responsible for preparing the scientific opinion
– Results in a single Community authorisation granted by the European
– No country withdrawals - ‘all or none’
Centralised Procedure
– A Rapporteur and Co-Rapporteur are appointed from CHMP members
– The role of the Rapporteurs is to perform the scientific evaluation and to
prepare an assessment report, according to the agreed timetable
– In the context of quality assurance, CHMP members may be assigned to
peer review the Rapporteurs’ scientific evaluation
– CHMP may consult its scientific advisory groups (e.g. SAG-O) and
working parties (e.g. Biologics Working Party – BWP)
– The opinion of the CHMP is given within 210 days (less clock-stops for
the applicant to provide answers to questions from the CHMP)
Accelerated Assessment
– When a MAA is submitted for a product which is of major public health
interest, in particular from the viewpoint of therapeutic innovation, the
applicant may request an accelerated assessment procedure
– The standard timetable is reduced to 150 days
– An applicant should notify the intent to submit a request for an accelerated
assessment procedure
– Justification for a request for accelerated assessment should include a
description of:
– The unmet medical needs
– The extent to which the medicinal product is expected to have major
impact on medical practice
Centralised Procedure
– A marketing authorisation application may result in:
– Grant (full approval)
– Grant with conditions
» The Commission is empowered to impose on the marketing
authorisation holder the obligation to conduct post-authorisation
studies on safety and on efficacy, as a condition of the marketing
– Conditional approval
» For certain medicines, in order to meet unmet medical needs of
patients and in the interest of public health, it may be necessary
to grant marketing authorisations on the basis of less complete
data than is normally required
– Approval under exceptional circumstances
» The Applicant must demonstrate that he is unable to provide
comprehensive data on the efficacy and safety under normal
conditions of use
Summary of MA routes
Fast track
(National only)
Marketing authorisation
Grant (full approval)
Grant with conditions
Conditional approval
Exceptional circumstances
Grant with conditions
Exceptional circumstances
Adaptive Licensing (AL)
– Adaptive licensing is proposed to be stepwise learning under conditions of
acknowledged uncertainty, with iterative phases of data gathering and
regulatory evaluation - a life-cycle approach
– This is in contrast to traditional drug licensing approaches that are based on
binary decisions, where an experimental therapy is transformed into a ‘fully’
vetted therapy at the moment of licensing
– The aim is to maximise the positive impact of new drugs on public health by:
• Balancing timely access for patients to treatments that promise to
address serious conditions where there is an unmet need
• With the need to provide adequate evolving information on the benefits
and harms
Adaptive Licensing (AL)
–AL is defined by the EMA as a prospectively planned, adaptive approach to
bringing drugs to market;
• Starting from an authorised indication, most likely a “niche”
• Followed by iterative phases of evidence gathering and progressive
licensing adaptations, concerning both the authorised indication and
further therapeutic uses of the drug
–AL uses the regulatory processes that exist with the EU framework
–Stakeholders other than regulators and industry need to be involved in
planning and agreeing the manner in which clinical trial and post-authorisation
data will be generated for decision making:
• e.g. Reimbursement authorities, patient organisations, societies involved
in treatment guidelines
The EMA pilot
– An AL discussion group was set up by the EMA in 2012, with members from
across the various scientific committees e.g. CHMP, COMP
– Following work performed by the group, the EMA recently launched an
adaptive licensing pilot (March 2014) to discuss prospective case studies
– The purpose of the pilot is to provide a framework for informal interactions by
discussing ‘live assets’, i.e. medicines currently under development
– It is hoped that all stakeholders will be able to address a range of technical
and scientific questions
• Help refine how future AL pathways might be designed
• What might be achieved by AL
• How best to address the potential blocking factors
• To identify additional hurdles or issues that may not have become
apparent yet
The EMA pilot
– Guidance and a framework to guide discussions of individual pilot studies has
been published, alongside some retrospective case studies
– Discussions on possible AL pathways of a live asset are of an exploratory
– Thus the pilot offers a safe-harbour environment for informal, non-binding
discussions between regulators and companies with an ‘asset’ that may be
suitable for this approach
– Strengths and weaknesses of all options for development, licensing and
assessment may be explored openly and discussed without fear or favour in
advance of more formal interactions e.g. scientific advice
– Companies who are interested in participating are invited to submit medicines
for consideration as prospective pilot cases
• Live assets shall be experimental drugs or biologicals in the early stage of
clinical development to enable actionable input from stakeholders (prior to
initiation of confirmatory studies)
The EMA pilot
– Companies should complete a high-level framework on which to base the
pilot study
– Product name/identifier
– Summary of relevant product data and development to date (Licensing
history and interactions with health authorities/payers/HTA bodies)
– Proposal for development under adaptive licensing
• ‘adaptive’ strategies for development, licensing, patient access,
appropriate utilization, and monitoring that could be considered, using
existing regulatory tools
– Outline a vision and timeline for how regulatory, payer and other
stakeholders’ interactions might look, including indicative timelines for
regulatory evaluation and decision making through the product lifecycle
AL Summary
– AL would not result in a new type of Marketing Authorisation as the process
would uses existing regulatory tools e.g. ‘Conditional’ MA
– The novel aspects of an adaptive licensing from the perspective of the
regulator relate to increased dialogue with other stakeholders and increased
collection and utilisation of post-authorisation data
– Possible benefits of AL could include:
• Maximize the positive impact of new drugs on public health by balancing
timely access for patients with the need to provide adequate evolving
information on benefits and harm
 More rapid access to patients in greatest need
• Streamlined drug development with efficient generation of evidence to
satisfy the needs of multiple stakeholders using parallel ‘Scientific Advice’
• Potential for more rapid return on investment
• Earlier dialogue promoting more certainty for the drug developer
Thank You
[email protected]
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Qualification of novel methodologies
David Brown, May 2014
Qualification opinions
Stored at this memorable URL:
Problem statement
• Failure rate of Phase III trial reaches to 50%, part
of the failure is attribute to improper target dose
estimation and selection in Phase II, and
incorrect/incomplete dose-response knowledge;
• A number of high-profile withdrawals from market
of approved drugs;
• FDA reported 20% of the approved drugs between
1980 and 1989 had the initial dose changed by
more than 33%, in most cases lowering it.
Current approaches
Differ by therapeutic area, but…
Narrow dose range (3-4 fold max?)
Few doses (2-3 max)
Analysed through pairwise comparisons to
placebo, e.g. ANOVA
– Inefficient
– Wrong question?
– Multiple tests
Other background
• EMA/EFPIA workshop on M&S, 2011. Re: dose-finding:
– Some surprise that we are interested
– Work done that we don’t see
• Regulatory attitude to exploratory development
- ‘therapeutic efficacy’ and ‘benefit-risk’ - in the end if
‘benefit-risk’ is positive we will (must) licence it
regardless of dose
- ‘dose-selection is the sponsors risk’
Other background
• EMA/EFPIA workshop on M&S, 2011. Re: dose-finding:
– Some surprise that we are interested
– Work done that we don’t see
• Regulatory attitude to exploratory development
- ‘therapeutic efficacy’ and ‘benefit-risk’ - in the end if
‘benefit-risk’ is positive we will (must) licence it
regardless of dose
- ‘dose-selection is the sponsors risk’
- selecting dose on a weak basis is a risk for development
Sound science (1)
• “What is most helpful in choosing the starting dose of a
drug is knowing the shape and location of the
population (group) average dose-response curve for
both desirable and undesirable effects.”
• “Assessment of dose-response should be an integral
component of drug development with studies designed
to assess dose-response an inherent part of
establishing the safety and effectiveness of the drug. If
development of dose-response information is built into
the development process it can usually be
accomplished with no loss of time and minimal extra
effort compared to development plans that ignore
Sound science (2)
• “Conducting dose-response studies at an early
stage of clinical development may reduce the
number of failed phase 3 trials, speeding the drug
development process and conserving development
• “in light of the studies that partly defined the proper
dose range, further dose-finding might be pursued
in the post-marketing period”
Sound science (3)
• “It is important to choose as wide a range of doses
as is compatible with practicality and patient safety
to discern clinically meaningful differences.”
• “It is all too common to discover, at the end of a
parallel dose-response study, that all doses were
too high (on the plateau of the dose-response
curve), or that doses did not go high enough. A
formally planned interim analysis (or other multistage design) might detect such a problem and
allow study of the proper dose range.”
Sound science (4)
• “Several dose levels are needed, at least two in
addition to placebo, but in general, study of more than
the minimum number of doses is desirable. A single
dose level of drug versus placebo allows a test of the
null hypothesis of no difference between drug and
placebo, but cannot define the dose-response
relationship. Similarly, although a linear relationship
can be derived from the response to two active doses
(without placebo), this approximation is usually not
sufficiently informative. Study designs usually should
emphasize elucidation of the dose-response function,
not individual pairwise comparisons.
Sound science (5)
• “Agencies should also be open to the use of
various statistical and pharmacometric techniques
such as Bayesian and population methods,
modeling, and pharmacokinetic-pharmacodynamic
• From which document are these quotes?
Sound science (6)
1994 !!
Not novel in principle
Background on MCP-Mod methodology
 MCP-Mod stands for:
Multiple Comparisons & Modelling
• Combines testing and estimation
 Design stage
• Pre-specification of candidate doseresponse models
 Analysis stage: MCP-step
• Statistical test for dose-response
signal. Model-selection based on
significant dose-response models
 Analysis stage: Mod-step
• Dose-response and target dose
estimation based on dose-response
• Difference to traditional ANOVA approach
– Use of dose-response modelling
– But, taking model uncertainty into account at design and analysis stage
| SAWP Discussion Meeting | Novartis | 10 July 2013
| MCP-Mod Qualification Opinion | Business Use
Basic idea - modelling
• As one of the two major classical strategies in dose finding
trials: multiple comparison procedures and model-based
– Assumes a functional relationship between the response
and the dose (a quantitative factor) according to a prespecified parametric model, e.g. logistic, an Emax or a
linear log-dose model;
– The fitted model is then used to estimate an adequate dose
to achieve a desired response.
– However, validity of trial conclusions highly depends on the
correct choice of the dose-response model, which is an
unknown priori.
• Choice of a working model may have a substantial impact
on dose selection, and model selection using observed
data needs to account for statistical uncertainty and
associated multiplicity issues.
MCP-mod - Description
• The MCP-Mod approach impacts both the design and
the analysis of dose finding studies
• At the trial design stage, a suitable set of candidate
models is identified in repeated clinical team
discussions, which also impacts decisions on the
number of doses, required sample sizes, patient
allocations, etc.
• At the trial analysis stage, dose response is tested
using suitable trend tests deduced from the set of
candidate models. Once a dose response signal is
established, the best model(s) out of the set of prespecified candidate models is (are) then used for dose
response and estimation of target dose or dose range.
MCP-mod - Description
Step 1: Set of candidate models
Step 2: Optimal model contrasts
Step 3: Testing for dose response signal
Step 4: Model selection
Step 5: Dose estimation
Power to detect dose response
under active DR profiles.
Probabilities of identifying
clinical relevant dose under
flat dose response.
MCP-mod - Validation
• It is concluded that MCP-Mod controls type I error rate and
is less likely (than ANOVA) to identify a clinically relevant
dose in the absence of dose-response (flat profile). It is
further concluded that under active dose-response profiles
the probability of identifying dose-response will be higher,
though the probability of identifying a clinically relevant dose
will depend on the shape of the dose-response curve. For
the simulations investigated MCP-Mod appears to be better,
at least on average, than an ANOVA based approach in
terms of bias and absolute error. It is widely known of
course that biased estimates will, on average, result when
selecting a dose based on a particularly impressive pairwise
comparison to control because of random highs and this
phenomenon is displayed in the simulations, but controlled
by MCP-Mod.
• Chronic Obstructive Pulmonary Disease (COPD).
The investigational drug NVA237 is a dry powder
formulation of the muscarinic receptor antagonist
glycopyrronium bromide being developed by
• The primary purpose of the A2205 study was to
provide data about the risk-benefit of four doses of
NVA237 (12.5, 25, 50 and 100μg o.d.) and openlabel tiotropium (18μg) so that an optimal dose of
NVA237 can be chosen for Phase III studies
• FEV1
Step 1: Set of candidate models
• Step 2: Optimal model contrasts
• Step 3: Testing for dose response signal
– Applying the optimal contrasts to the treatment
estimates, one obtains that all contrasts had test
statistics > 6 and multiplicity adjusted p-values <
0.0001. As a result, the significance of the dose
response signal was established and all models
were considered in the next step.
• Step 4: Model selection
• The AIC criterion was used to select the best
model. Note that, even though there are two Emax
shapes in the candidate set, only one Emax fit is
obtained. Based on the AIC results, the Emax
model was chosen to represent the dose response
• Step 5: Dose estimation
• Based on the fitted Emax of Step 4, the smallest dose giving the
clinically relevant improvement over placebo of 0.12 L is
estimated to be 44 μg. This is the MED estimate produced by
MCP-Mod in this study. The precision of the MED estimate was
evaluated via a bootstrap approach: The 90% confidence interval
for the MED, corresponding to the 5% and 95% quantiles of the
bootstrap sample, was [18, 81], reflecting the uncertainty in the
estimate. Figure 3-6 displays the fitted model and corresponding
confidence intervals.
• A side note on interpolation
MCP-mod - Conclusions
• … a strategy based on a modelling approach that attempts to
quantify a dose-response relationship may offer an improved
basis for decision making and it is arguable therefore that to
qualify MCP-Mod as an improvement over the commonly used
approach is uncontroversial … much of the theory underpinning
the proposed method is not novel, yet the use of this type of
approach in regulatory submissions remains rare and hence, the
fact that these sub-optimal approaches persist makes this a
relevant topic for a CHMP opinion.
• … more broadly, it is considered that the planning needed to
implement MCP-Mod will be beneficial for trial design both in
terms of the number of doses and the increase in the range of
doses studied, and also in that the consequences and risks of
selecting a particular trial objective, design and sample size will
be better understood by all stakeholders.
MCP-mod - Conclusions
• Another interesting part of the procedure relates to the
control for multiple comparisons. Designing an
experiment that permits conclusions to be drawn with
control of false-positive error rate is clearly desirable
for the study sponsor. It is mandated by regulators in
the confirmatory phase of development, though not in
the exploratory phase that is under discussion here,
where factors other than strict type I error control may
influence decisions regarding future clinical
development. The choice of 5% used by the applicant
in their illustrations is arbitrary and could be varied
based on the certainty that the applicant wish to have
for their decision-making.
MCP-mod - Conclusions
• It is concluded that the MCP-Mod approach can be
qualified as an efficient statistical methodology for
model-based design and analysis of phase II dose
finding studies under model uncertainty
• MCP-Mod represents one tool in the toolbox of the
well-informed drug developer. In that sense, this
opinion does not preclude any other statistical
methodology for model-based design and analysis
of exploratory dose finding studies from being
MCP-mod - Public consultation
• Lots of modelling approaches are possible
– Most modelling is (almost by definition) without
control for multiple testing
– Don’t only focus on dose
• Agree, providing this is not the only permitted
• A side note on adaptive allocation
MCP-mod - Public consultation
• The current work covers a very important topic. Phase II dose
response studies should be designed and analysed around dose
response modelling. It is woeful that in 2013 we are discussing
whether dose response modelling should be employed for dose
response studies. Of course they must be. Are there idiots out
there who would disagree?! The "current practice" of multiple
pairwise comparisons to placebo is truly terrible. The document
comments that "...that current practice is repeatedly sub-optimal
and inefficient." This sentence is "too polite". To design studies to
determine the dose response without consideration of dose
response modelling is wholly unscientific and unethical.
• For an overview on how I see drug development, you might wish
to view:
What does it mean for us?
• Not sure yet
• Potentially, more complex, but larger and more
informative exploratory trials
• EMA workshop on dose-finding, Dec 2014
• MCP-Mod approach is qualified as an efficient
statistical methodology for model-based design
and analysis of phase II dose finding studies under
model uncertainty
= we have seen it, thought about it and, within the
context of use, endorse it (in principle).
• Qualification speaks to MCP-mod but should also
stimulate awareness that regulators value dosefinding and exploratory development
The CAMD Consortium
Nonmember participants: Academic key opinion leaders, CROs
Broad and Complete Data Sources Used for Model Development
Data to inform natural history of AD
Data from multiple sponsors to inform
control arm elements
-Placebo response
-Covariate effects
Tool is unique in that it also utilizes
Literature meta data to inform drug
-Marketed Symptomatic
o Magnitude, onset of effect, offset
• The idea is to model the data from the placebo
arms of clinical trials in Alzheimer’s disease
• Use the model to help the planning of future trials
• Perform clinical trial simulations
• Optimise the design in terms of aspects such as
time-points to measure at, study duration,
important covariates, sample size,
crossover/parallel group etc
Context of use
Baseline severity
MMSE 27+/30 is normal
Gender and ApoE4 genotype
Independent validation
In a way risk free for CHMP
Not going to replace clinical trials
But can help their design
So happy to endorse based upon our assessment

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