Download A Marketing Authorisation Application (MAA) can be the same

A Marketing Authorisation
Application (MAA) can be the same
document as a New Drug Application
(NDA) except for Module 1, correct?
Close, but not entirely true!
Authors: Bob Milsted, Flic Gabbay
Date: 10th May 2016
Introduction
Harmonisation of the regulatory approval process for new medicines in
Europe and the USA has advanced dramatically in recent years. Guidelines
from both the European Medicines Agency (EMA) and the Food and Drug
Administration (FDA) have been revised in line with these harmonisations.
Despite this, TranScrip are often asked by pharmaceutical companies
whether the Marketing Authorisation Application (MAA) dossier for the EU
and the New Drug Application (NDA) dossier for the USA differ and, if so,
in which sections and why. This appears to be a topic of some confusion,
particularly when the submission dossier is for an anti-infective product.
TranScrip is involved with one or two MAAs each year and, for some, is
also involved with the NDA as well. To date, no products have failed to get
a license. TranScrip’s involvement has varied from writing the major
sections of the submission dossier to assisting with responses to questions
from the agencies, to managing much of the sponsor’s required activities
during the regulatory review procedure. Consequently, TranScrip has
gained a lot of experience and knowledge which help companies prepare
their regulatory submissions and maximise the likelihood of a successful
registration. There are a few small, but important differences between the
two documents. This is a summary of where differences between an MAA
and NDA might lie in order to help companies plan their approach to their
regulatory submissions.
Which comes first, the NDA or MAA?
The most efficient approach to preparing submission documents for both
EMA and FDA is to do so in parallel or slightly offset, where documents
need to be tweaked for one or other authority. Obviously, one needs to
start writing from the bottom of the pyramid upwards, but the key
messages must have been determined top down beforehand to ensure
that there is a logical thread to important areas at all levels of the
submission. Crucial to this, is that areas of difference between different
geographical regions, particularly with regard to approvable endpoints and
variation in clinical practice, have been recognised and addressed at end
of Phase II.
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An advantage of the parallel approach, is the potential to minimise time to
approval in two of the major global markets, but this requires appropriate
planning and project management.
In order to facilitate an efficient approach to submitting in parallel in more
than one geographical region, companies need to have had discussions
with relevant Health Authorities at End-of-Phase II meetings, and to have
determined and addressed any major differences in the regulatory
environment. The aim of such discussions will always be to achieve
concordance wherever possible. However, there are disease areas where
differences have to be addressed during the writing and analysing of the
Phase III trials so that writing of the core dossier is facilitated, and the
chances of approval in all geographical regions is maximised. The main,
and most difficult, differences are in the variation in clinical practice and in
the acceptance of different approvable endpoints, which may or not be
connected. There may also be differences in favoured analytical
techniques, with the EMA statisticians tending to have a more flexible and
pragmatic approach than their transatlantic cousins.
FDA and EMA have for some years operated a process allowing joint
consultation meetings which may help in gaining common ground,
allowing a sponsor to design trial programmes which can gain approval in
both regions. There are a number of ways of accommodating any residual
differences which are outside the scope of a brief article. The least worst
option may be to have two Phase III trials, each of which acts as the lead
trial for one region with the other being supportive. This may be the only
resolution where the problem is one of differences in clinical practice.
Such a situation obviously leads to major differences in the emphasis in
the summary of efficacy prepared for the two regions. Fortunately, most
differences can be dealt with in a less extreme manner. The key thing is
to have the discussions and agree the way forward.
Companies need to understand the resource requirements between
database lock and submission because this is one of the few parts of the
process which are under their control and which is resource sensitive.
Resource requirements in obtaining regulatory approval for a product may
be quite demanding because, not only must the Common Technical
Document (CTD) be written and submitted, but the associated drug safety
and risk management documents must also be prepared, and there is
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likely to be an intense push within the company in the preparation for
launch of the product.
Companies come to TranScrip for help and advice when considering their
submission strategy, including key messages. Once the strategy has been
determined, TranScrip can provide any external support required by the
company in terms of appropriate expertise and the additional resource
needed to ensure successful submission.
So what differences may there be between an MAA and an NDA
submission?
The following are some examples of the differences that may exist
between an NDA and an MAA which can influence the writing of various
sections for each submission dossier:

Regulatory guidelines on drug development, especially with respect
to the approvable endpoint for some indications, can vary between
the USA and Europe. This means that Module 2, Section 2.5 and
Section 2.7.3 within the MAA and the NDA may need to be written
with a focus primarily on endpoints relevant to each agency or
written such that both are encompassed. Thus, if the MAA is being
prepared from an NDA, re-writing of these sections may be required
for some indications. For example, in the case of antibiotics for the
treatment of complicated skin and soft tissue infections, guidance
for the studies (and thus for the clinical study report and statistical
analysis plan) differ between Europe and the USA. Therefore, the
relevant sections within the MAA and the NDA may be written
differently since attempting to encompass the requirements of both
agencies may become confusing for the reviewer.

Scientific advice and feedback must be obtained at end of Phase II
as described above. If, for some reason, there are outstanding
issues that have not been addressed and resolved prior to
conducting the Phase III programme, then pre-submission
meetings must be held to attempt to do so, although this is
inevitably more difficult once the trials have been conducted.

The EMA guidance on MAA preparation may specify practical
aspects on how missing data should be handled or where sensitivity
analyses may be required. In situations where a lot of missing data
is expected (for example trials of schizophrenia), the approach to
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missing data is an important point for discussion at end of Phase II
or pre-submission meetings. Failure to do so can result in FDA
statisticians applying ultra-conservative methods in re-analysis,
greatly affecting the conclusions drawn. TranScrip can advise on
less conservative approaches which have been found acceptable in
the past.

One of the most critical pieces of the CTD dossier is the rationale
for medical need in Section 2.5 which must be tailored to the
countries where the drug is to be registered. For antibiotics,
patterns of resistance may differ between the USA and Europe, and
there may be differences in dominance of distribution of bacterial
strains. In addition, clinical treatment practices and approaches to
risk management in each region may differ significantly.

The need to cover for regional variations in clinical practice in
Section 2.5 may drive information to be included in Section 2.7 that
is required for one agency, but is redundant to the other agency,
and vice versa, e.g. analysis of antimicrobial susceptibility profiles
of isolates by region.

Both FDA and EMA are perfectly willing to accept data generated in
other regions than their own. However, the onus is on the sponsor
to show that the data are of adequate quality and that the patient
population is relevant to clinical practice in their region. Where
there are differences in clinical practice, or where it is helpful
operationally to do so, trials can be separated by geographical
region, but it is not otherwise necessary to do so, and sometimes
there may be advantages to having centres from both geographical
regions. In most therapeutic areas that TranScrip works in, we
submit the same Module 2 for both the NDA and MAA, but we may
make small adjustments to the text and add or delete some
appendix tables depending on whether we are translating from NDA
to MAA or vice versa. In general, there are usually more Tables and
Listings in the NDA even though the text is essentially the same.

With respect to the drug safety section, Section 2.7.4, provided this
is written closely following the requirements of the CTD format,
very little amendment is necessary between a MAA and a NDA
except for the tables that support the adverse reaction data,
included in the USPI and the SmPC, which differ slightly in format.
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
Some differences in specialist pharmacology, such as microbiology,
may need to be considered for the MAA and NDA. For example,
susceptibility data presented may need to be primarily those
determined using the Clinical and Laboratory Standards Institute
(CLSI) methodology for the NDA, but using the European
Committee on Antimicrobial Susceptibility Testing (EUCAST) for the
MAA.

The way the FDA and the EMA assess dossiers is fundamentally
different. The FDA essentially notes what the sponsor presents in
the clinical section, but re-analyses these data from the bottom up.
In Europe, the review tends to take a more top down approach and
wholesale re-analysis of data is not the norm. Also, the European
system now uses expert working groups to advise the Committee
for Medicinal Products for Human Use (CHMP) and these will contain
clinicians who are not professional regulators. FDA may occasionally
use outside consultants at advisory meetings and obviously do so in
the Advisory Committee system, but in general the review of the
submission is done in-house.
So what does this mean for pharmaceutical companies?
Whilst an NDA and an MAA may include the same core data, regulatory
requirements, regulations, guidelines and clinical practice between the
USA and Europe may be quite different.
Any differences between the regions in approvable endpoints,
comparators and clinical practice must be resolved at end of Phase II
meetings and/or a strategy for the design and analysis of Phase III trials
must be determined and agreed to cope with them.
Having done this, when the trials are completed, appropriate local skills
and adequate overall resource for submission plans must be put in place
to deal with the dossier for each region. For large pharmaceutical
companies, this is “motherhood and apple pie”, but for smaller
organisations this can be quite daunting. However, with external support
from experienced companies to help identify where the differences lie and
to fill any gaps in resources required to prepare each dossier, the
probability of a successful registration can be increased.
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