ITEM 6

   National Institute for Health and Clinical

Pilot project on providing scientific advice early in the
           development of a new compound

                             Evaluation Report

Prepared by

Dr Carole M Longson, Director
Dr Elisabeth George, Associate Director
Zoe Garrett, Technical Advisor

Centre for Health Technology Evaluation
March 2008

DATE: 19 MARCH 2008
                                                                          ITEM 6

Regulatory authorities currently provide guidance and scientific advice to
pharmaceutical sponsors on evidence requirements for new products, prior to
the commencement of sponsors’ Phase III clinical trials. Regulators are
devoting an increasing amount of time to such activities at various stages of
development of a new medicine.

NICE is interested in establishing an equivalent process to provide scientific
advice on evidence plans and evidence requirements prior to companies
starting their Phase III development activities. The aim of this advice is to
foster the development of- and accelerate access to- new innovative
medicines by increasing the likelihood that the clinical trials and other
research activities undertaken during drug development will meet the
evidence requirements needed to inform decisions on the clinical and cost
effectiveness of new technologies.

Aims of the pilot project

A pilot project was established in order to investigate the feasibility of NICE
engaging in this type of activity.

The aim of the pilot project was to develop and evaluate a draft process. The
process was designed to provide advice to pharmaceuticals companies about
a specific compound under development prior to Phase III.

Although a pilot project, the project also aimed to provide Novartis Pharma AG
with formal, written advice at the end of the process about the Phase III
clinical development plans and the evidence requirements for cost
effectiveness analysis for a specific compound. The pilot project was carried
out in partnership with Novartis Pharma AG using a compound (NOV001) for
psoriasis under their development.

1.1         Selection of the topic for the pilot project
There were no specific requirements for the topic to be used for the pilot
project. However, it was decided that it was most useful to all participants of
the pilot project if a ’real’ drug in pre-Phase III development was chosen.

Novartis Pharma AG selected a new potential treatment for patients with
psoriasis, referred to as NOV001 for the purpose of this pilot project. NOV001
is currently in Phase II development having completed a small proof of
concept study in people with psoriasis. In Phase II it is planned to establish
the doses and duration of induction treatment for use in Phase III, to explore
time to relapse and possible maintenance doses for Phase III clinical trial
design, to study safety and to explore response to re-treatment.

Novartis Pharma AG sought advice from NICE in relation to key clinical trial
design characteristics and key economic characteristics required to inform
decisions about the potential positioning and use of NOV001 within the
DATE: 19 MARCH 2008
                                                                        ITEM 6

current systemic treatment sequence. The Phase III clinical trials were
estimated to start within 12 to 18 months of the submission of the briefing

1.2         Draft Process for the pilot project
NICE and Novartis Pharma AG discussed initial ideas based upon existing
processes through which scientific advice is provided to pharmaceutical
companies by regulatory authorities. A review was undertaken by Novartis
Pharma AG of processes for obtaining scientific guidance and advice from
regulatory agencies in Australia, Canada, Europe and the United States. This
review served as a basis for informal discussions of a draft process for
receiving pre-Phase III guidance on evidence requirements from NICE (see
Figure 1). NICE and Novartis Pharma AG mapped out a process and timeline
for a pilot project for obtaining scientific advice to be undertaken in Autumn
2007 (see Figure 2) and running in parallel with advice being requested from
regulatory authorities.

Project team

The pilot project was supported by a project team at NICE comprised of:

Dr Carole Longson – Director, Centre for Health Technology Evaluation

Dr Elisabeth George – Associate Director, Technology Appraisals

Ms Zoe Garrett – Technical Advisor, Technology Appraisals

Ms Michelle Adhemar – Coordinator, Technology Appraisals

The NICE project team was supported with economic and clinical advice
provided by:

Dr Allan Wailoo – Senior Lecturer in Health Economics, University of Sheffield

Mr Steve Palmer – Senior Research Fellow, University of York

Prof Mark Sculpher – Professor of Health Economics, University of York

Dr Robert Chalmers – Consultant Dermatologist, University of Manchester

The pilot project was supported by a project team at Novartis Pharma AG
comprised of:

Mr Asad Ali – Global Brand Marketing Director, Novartis Pharma AG.

Dr Martin Backhouse – Head of Health Technology Assessment, Novartis
Pharma AG

Dr Sylvie Darrigol – Global Brand Pricing Director, Novartis Pharma AG

DATE: 19 MARCH 2008
                                                                    ITEM 6

Dr Jens Grueger – Head of Global Pricing and Reimbursement, Novartis
Pharma AG

Dr Rafiq Hasan – Head of Opthalmics Division and of Market Access, Novartis
UK Ltd

Mr Edward Hornby – Health Technology Assessment Director, Novartis
Pharma AG

Dr Friedrich Karl Mayer – Global Brand Medical Director, Novartis Pharma AG

Dr Vince Thomas – Senior Health Economics Research Manager, Novartis
Pharma AG

Mr Michael Wonder – Health Technology Assessment Director, Novartis
Pharma AG

Dr Katerina Zakrzewska – Head of Health Technology Appraisal, Novartis UK

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                                                                                                                                                     ITEM 6

Figure 1: Draft process

                                                                       Meeting is                            No face-to-face
                                                                   premature or clearly                         meeting


                       Sponsor submits
                       written meeting
                       request in pre-
                       specified format

    Sponsor contacts                           NICE officer
    NICE to request                            assigned to
      meeting and                             coordinate the     Sponsor submits           NICE provides
        advice                                meeting with the   questions and            written response
                                                 Sponsor         information

                                          NICE agrees face
                                          to face meeting                                                                              Sponsor develops
                                                                    Meeting with NICE                          Sponsor considers         evidence for
                                                                                                                NICE advice and       regulatory approval
                                                                                                               modifies evidence        and pricing and
                                                                                                             plans (as feasible and     reimbursement
                                                                                                                  appropriate)          determinations

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                                                                                                                                          ITEM 6

Figure 2: The stages of the pilot and timeline (See also Appendix A)

                                                                                      FEBRUARY 2008                         FEBRUARY 2008
                                                                                      Evaluation report                        ABPI input

                                                OCTOBER 2007                                      FEBRUARY 2008               MARCH 2008
                                                 Clarification                                      Clarification             To the Board

                                OCTOBER 2007               NOVEMBER 2007       JANUARY 2008
     Request for                Sponsor submits            Meeting with NICE    NICE provides
     meeting and                  questions and                                written response
       advice                 information package

                                                                                                                            Sponsor develops
                                                                                                    Sponsor considers         evidence for
                                                                                                     NICE advice and       regulatory approval
                                                                                                    modifies evidence        and pricing and
                                                                                                  plans (as feasible and     reimbursement
                                                                                                       appropriate)          determinations

DATE: 19 MARCH 2008
                                                                             ITEM 6

2           Evaluation of the process
This section is addressed in seven subsections reflecting they key stages of
the process. Each subsection includes a summary of the process, and
commentary on the appropriateness of the process and consideration of
possible changes.

2.1         Timing of request for advice from NICE
The meeting was initiated by Novartis Pharma AG at the point at which they
had completed a proof of concept study but before the Phase IIb study was
started. Novartis Pharma AG had already approached a number of regulatory
authorities for advice on the Phase II clinical trial design.

NICE Commentary

The point at which the advice request was initiated was appropriate for the
aims of the pilot project, and NICE was able to provide advice on clinical trial
design and the proposed economic analysis.

It may be appropriate to initiate an advice request at a slightly later timing, at
the point which companies have draft Phase III clinical trial protocols which
they consider would meet regulatory requirements. NICE could then
comment on aspects of the trial designs that could be enhanced or suggest
additional research to support an assessment of clinical and cost

Novartis Commentary

The timing of the consultation was good in order to be useful for informing the
clinical development programme generally, not just the specific designs of the
Phase III clinical trials. If consultation was to take place once detailed Phase
III clinical trial protocols were available, the possibility of making substantive
changes would be rather limited. Moreover, the advice provided by NICE has
to be assessed in conjunction with the advice provided by other stakeholders
and from other jurisdictions which takes a long time to assemble. This
suggests that the opportunity for consultation should not be limited to
instances where detailed Phase III clinical trial documentation (protocols,
case-report-forms and statistical analysis plans) are available. Advice given
before Phase II is valuable: for example, hypotheses are often tested in Phase
II to assist with Phase III clinical trial designs and, increasingly, Phase II
clinical trials often continue as Phase III trials. It needs to be considered that it
may be necessary to test clinical trial design elements suggested by NICE
before they are used in Phase III. So any process for seeking advice should
be flexible enough to be help with decisions taken at different points in the
development cycle.

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                                                                            ITEM 6

2.2         Content of the briefing book
The draft process specified that an information package (Appendix B),
hereafter called briefing book, would be sent by Novartis Pharma AG to NICE.
The briefing book included background information on the compound on
which advice is sought, the disease area, current standard treatment and
regulatory guidelines. The briefing book included some information on
ongoing and planned research.

NICE Commentary

The areas included in the briefing book were helpful to the project team and
considered appropriate for the purpose of the pilot project.

The background information provided in the briefing book was comparable to
the type of information which health technology analysts at NICE use during
the scoping of new appraisals. Therefore, as a starting point for considering
an appraisal the proposed structure and content of the briefing book is
appropriate for the existing competencies of the analysts in technology
appraisals. The understanding of the topic was facilitated by familiarity with
the therapeutic area from previous appraisals, and documents available to the
analysts from previous appraisals.

Applying the process to disease areas where no appraisals have previously
been carried out may require more resources either from the manufacturer in
providing information or from the NICE information services and technical

The information provided about the compound was sufficient for the NICE
project team. The clinical trial plans included in the briefing book were not
sufficiently developed to be assessed in the same way that NICE would
generally approach a technology appraisal submission. The NICE project
team were able to manage this, but felt that there was a greater emphasis on
exploring all possible trial design plans rather than assessing, and
commenting on, the preferred trial design plan proposed by Novartis. The
level of detail given in the clinical trial plans meant that it was not possible to
gauge the likely impact of our advice on development cost or time, and to
gauge the feasibility and practicality of the advice given.

Novartis Commentary

The development of the briefing book was not particularly difficult or time
consuming given the experience of the team members in relation to the
disease area of interest and the duration of existence of the team (12
months). The process may be more challenging for newly formed teams or
those with less experience. Novartis was interested in exploring outline
clinical trial designs most relevant to support a number of different
positionings of the compound in the psoriasis treatment sequence. The team
did develop different outline trial designs for that purpose but decided against
including them in the briefing book so as to avoid ‘second guessing’ the
DATE: 19 MARCH 2008
                                                                         ITEM 6

preferences of NICE. Given the properties of NOV001 as we understand
them today, various positionings seem possible depending upon the
competitive landscape at launch and the data/evidence required by NICE to
support them. In that sense the opportunity to discuss scenarios is highly
valuable. The advice received from NICE has already influenced where the
development focus should be and at a time when major development and
investment decisions are being taken. It is encouraging that NICE are keen to
offer advice around detailed Phase III clinical trial documentation although we
believe that this would be very demanding on NICE resources.

2.3         Questions asked
Novartis posed a series of clinical, economic and general questions to NICE,
which broadly reflected areas identified in the draft process document
(Appendix C). Some questions were general in nature (e.g. appropriate
methods for collecting health related quality of life data) and some were
specific to the compound under development (e.g. definitions of severity).

NICE Commentary

Most questions raised were considered to have immediate relevance to the
development of the compound. The questions that Novartis Pharma AG
posed were within the technical scope of the NICE staff involved. Further
clinical advice was sought to clarify issues related to current standard practice
in the UK. Further specialist advice was also sought in relation to the
economics, because some questions specifically related to the economic
modelling in a previous appraisal in the area.

However, some questions focused on more general aspects of NICE process
and methods and the context within NICE operates. It was agreed that these
questions would not be addressed at the face to face meeting or replied to in
the written response. The nature of the questions indicated that it would be
useful to provide a more general understanding of NICE methods and

Novartis Commentary

The inclusion of a small number of general questions reflected different
degrees of familiarity with NICE methods and processes within the Novartis
team. Internally, we would advise teams against including general questions
about how NICE operates.

2.4         Clarification questions from NICE and preparation for
            the meeting
Two weeks after receipt of the briefing book, NICE sent questions to Novartis
Pharma AG to clarify issues raised in the briefing book, and Novartis Pharma

DATE: 19 MARCH 2008
                                                                          ITEM 6

AG responded to the clarification questions two weeks later. The face-to-face
meeting was scheduled at eight weeks after receipt of the briefing book.

It had initially been suggested that a draft briefing book would be submitted,
and following NICE’s clarification the final briefing book would be sent to
NICE. However, the project plan was adapted so that following the clarification
questions from NICE, Novartis Pharma AG only sent responses to those
questions because this was seen as a more efficient way of proceeding.
Additionally, this more closely reflected the clarification stage already in place
for the single technology appraisal process and was considered to meet the
aims of this pilot project. Similar to the single technology appraisal process the
option of a teleconference to discuss the clarification questions was included,
but, in this case, this was considered unnecessary by both parties.

NICE commentary

The timing of submission of the briefing book, clarification and the face-to-face
meeting was appropriate for the aims of the pilot project and enabled sufficient
time for preparation for the face-to-face meeting. Additionally, a clarification
step prior to the face to face meeting was a very useful component of the
process. The responses to our clarification included supplementary questions
from Novartis Pharma AG which focused on specific aspects of the general
questions included in the briefing book. These specific questions helped the
NICE project team to direct their response to these general questions more

Novartis Commentary

The two step approach worked well and receipt of questions for clarification
helped with the preparations for the face to face meeting. We were pleased
that NICE was prepared to address the few additional questions posed during
the clarification step. The two-step process helps in keeping the briefing book
short, and both parties are required to consider issues before a face-to-face

2.5         Face to face meeting
The face-to-face meeting was scheduled to last for 3 hours including a lunch
break. The meeting was divided into clinical and economic sections and
focussed on identification and general discussion around the key issues rather
than response to individual questions. The meeting was structured in this way
because it was felt that some issues were addressed in more than one
question, and the aim was to avoid repetition and overlap. There was no
general introduction to the work of NICE or the appraisals programme during
the meeting, as this was considered unnecessary. The meeting included brief
presentations of the NICE understanding of the current evidence plans and
the main issues followed by an interactive discussion around these issues.
The presentations were delivered by the NICE project team.
DATE: 19 MARCH 2008
                                                                        ITEM 6

NICE Commentary

Having a face-to-face meeting was useful and important to allow for more
understanding of, and insight into, the issues for which Novartis Pharma AG
sought advice. The face to face meeting also allowed us to explain general
points about the context in which NICE makes decisions, and the methods
and processes that NICE adopts.

The draft process suggested that the duration of face-to-face meetings was
flexible, but that they would not normally be expected to last longer than 2
hours. Based on the experience of the pilot project, it is suggested that 2
hours may be insufficient and 3 hours may be a more realistic timeframe. For
some manufacturers or sponsors of technologies with less experience of
NICE’s processes and methods, or where a large proportion of meeting
participants are from early research and development rather than health
technology assessment, it may be useful to provide additional background
information which would extend further the timeframe needed for the meeting.

The presentations were helpful in directing the discussions at the meeting and
ensuring that there was a shared understanding between meeting
participants. NICE staff frequently give presentations of this nature at scoping
workshops or Appraisal Committee meetings. Therefore, the use of
presentations during the face-to-face meeting complements existing methods
of working at NICE and is within the competencies of NICE staff.

The division of the meeting into main clinical and economic issues and
general discussion around these issues worked well for the types of questions
asked in the pilot project.

Novartis Commentary

The meeting was well conducted and kept to time and the approach taken by
NICE, including the presentations, was very useful. The Novartis team felt that
the attendance of the clinical scientific advisor would have been helpful. There
were some issues with the acoustics in the meeting room. Written draft
responses to the questions in advance of the meeting would have been useful
as this would enable the meeting to be focused on specific issues requiring
clarification and more in-depth discussion. The duration of the meeting was
good given the format and nature of the briefing materials. However, if more
detailed briefing materials were to be made available ( e.g. fully developed
Phase III clinical trial documentation) a longer period for discussion would
probably be required. However, once fully developed Phase III clinical trial
documentation has been developed, there are fewer options to discuss and
less chance of making changes. We believe that a valuable service for NICE
to consider would be the development of short disease-specific evidence
development guidance documents similar to those produced by the EMEA.
This would help with the efficiency and focus of scientific advisory meetings.

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                                                                             ITEM 6

2.6         Preparation of response document and further
Following the face to face meeting a document was prepared by NICE
comprising a response to each of the questions posed by Novartis Pharma
AG, and taking into consideration the issues raised at the face to face
meeting. The responses drew on published NICE methods and process
guides, clinical and economic specialist advice and previous appraisals. A
stage of further clarification is included in the draft process, where Novartis
Pharma AG is able to ask for clarifications to the response provided by NICE.

The draft process suggests that NICE will normally issue a written summary of
their responses/advice within 15 working days of the face-to-face meeting.

NICE Commentary

The pilot project provided the written response within 35 working days of the
face to face meeting (excluding Christmas and New Year). 15 working days
was insufficient to enable iteration with external specialists and internal review
and sign-off by senior NICE staff. A period of 25 working days weeks may be
more appropriate.

Novartis Commentary

It seems very reasonable to aim for a period of no more than 25 working days.
Generally, the closer a project is to the start of the Phase III clinical trials, the
shorter the ideal time to obtain a written response will be. Written responses
to the questions in the briefing book in advance of a face-to-face meeting
would also help keep the interval between the meeting and the final response
document short.

2.7         Specialist expertise
For the pilot project additional specialist expertise was identified through the
NICE Decision Support Unit, who were able to draw on members with clinical
and methodological expertise from previous appraisals in this therapeutic

NICE Commentary

The responses to the questions raised in the pilot project were greatly
facilitated by reference to previously undertaken technology appraisals in the
therapeutic area. Using advisors who had worked on previous appraisals in
the area was very helpful, particularly in generating insights into where
weaknesses in the evidence base lay and how these could be most
appropriately overcome/ addressed.

It may not always be possible in all situations to include specialists from
previous appraisals. Additionally, providing advice may require the use of
DATE: 19 MARCH 2008
                                                                           ITEM 6

multiple specialists in a wide range of areas, not all of which will have been
subject to appraisals. NICE will need to consider how to ensure an adequate
availability of specialist advisors and, for example, whether multiple clinical
specialists are required so as to ensure a balance of input and opinion.

Because of the comparatively short period of time between clarifying the
questions and the face-to-face meeting taking place, it was not possible to
have a clinical specialist at the face to face meeting. This was not ideal. It will
be necessary to ensure sufficient time in the planning to enable specialists to
attend the face to face meetings. This is less likely to be an issue where an
initial meeting request is made and a list of questions is provided prior to the
submission of a briefing book. Furthermore, it is conceivable that
manufacturers or sponsors of technologies know far in advance when advice
from NICE will be sought. These factors could be included in the long term
scheduling of advice work at NICE.

Novartis Commentary

As mentioned above, the Novartis team felt that the attendance of the clinical
scientific advisor would have been helpful. It would be very helpful if NICE
were able to produce disease-specific evidence development guidance notes
based on a synopsis of the key evidence issues and weaknesses arising from
its assessments / appraisals. The purpose would be to enhance the efficiency
and focus of the scientific advisory meetings as is the case with advisory
meetings with the EMEA. It would also assist with the preparation of outline
research plans contained in the briefing book.

3           Summary of evaluation criteria
Evaluation criteria were developed in liaison with Novartis. A summary of the
key points is given in the table below.

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                                                                                                                                            ITEM 6

NICE and Novartis evaluation
Evaluation Criteria             NICE Project Team Response                                       Novartis Project Team Response

Resources and                   We were able to identify appropriate resources and               The exercise was integrated with the NOV001 team’s
competencies required           competencies for the pilot project.                              activities and plans so the incremental effort was relatively
                                We will need to develop robust systems to identifying clinical
                                advisors and methods experts that have sufficient                Attendance of the clinical scientific advisor at the meeting
                                methodological expertise and are available at appropriate        would have been useful.

                                The NICE project team was familiar and experienced in the
                                therapeutic area.

Quality and relevance of        The quality and relevance of the briefing materials was          The timing of the meeting was optimal from the point of view
briefing materials              appropriate.                                                     of being able to influence development decision-making and
                                                                                                 thinking about the suitability of Phase III clinical trials for
                                We will have to consider the optimum point in development        non-regulatory purposes.
                                at which briefing materials can be sufficiently
                                comprehensive for NICE to be able to give the appropriate        There may not be a generic “optimum point”. Given the
                                level of detail in response to the questions posed               importance of NICE appraisals for a drug company, one
                                                                                                 should not exclude the possibility of multiple meetings on a
                                It would be useful to develop a template for briefing books or   project, as is normally done with regulatory agencies.
                                a guide to the key elements of the content of a briefing book.

Quality of written and verbal   The quality of written and verbal communications was             The quality of written and verbal communications was
communications                  appropriate, timely and professional.                            appropriate, timely and professional.

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                                                                                                                                                  ITEM 6

Evaluation Criteria               NICE Project Team Response                                         Novartis Project Team Response

Practicality and feasibility of   In general the timelines are feasible and practical. We will       The timelines were practical and feasible.
timelines                         need to ensure that sufficient notice is given to allow clinical
                                  specialists to attend the face to face meeting.

                                  Further time will be required following the meeting to
                                  develop the written advice to allow iteration with clinical and
                                  methodological specialists and sign off

Relevance of questions            The questions were generally relevant to the development of        We agree with the comment by NICE.
                                  NOV001. We may need to consider whether less specific
                                  but nevertheless important questions on context, methods or        The clarification step provided a good opportunity for NICE
                                  processes could be handled prior to the face to face meeting       to highlight any important issues or questions that we may
                                  to help facilitate understanding of NICE.                          have overlooked.

Nature and ease of                The interactions were positive and professional. There was         The interactions were positive and professional. There was
interactions                      a general understanding of mutual benefit of this type of          a general understanding of mutual benefit of this type of
                                  engagement and high degree of openness and cooperation.            engagement and high degree of openness and cooperation.

                                  NICE did not encounter any issues or difficulties interacting      Novartis did not encounter any issues or difficulties
                                  with Novartis Pharma AG in discussion at this stage of the         interacting with NICE in discussion at this stage of the
                                  development process.                                               development process.

Degree of mutual                  The understanding between NICE and Novartis Pharma AG              We agree with the comment by NICE.
understanding                     was sufficient for the provision of advice. The provision of
                                  advice has the potential to improve the mutual
                                  understanding between NICE and pharmaceuticals

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                                                                                                                                              ITEM 6

Evaluation Criteria               NICE Project Team Response                                      Novartis Project Team Response

Enthusiasm to repeat the          The process is both feasible and useful and the interaction     We agree with the comment by NICE. The face-to-face
process                           was stimulating.                                                discussion and written comments were both valuable.

Clarity of advice                 We felt able to provide clear and relevant advice on the        The advice received was clear and valuable.
                                  Phase III development plans. It may be possible to provide
                                  more specific advice if requested at a slightly later stage
                                  when a more comprehensive outline of the Phase III clinical
                                  clinical trial had been developed.

Practicality and feasibility of   There is a balance to be struck between providing advice        Advice that would generate “perfect evidence” might actually
advice                            that would generate perfect evidence and advice that is         be a good starting point for discussions. What is practical
                                  practical and feasible. Further discussions with individual     and feasible would actually be critical input into a fully
                                  companies may be required to identify the appropriate           developed Phase III clinical plan.
                                  balance for individual circumstances. Providing practical and
                                  feasible advice may be easier with a more fully developed       The practically and feasibility of advice given will diminish as
                                  Phase III clinical trial plan.                                  one approaches the start of Phase III clinical trials.

                                                                                                  It will be challenging balancing advice based on actual
                                                                                                  clinical practice today, recommended clinical practice today,
                                                                                                  and how these might differ from the actual situation at the
                                                                                                  time of launch.

Impact of sponsor evidence        N/A                                                             The advice received has been valuable for development
plans/development decision                                                                        decision-making. Together with comments from other
making                                                                                            stakeholders, the advice is already having an impact on our
                                                                                                  evidence plans.

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                                                                                                                                                 ITEM 6

Evaluation Criteria            NICE Project Team Response                                            Novartis Project Team Response

Impact on development cost     N/A                                                                   This is difficult to gauge at this point in time although we do
and times                                                                                            not anticipate a particularly negative effect on either. The
                                                                                                     consolidated advice from different stakeholders is likely to
                                                                                                     make Phase III more expensive. On the otherhand, since
                                                                                                     we are collecting advice early will help minimise delays.

Comparison against             We do not consider that the advice we provided is directly            It is too early to provide a complete assessment of how the
advice/insights gained from    comparable with that of regulatory agencies. Inevitably NICE          advice and insights compare with that received from other
others                         advice will look at factors additional to those required by           jurisdictions and stakeholders. We believe the “overlap
                               regulatory authorities such as evidence of comparative                between the questions” is unavoidable. There is one
                               effectiveness, resource use and cost effectiveness.                   integrated development plan that has to provide answers to
                               However, there was overlap between the questions posed to             various customers.
                               us and those likely to be posed to regulatory agencies. In
                               responding to these overlap questions we were mindful of
                               the general instructions provided by regulatory agencies.
                               Whilst our advice was given in this context we were also
                               able to provide advice on the additional evidence
                               requirements needed for clinical and cost effectiveness

New insights gained            The pilot project has helped us understand the constraints of         New insights were definitely gained. The project has
                               the product development process in relation to what is                demonstrated to us that seeking advice early during Phase
                               practical and feasible to build within the design of the pivotal      II helps the company shape its development plan.
                               Phase III registration trials. There is a difficult trade off to be
                               made between comprehensiveness and timeliness in
                               developing the optimum clinical trial design.

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                                                                                                                                          ITEM 6

Evaluation comments from the external specialists
Question                           Response clinical specialist                                  Response economic specialists
Whether you felt comfortable       From my point of view I would say definitely “yes”. There     The DSU role was to provide specialist support to the
and able to provide advice at      are a lot of issues relating to dermatology trials that are   NICE internal team. In terms of health economics input,
the stage of development of the    generic and I think it is valuable to be able to comment on   this advice had to cover a) knowledge of the York model
compound that Novartis             proposed designs rather than regret the omission of           and b) how the Novartis plans might improve on that
requested?                         important information in the final published trial report,    model. This component of the input was not limited by the
                                   when it is of course too late to do anything.                 stage of development of the Novartis compound – the
                                                                                                 stage of development dictated the types of questions
                                                                                                 Novartis were able to ask for advice on. These tended to
                                                                                                 be more general than would be the case at a later stage of
                                                                                                 development, or were hedged around different alternatives
                                                                                                 particularly in relation to the positioning of NOV001 in the
                                                                                                 treatment sequence. However, this was not a limitation
                                                                                                 given the aim of informing Phase III clinical trial design.
If the contents of the briefing    Yes                                                           In general, Novartis provided sufficient detail within the
book were sufficient for you to                                                                  briefing book given existing knowledge of the disease area
provide advice, particularly the                                                                 and modelling issues gained from the York HTA report.
content areas covered in the                                                                     Many of the details that were not included in the original
advice book and the depth of                                                                     briefing book were dealt with in the responses to the
information, if there were areas                                                                 questions from NICE e.g. details of the planned approach
that you thought were missing                                                                    for follow up of non responders in Phase III.
please let us know
Whether you considered that        They were clear but, by their nature, not necessarily         Several questions related to general NICE policy/guidance
the questions posed were           answerable, even though they could be commented on            and were perhaps not appropriate for this setting given
relevant to the development of                                                                   that they are dealt with in the NICE methods guide e.g. the
the compound, clear and                                                                          threshold ICER, how the institute would view lack of direct
answerable                                                                                       evidence, etc. In addition, the current revisions to the
                                                                                                 NICE methods guide make these more uncertain.

DATE: 19 MARCH 2008
                                                                                                                                          ITEM 6

Question                           Response clinical specialist                                  Response economic specialists
Whether the face-to-face           I am sorry I was unable to make it as I think it would have   No problem
meeting was a useful               been very valuable
mechanism to explore
questions and issues?
Whether the content and lay-out    N/A                                                           The layout did seem a little confrontational by having
of the face-to-face meeting                                                                      Novartis on one side and NICE/DSU on the other.
facilitated discussion of the
Whether you found being            Yes, if asked                                                 The involvement of DSU in the process was appropriate
involved in the process                                                                          but it was not feasible to involve the health economic
interesting and valuable, and if                                                                 experts with the most intimate knowledge of the York
you would be willing to repeat                                                                   model in the discussions due to potential conflicts of
the experience?                                                                                  interest. It would be worth considering how these conflicts
                                                                                                 might be dealt with in the future in order to ensure
                                                                                                 appropriate expertise is available. In this setting, where a
                                                                                                 product is so far from submission to the Institute/NHS
                                                                                                 use/licensing, it could be appropriate to have a different
                                                                                                 approach to dealing with potential conflicts than for other
                                                                                                 NICE activities. This could enable more appropriate
                                                                                                 experts to be involved.

DATE: 19 MARCH 2008
                                                                                                              ITEM 6

Question                           Response clinical specialist       Response economic specialists
If you consider based on your      Very important and sensible move   The process has the potential to be extremely valuable to
clinical and professional                                             both the Institute and sponsors. There are two pieces of
experience that this would be a                                       information that might eventually help in judging whether
valuable activity for NICE to be                                      this has been valuable and it would be useful to get
engaged in?                                                           feedback from Novartis on the first of these in due course:
                                                                              a) the extent to which trial design reflects the
                                                                                  advice given in this pilot
                                                                              b) the impact on committee decision making in
                                                                                  situations where sponsors have received but
                                                                                  not acted on such advice.
                                                                      It could be valuable for the institute to publish general
                                                                      guidance to sponsors considering submissions/trials of
                                                                      products for the treatment of psoriasis (and other disease
                                                                      areas). There are a number of general issues which arose
                                                                      from the York model and consideration of that work by
                                                                      NICE, that were highlighted to Novartis that would be
                                                                      equally valuable to other manufacturers.

DATE: 19 MARCH 2008
                                                                         ITEM 6

4           Conclusions
We have developed a draft process and have demonstrated its
appropriateness in allowing NICE to provide early advice to pharmaceutical
companies on the development of their compounds prior to Phase III clinical
trial development. The competencies required to provide such advice pilot are,
in general, compatible with the competencies of members of the Appraisals
Programme at NICE.

We believe that providing ‘early’ advice is an appropriate activity for NICE. It
helps raise awareness of the nature of the evidence that NICE requires for
cost effectiveness analyses at the point at which pharmaceuticals companies
are best able to address these issues.

NICE will need to work with stakeholders to raise awareness of the most
appropriate point in drug development at which advice should be sought and
to identify the appropriate level of specificity of the advice which
pharmaceuticals companies require.

NICE will need to establish a mechanism to identify and have available
sufficient external specialists to support this activity.

DATE: 19 MARCH 2008
                                                                     ITEM 6

Appendix A: Stages of Pilot project
Early discussions: June 2007

Agreement to run the pilot: August 2007

5 Oct 07 Briefing book received by NICE

19 Oct 07 Clarification questions sent to Novartis

1 Nov 07 Clarification responses received from Novartis:

On 26 Nov 2007 a meeting was held to provide an opportunity to explore the
questions posed by Novartis, and discuss NICE’s initial responses. Attendees
at the meeting were:

Attendees NICE: Carole Longson, Elisabeth George, Zoe Garrett, Michelle
Adhemar, Allan Wailoo, Stephen Palmer, Mark Sculpher

Attendees Novartis: Asad Ali, Martin Backhouse, Sylvie Darrigol, Jens
Grueger, Rafiq Hasan, Edward Hornby, Friedrich Karl Mayer, Vince Thomas,
Michael Wonder, Katerina Zakrzewska

DATE: 19 MARCH 2008
                                                                          ITEM 6

Appendix B: Illustrative content of the information
package provided by sponsor

It is envisaged that the briefing book would not exceed 50 pages.

1. Administrative
            •     Meeting objectives
            •     Proposed meeting agenda
            •     Proposed meeting dates, location and times
            •     Proposed participants from agency
            •     Proposed participants from Company

2. Background: disease area/indication and current treatment practices
The purpose of this section would be to demonstrate clearly the company
understanding of the current management of the condition in which it is
proposed to develop a new product. This understanding needs to be specific
to the country in which the discussions are to take place.

            •     Treatment pathways/sequences and associated outcomes
            •     Treatment guidelines/recommendations
            •     Results of health technology assessments (clinical and
                  economic), appraisal determinations and evidence
                  issues/deficiencies identified
            •     Future outlook for treatment developments

3. New compound: data currently available and proposed evidence
The primary purpose of this section would be to provide clear statements of
the positioning option(s) being considered and the clinical and economic
evidence plan(s) to support it (them).

            •     Name/code of compound, mode of action/pharmacological
                  class, proposed dosing regimen and route of administration
            •     Results of clinical studies performed to date
            •     Proposed therapeutic value proposition (TVP): defined in
                  terms of unmet need, positioning in the treatment sequence,
                  disease severity and patient characteristics
            •     Proposed clinical trial design to support value assessment for
                  the proposed TVP: including study population, comparator,
                  endpoints, duration of observation, statistical properties etc.
            •     Proposed plan for economic evaluation: modeling versus
                  trials, availability of existing models, sources of data,
                  measurement of benefit, budget impact.
DATE: 19 MARCH 2008
                                                                         ITEM 6

            •     Expected outcomes: results of any ‘what-if’ modeling of trial
                  outcomes, cost-effectiveness and budget impact e.g. using
                  ‘shadow’ payer models
            •     Interpretation of clinical trial, Pricing & Reimbursement
                  submission and methods guidelines and their implications for
                  the proposed evidence plans for the new compound

4. Questions / topics for discussion
The questions and topics for discussion would appear in this section. It is
envisaged that they could cover any of the topics listed in Appendix C.

DATE: 19 MARCH 2008
                                                                         ITEM 6

Appendix C: Potential areas for advice
Scientific advice could be given for many issues pertinent to the development
of evidence for post regulatory evaluation bodies. The following illustrates
potential areas:

            •     Interpretation of submission guidelines, methods guidance,
                  previous HTAs and their relevance for the evidence plans for
                  the compound under discussion.
            •     Health system priorities for the disease area and the evidence
                  of unmet needs.
            •     Healthcare provider positioning options for a new product
                  related to unmet needs.
            •     Trial design considerations / preferences to support each
                  proposed position e.g. study population, duration,
                  comparators, endpoint(s) etc.
            •     Economic evaluation design considerations / preferences e.g.
                  form of evaluation and approaches to benefit measurement;
                  modeling vs. trials; relevant trial(s) for economic evaluation;
                  approaches to the generation of QALYs.
            •     Potential for demonstrating cost-effectiveness based on
                  insights from existing models e.g. acceptable range of the
                  cost-effectiveness ratio; EVPI calculations to highlight
                  greatest areas of uncertainty and assist with trial design;
                  Bayesian simulations.
            •     Methods issues e.g. selection of instruments / research to
                  derive QALYs; extrapolation of long-term outcomes; planning
                  for indirect comparisons.

DATE: 19 MARCH 2008

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