1. NICE follows an open, structured and widely publicised process for all its technology appraisals. The process was developed following consultation and is the process we are following for the beta interferon/glatiramer review. The details of the process and the dates for all appraisals are published in the technology appraisal section of the NICE web site (www.nice.org.uk).
2. NOTE: NICE has not issued any guidance to the NHS on the use of either beta interferon or glatiramer in Multiple Sclerosis.
3. The Department of Health (DH) has reminded the NHS in England that existing guidance to the NHS on drug treatments for multiple sclerosis (MS) remains in place pending publication the Institute's guidance. This guidance is contained in DH documents EL(95)97 and HSC 1999/176 both of which can be accessed from the DH website at www.doh.gov.uk/multiplesclerosisdrugsguidance.
4. The DH guidance asks NHS organisations to develop and implement local arrangements to manage the entry of such drugs into the NHS, in consultation with other key interests, and in particular, to initiate and continue prescribing of beta-interferon through hospitals. HSC 1999/176 asks NHS bodies to continue with these local arrangements until the NICE guidance becomes available.
What's happened so far in the NICE appraisal?
5. The Department of Health (DH) and the National Assembly for Wales (NAW) asked NICE to appraise beta interferon/glatiramer for MS on the 6 August 1999.
6. NICE wrote to interested parties (manufacturers, national patient/carer groups and professional bodies) on the same day, asking that any submissions they wished to make should be made by 1 November 1999.
7. Following the consultation between the manufacturers and the DH / NAW the Institute agreed an extension to the submission date until February 2000.
8. During this time NICE commissioned a review of the published evidence of the clinical and cost effectiveness of these medicines from the Northern and Yorkshire Drug and Therapeutic Centre.
9. In February 2000 NICE received submissions from the manufacturers, patient/carer groups and the professional bodies involved (the 'consultees'). Some of these submissions contained both published and unpublished information, and some of this material was classed as 'commercial in confidence.
10. The submissions from the manufacturers were assessed and combined with the review of the published literature into an Assessment Report by the Northern and Yorkshire team.
11. The Assessment Report, and the original submissions from patient/carer organisations and the professional groups, together with the manufacturers' submissions were made available to the Appraisal Committee as an Evaluation report.
12. The first meeting of the Appraisal Committee (membership published in the technology appraisal section of the NICE web site) for beta interferon /glatiramer in MS was held on the 30 May 2000. In addition to the written submissions the committee also had 'experts for the day' at its meeting. They represented a patient/carer organisation and health professionals with experience in this area. These individuals were nominated by their own organisations. The minutes of this meeting are published in the technology appraisal section of the NICE web site.
13. Following the committee meeting, the Appraisal Committee then prepared its provisional views on the evidence - known as a PAD (Provisional Appraisal Determination). The PAD is only sent for consultation to the groups identified as consultees.
14. NICE asked for comments on the PAD from the consultees. This means that they circulated the PAD to the patient/carer groups, professional groups and the manufacturers involved and also the Department of Health and the National Assembly for Wales.
Note: The organisations that represent pharmaceutical and medical device manufacturers had previously informed the Institute that a PAD, (which may differ from the final guidance) could have a significant impact on their share price and on patients' confidence and asked that it and the remaining appraisal documentation be treated as confidential material. Therefore for appraisals that commenced before February 2001 the appraisal documents are circulated to consultees as strictly confidential material. The beta interferon / glatiramer appraisal is therefore subject to this confidentiality arrangement.
15. The Appraisal Committee met again on the 27 July 2000 to consider its provisional determination in the light of the feedback received from the consultees. The minutes of this meeting are published in the technology appraisal section of the NICE web site. At this meeting the Appraisal Committee made their final determination (Final Appraisal Determination - FAD) and submitted it to NICE.
Note: At this point, the appraisal for glatiramer in the treatment of MS was put on hold until the manufacturer received its UK Marketing Authorisation (license for sale in the UK) from the licensing authority.
16. NICE received the FAD and as part of the process of developing the final guidance circulated it to the consultees (including patient/carer groups, professional groups and the manufacturers) for them to decide if they wished to appeal.
17. Eight appeals were received against the draft guidance (FAD) for beta interferon . An independent appeal panel considered the appeals on the 22 and 23 September 2000.
18. Their decision was published on 8 November 2000. Parts of the Appeal were rejected and parts were upheld. Full details of the appeal are published on the technology appraisal section of the NICE web site. A summary is attached to this document.
19. NICE asked the Appraisal Committee to reconsider the original evidence in the light of the Appeal Panel's decision. NICE also asked the committee to look at a new economic model submitted, by a manufacturer (Schering), as commercial in confidence material at the appeal hearing.
20. The Appraisal Committee met to reconsider the evidence on 13 December 2000. The committee considered the original evidence in light of the appeal panel's decisions. In addition they considered the new evidence and heard again from the groups that represent people with MS and their carers. The groups were the MS Society and the MS Research Trust and their representatives included people with MS. The minutes of this meeting are published in the technology appraisal section of the NICE web site.
Note: In the meantime, glatiramer was granted its UK license. The appraisal of this technology has recommenced and the Appraisal Committee considered this technology alongside beta interferon at their meeting on 13 December 2000.
21. During this appraisal the Committee has considered evidence that included economic models supplied by manufacturers and independent researchers. The models are used to inform their judgement on the cost effectiveness of these medicines.
22. At the meeting on December 13 2000 a review of the economic models was presented which raised a number of concerns (refer to the published minutes). The Committee gave careful consideration to each of these concerns and then reflected generally on the evidence relating to cost effectiveness for both medicines. During this discussion, it was noted that the economic models for both medicines had been challenged on methodological grounds and had doubts cast on the reasonableness of the assumptions they had used.
23. Having considered the evidence and comments made by the people with MS and the patient organisations and having reflected on the analysis of the existing and new economic modelling, the Committee considered the merits of preparing an appraisal determination for either beta interferon or glatiramer.
Note: Serious reservations were expressed about the economic models. Given the importance of the advice which the Committee was being asked to provide it was suggested that if the flaws, which had been identified in the models presented so far, were capable (in whole or part) of being rectified, there would be benefit in doing so. If there were no opportunity to undertake any further work on the economic modelling, the Committee would need to prepare an appraisal determination.
24. On the basis of the information in front of it the Committee asked their Chairman to prepare an appraisal determination which reflected that, on the basis of the evidence presented, the Committee did not consider that either the beta interferon or glatiramer had demonstrated that their use in the NHS in England and Wales could be considered to be cost effective. The Chair agreed to do so and indicated that he would advise the Institute of the Committee's serious reservations over the economic modelling.
25. The evidence relating to the cost effectiveness of these medicines is critically important in this appraisal. Therefore the Institute carefully considered the Appraisal Committee's concerns and decided to commission further economic modelling on the beta interferon and glatiramer acetate. As soon as this decision had been made NICE informed the consultees and after the pre-agreed time they notified the public on the 22 December 2000.
26. It was known that the commissioning, construction and evaluation of the new modelling would take around 5 months and therefore the timeline for the appraisal process for both medicines was extended. Although the Institute accepted this would delay production of the final guidance, it considered that this action was in the best interests of people with MS and those who care for them. It is of the utmost importance that the Institute's guidance is both evidence-based and seen to be fair by those effected by it.
27. In January 2001 the Institute wrote to the consultees on 3 issues:
Consulting on its proposals for the process for commissioning the development of the new economic modelling and identifying where stakeholders could become involved (the draft process document is attached to press release 2001/04 and published on the Institute's web site - use the search engine within the site and search on 'multiple sclerosis')
Asking if manufacturers were prepared
to release data they may have, including patient specific data from clinical
trials likely to be of use to the modellers. Data would be made available
through the Institute and treated in accordance with the Institute's standard
arrangements for handling data supplied by consultees.
Requesting nominations of individuals or organisations that consultees' consider have the capability and experience to undertake the economic modelling.
The Institute asked for responses by the 9 Feb. 2001.
28. The Institute's Research and Development Committee met in February 2001 to consider the consultation feedback and agree the process and timetable for commissioning the new economic model. Following this meeting the Institute also advertised for health economic modellers.
29. The Institute appointed a consortium based on the Sheffield School of Health and Related Research (ScHARR) and the Department of Mathematics and Statistics at the University of Sheffield working with colleagues from Oxford, City, Newcastle, Nottingham and York Universities to undertake the work.
30. The Institute, the consortium and the consultees met on 30 March 2001. The meeting was constructive and provided an opportunity for a useful exchange of views on the approach being taken by the Institute to the final phase of the appraisal. Work began to construct the new economic model and the Institute asked the manufacturers to provide relevant clinical trial data to the consortium. They considered this request and some data was provided to the consortium.
31. A further meeting with consultees was held on 8 June 2001 and the consultees were given the opportunity to examine the new model in detail.
What stage is the process at?
32. The Appraisal Committee met on the 26 July 2001 to consider the new economic modelling.
33. After this meeting the Appraisal Committee produced a Provisional Appraisal Determination (PAD). This was sent to the consultees (including patient/carer organistaions, professional bodies and manufacturers) on 4 August 2001.
34. The Institute has not yet issued guidance on the use of beta interferon or glatiramer for MS and will not do so until November 2001 at the earliest. Because of speculation in the media surrounding the content of the PAD, the Chairman on the recommendation of two of the Institute's Executive Directors, has taken the decision, in line with Institute policy, to publish the PAD on the nice website (www.nice.org.uk).
Note: The Provisional Appraisal Determination is a consultation document, NOT guidance to the NHS. NICE has not issued any guidance on the use of beta interferon or glatiramer.
35. The consultation period closes on 7 September 2001.
Note: Those wishing to make comments on the Provisional Appraisal Determination should do so through the designated consultees. Details of the consultees can be found below. Although the Institute will respond to any correspondence, comments from individuals cannot be included in the formal consultation.
What happens next?
36. The Appraisal Committee will meet again on the 25 September 2001 to consider the comments from the consultees. After which they will produce a Final Appraisal Determination (FAD) on which the consultees may appeal. If the Institute receives no appeals, guidance will be issued as soon as possible after the close of appeal. The earliest likely date for the issue of guidance is November 2001.
37. If any appeals are received these will be heard by an Appeal Panel.
Consultees in this appraisal are:
1. The facility for consultees to make an appeal is part of the Institute's process for developing its guidance for the NHS. The manufacturers and the nationally based patient and professional organisations that are invited to make a submission to an appraisal are provided with the opportunity to make an appeal.
2. The three grounds upon which an appeal can be heard:
The Institute has failed to act fairly
and in accordance with the Appraisal procedure set out in the Interim Guidance
for Manufacturers and Sponsors.
The Institute has prepared guidance that is perverse in the light of the evidence submitted.
The Institute has exceeded its powers.
3. There were 8 appellants and each appealed a number of points during the hearing. Some of these points were rejected and some were upheld (see below). In addition during the hearing Biogen and Schering asked the Appeal Panel to receive some new data that had not been placed before the Appraisal Committee. They requested that the Appeal Panel submit this new data back to the Appraisal Committee for consideration. Appeals were lodged by the following:
In summary the Appeal Panel was satisfied regarding the following points and rejected the appeals in these areas:
a. No specific threshold (cut off point) for cost effectiveness had been set by either NICE or the Secretary of State / National Assembly for Wales.
b. The evidence of all the clinical benefits of beta interferons in the broadest sense, including the impact on the quality of life and estimates of associated costs had been considered and assessed by the Appraisal Committee.
c. It was not perverse for the Guidance to state that a major reduction in the cost of beta interferons would be needed before they could be considered cost effective.
d. The Appeal Panel did not accept that the Appraisal Committee should specify the cost at which the beta interferons would become cost effective as the cost of the products is only one element in their cost effectiveness
e. All the economic models and data submitted, including the Biogen model, (recently published by Kendrick and Johnson and referred to in the national press), had been considered by the Appraisal Committee.
f. The Appeal Panel accepted the Committee's conclusion that the Biogen model (recently published by Kendrick and Johnson) was flawed and decided that it was not unreasonable or unfair to reject this economic model.
g. The Appraisal Committee made their judgement by considering the clinical effectiveness, cost effectiveness and the wider implications for the NHS.
h. The Appraisal Committee did consider non-NHS costs.
i. The Appraisal Committee did consider the broad balance of benefits and costs.
j. The Appeal Panel was satisfied that the Appraisal Committee did not reach its conclusions on a consideration of cost effectiveness alone.
k. The Appeal Panel was satisfied that the Appraisal Committee, in referring to management strategies for MS in the Guidance, had wished to underline the importance of providing adequate therapy and rehabilitation services for patients with MS.
l. The Appeal Panel was satisfied that the Appraisal Committee had considered the patient survey conducted by the MS Research Trust
m. The Appeal Panel believed that an appreciation of this need and of the seriousness of the symptoms of multiple sclerosis for patients is implicit in the recommendations for further research, and review of the Guidance.
n. The Appraisal process had followed the Institute's Interim Guidance for manufacturers.
o. The Appraisal Committee was aware of the National Guidance on NHS Priorities, and was not required to seek further specific guidance from the Secretary of State.
p. The Appraisal Committee's awareness of the need to encourage innovation is evident in the Guidance.
q. The Appraisal Committee did demonstrate transparency in the process.
r. The Appeal Panel rejected the assertion that the Institute had not followed an evidence-based approach, and recognised that the Appraisal Committee had not only considered all the evidence submitted, but had also assessed the limitations of the models used within the submissions received from consultees.
s. The Appeal Panel was satisfied that as data submitted by Schering and Serono Pharmaceuticals Limited was submitted to the Institute as confidential, it was therefore legitimate that the Institute did not disclose this to the other consultees.
t. The Appeal Panel did not accept the appellants' assertion that the sole basis for the Appraisal Committee's conclusion was the calculation of QALYs for beta interferons. Moreover, the Panel did not accept that the Appraisal Committee was required to consider the effects of the PPRS (Prescription Pricing Regulation Scheme).
u. The Appeal Panel rejected the assertion that undue emphasis was placed on the side effects of the beta interferons.
v. It is an inherent part of the appraisal process that changes may occur between the PAD and FAD stages as a result of the consultation exercise. The Appraisal Committee is not obliged to provide reasons for any changes.
In summary the Appeal panel upheld the appeal on the following points:
a. The Institute wrote to the MS Society in January 2000 inviting the Society to send a representative to the Appraisal Committee meeting on 30 May. Due to an administrative error the letter mistakenly asked for a clinical expert when it should have asked for a patient advocate, the Society responded by nominating its Medical Director. Mr. Cardy (MS Society) wrote to NICE on the 25 May 2000 asking why the MS Society had not been asked to send a patient advocate. Realizing the error, Andrew Dillon responded on the same day, apologising and inviting Mr. Cardy, the Chief Executive, to attend the meeting or to send a senior colleague in his place. In the event, four representatives from the MS Society attended the meeting on 30 May.
b. The Institute accepted that there had been an administrative error and although this error was discovered in time to allow a patient advocate nominated by the MS Society to attend the Appraisal Committee's meeting, the short notice restricted the MS Society's choice as to whom to nominate as the patient advocate and did not give the patient advocate adequate time to prepare. The Panel concluded that the Appraisal Committee's understanding of the perspective of patients might have been adversely affected as a result.
The Appeal Panel was satisfied that the Appraisal Committee had considered the patient survey conducted by the MS Research Trust, however the appeal panel concluded that the decision by the Institute to regard the MS Research Trust as a professional rather than a patient group had a similar effect.
b. The Appeal Panel concluded that because general information on the cost effectiveness of other treatments was widely available it was not necessary to set out direct cost comparisons in the Guidance. Nevertheless, the Panel concluded that the Appraisal Committee had not explained the basis of its conclusion that the beta interferons are not cost effective, when compared with alternative uses of current resources and therefore the reasoning in this part of the proposed Guidance was not sufficiently transparent.
c. The Appeal Panel accepted the Appraisal Committee's conclusion that the Kendrick and Johnson model (Biogen model) was flawed; however, the reasoning given in the Guidance for rejecting the model is misleading.
d. The Appeal Panel questioned whether the issues relating to the long-term benefits of treatment with beta interferons had been fully considered by the Appraisal Committee.
e. Whilst the Appeal Panel recognised that the decision to allow patients already on treatment with interferon beta to continue, and those on the placebo arm of a clinical trial to be treated with beta interferons after the trial, was made on compassionate grounds, it considered this to be insufficient justification for selecting these patient groups over others.
f. The Appeal Panel noted that the European Transparency Directive requires the Institute to ensure that its Guidance contains a full statement of the reasons supporting its decisions. The Appeal Panel felt that the explanation in the Guidance as to why the beta interferons are not cost-effective when compared with alternative uses of NHS resources, did not fully comply with this requirement.
g. The Guidance gives insufficient weight to the significance of MRI data, in particular evidence of correlation with disease activity in early relapsing remitting MS.
h. Although it was clear from the wording recommending further clinical trials in the Guidance that the Appraisal Committee was simply making a recommendation, the Appeal Panel did not consider that this was the case with regard to the audit section of the guidance. The audit section appeared to be more directive and the panel was concerned that this may lead some Health Authorities to believe that they had no discretion in the matter.
4. During the hearing Biogen and Schering asked the Appeal Panel to receive some new data that was not placed before the Appraisal Committee. They requested that the Appeal Panel submit the new data back to the Appraisal Committee for consideration. Having upheld parts of the appeals, the Appeal Panel would expect this appraisal to be referred back to the Appraisal Committee for reconsideration. The Appraisal Committee should consider these new data at that time.