EXECUTIVE SUMMARY

  On behalf of Merck Serono we wish to provide our experiences of working with the National Institute for Health and Clinical Excellence (NICE). We wish to draw your attention to a number of issues that we have observed from our work with NICE and communication with the NHS:

—  Applicability of NICE guidance to the NHS; When NICE state that a particular technology is "not recommended" this guidance generally covers routine practice and does not state "exceptional case criteria". In the absence of NICE guidance in this area, implementation in the NHS is inconsistent and proves to be time consuming for both patients and physicians.

—  Relevance of NICE guidance once it is published; Innovative medications often collect a broader set of information in the period after marketing authorisation has been received. On many occasions given the timing of appraisal initiation, length of the appraisal process and the short time frame in which new data is considered, often new data can make published NICE guidance out of date.

—  Independence of NICE appeals; In appeals to NICE, the appeal committee contains members of NICE which does not make it an independent and neutral environment for assessment.

—  Grounds of NICE appeals; The grounds for appeal are based on procedure rather than a difference of scientific opinion. The second ground for appeal is, "the decision is perverse in light of the evidence submitted". When decision making is based upon uncertain economic estimates, "reasonability" is a much more appropriate assessment.

—  Public confidence in NICE; Public confidence in NICE has been questioned due to recent decisions denying patients access to the only licensed treatment available for their condition for, "cost effectiveness" reasons. This is the case with regards to bortezomib for multiple myeloma, pemetrexed disodium for malignant pleural mesothelioma, and cetuximab for the third line treatment of metastatic colorectal cancer.

—  Inconsistent NHS implementation of guidance; A number of factors contribute to this, the most important being poor NHS financial management, clinical resistance, and lack of sanctions against poor implementation.

RECOMMENDATIONS

—  When NICE issue a guidance which states that a technology should not be used routinely in the NHS, it should define, "non routine use", then a set of, "exceptional case" circumstances to be included in guidance. This will ensure consistency of use and decrease the current postcode prescribing which occurs through "exceptional case" decisions at the present. In addition, this will reduce the number of patients being disadvantaged and aid clarity as to when, "non-routine use" of technology should or should not be used.

—  When important new information becomes available within the timeframe of a NICE MTA appraisal then it should be considered by NICE. This will reduce the number of decisions being made with the use of old, out of date information.

—  The constitution of the NICE appeal panel should be reassessed to increase impartiality and independence of such decisions. The Appeal panel itself should be more independent with a decreased role for members of NICE.

—  The second grounds for a NICE appeal are limited to the assessment of "perversity" of the decision. This criteria should include the possibility to discuss differences in opinion and interpretation of scientific evidence and should be assessed on grounds of "reasonability", and not "perversity". This wording should be revised to read, "the decision is unreasonable in the light of the evidence submitted".

—  When NICE is reviewing the only licensed treatment available for a disease state then cost effectiveness should not be the overruling driver of the decision making process. In these circumstances other factors such as whether the condition is life-threatening or whether there are any other direct treatment alternatives should be given equal consideration.

—  A review of NICE guidance implementation should be carried out with recommendations that result in clear action, but in particular, that NICE approved medicines are automatically included in local formularies.

INTRODUCTION

  1.  Merck Serono understands and values the objectives of NICE to improve the quality of care in the UK NHS. We are sure, if the system is modified, that the institute can be of even greater benefit to patients and the NHS.

APPLICABILITY OF NICE GUIDANCE TO THE NHS

The institute's evaluation process—and whether particular groups are being disadvantaged in the process

  2.  Guidance issued by NICE falls into a set list of definitions: recommended, not recommended or for use in clinical trials. A guidance of, "not recommended" can be most often found in recent decisions for oncology in particular, and is dissimilar to guidance issued in mental health, neurology and dermatology where guidance may provide criteria for which patients may receive a particular treatment. Absence of "non-routine use" and, "exceptional case criteria" is a major issue that impacts upon how NICE recommendations are implemented. Each hospital has its own procedure and definitions for what may be termed an "exceptional case", and this can vary from symptomatology, patient personal circumstance and the disease knowledge of the hospital appeal committee.

  3.  For a patient to receive treatment under the, "exceptional case" procedure, it is dependant upon their particular physician, and the physician's motivation/time to fight for the particular treatment. At present, the time taken for a physician to forgo normal practice to prepare and attend an "exceptional case" meeting is significant and negates the efficiencies that NICE are trying to promote. Additionally, the strain on the patient is significant, by focusing their energies on fighting for treatment, when they should be using their energy to fight their illness. To add a further variable, the success of a patient being determined as an "exceptional case" and granted treatment can be increased through having legal representation.

  4.  This failure to define "exceptional case" criteria within NICE guidance only increases inequalities and promotes post code prescribing. It is relatively easy for the NHS to implement positive and negative criteria for a broad group of patients, however the way the NHS defines "exceptional case criteria" is variable and depends upon a number of factors. To make guidance more applicable and aid implementation, NICE should, as standard, include "exceptional case criteria" in their guidance to increase NHS efficiency and promote common standards across the country. This will also promote greater efficiencies for physicians in prescribing and guide them further, in defining when a patient may be determined as an "exceptional case" and reduce the number of patients being disadvantaged.

RELEVANCE OF NICE GUIDANCE ONCE IT IS PUBLISHED

Why NICE's decisions are being challenged more frequently

  5.  Innovative medications often collect a broader set of information in the period after marketing authorisation has been received. This can mean that NICE guidance can be irrelevant or out of date once it is published. This is found mostly in the Multiple Technology Assessment (MTA), because of the length of such an appraisal and the short window of time in which new data is considered. When important information becomes available within the timeframe of a NICE MTA appraisal then it should be considered by NICE to reduce the number of decisions being made with the use of old, out of date information.

  6.  This whole issue falls within the inflexibility of the NICE process for assessment of data. NICE will only consider evidence for a technology appraisal within a given timeframe. However if the technology appraisal takes 18 months (typical for an MTA) from first manufacturer submission to guidance granted then there is a very strong likelihood that further key evidence may become available within this timeframe, but outside of the technical assessment group's window of data assessment.

  7.  In the case of oncology this is especially a concern since new data is constantly being published, and in some cases the new evidence can significantly inform decision making, and health economic calculations. Within such health economic calculations there is often a high degree of uncertainty for the final result. This is caused by uncertain variables used due to the lack of information available to make more considered judgement. In such cases it is not uncommon for a manufacturer to have a different opinion to NICE with regards to a crucial element of the calculation which significantly impacts on decision making. In many cases NICE make uncertain areas certain and will only consider their opinion of the data. A major problem arises when new data does become available which proves that NICE were wrong in their assessment, but this data becomes available outside of the data assessment window. In this circumstance such data will not be considered by NICE which means that decision making is flawed and published guidance is incorrect.

  8.  It is clear that NICE cannot constantly reassess the public domain for new information, however failure to show flexibility in the procedure to take into account significant new evidence during the appraisal leads to guidance which is unreasonable in light of the total information available in the public domain. As standard, such information will not be heard at NICE appeal hearings even if it proves that one party was correct in making an assumption of data.

  9.  An example of such a decision can be found in technology appraisal 118 for bevacizumab and cetuximab in the treatment of metastatic colorectal cancer. NICE announced it would assess these drugs in April 2005 with a closing date for evidence submission by August 2005. A technical assessment group (ScHAAR) were commissioned to organise evidence and report to NICE by February 2006 and a closing date for all submissions was set for the end of April 2006. In August 2006 draft guidance (Appraisal Consultation Document (ACD)) was published giving a negative decision for both drugs, stating that guidance would not be reviewed before May 2009. An appeal for cetuximab was heard in November 2006 but no new evidence was allowed to be presented at this meeting. The NICE appeal committee rejected this appeal at the end of January 2007 and guidance was published.

  10.  In September 2006 new evidence became available for cetuximab which validated the use of particular assumptions within its economic modelling. However this information could not be assessed by NICE. Therefore a total of 21 months elapsed with no possibility of any new evidence being considered for nearly 18 months. This new evidence could mean that drugs originally given negative guidance might be given a positive guidance.

  11.  With the creation of the new Single Technology Appraisal (STA) process this problem should be minimised, however such appraisals are not as rapid as those performed by the Scottish Medicines Consortium (SMC) in which an appraisal is complete in four months from submission of a manufacturer dossier. This greatly decreases the possibility that new vital information may become available during the appraisal and alter the context of guidance issued.

  12.  In addition, SMC allow resubmission based upon new data becoming available. Such a flexible system promotes the use of the best medicine recommended based on the best available information. How does this compare to the NICE STA process? An STA can be significantly longer than an SMC submission. In the experience of Merck Serono it has been greater than eight months. In addition, NICE only re-reviews its guidance every four years.

INDEPENDENCE OF NICE APPEALS

The appeal system

  13.  In appeals to NICE there are concerns over the independence of the constitution of the Appeal Panels. NICE's procedures envisage that two or three members of the five person Appeal Panel (including the Chairman of the Panel) will be members of NICE's own Board (one of those three persons may instead be an NHS representative). The constitution of such an appeal panel may consequently have an inherent interest in supporting the decision previously reached by NICE's Appraisal Committee. Hence, this may not make a NICE appeal an independent and neutral environment for re-assessment of the technology appraisal.

  14.  The constitution of the NICE appeal panel should be reassessed to increase impartiality and independence of such decisions. The Appeal panel itself should be more independent with a decreased role for members of NICE.

GROUNDS OF NICE APPEALS

The appeal system

  15.  The stated grounds for a NICE appeal are based on the procedure of the technology assessment rather than a difference of scientific opinion. The second ground for appeal is, "the decision is perverse in light of the evidence submitted". This criteria is very stringent and presents a very high bar to prove the, "perversity" of a decision made. NICE procedures explain that it is theoretically possible for two Appraisal Committees to be given the same facts, yet to reach different conclusions, without either being perverse. This greatly reduces the possibility for any successful challenge of an Appraisal Committee conclusion. While a finding may be termed as incorrect, this may still not be termed as perverse.

  16.  This particular issue is highlighted in the assessment of health economic information when, in the absence of compelling data, informed assumptions must be made to overcome uncertainty and complement harder scientific information. Hence, in many areas information utilised may not be perverse but termed as, "unreasonable". A test of "reasonability" is a much more appropriate assessment of such data. With the use of such wording this allows differences in opinion and interpretation of scientific evidence to be discussed.

  17.  The "perversity", ground of appeal also prevents the discussion of new data which may greatly inform and potentially change decisions made. As previously mentioned, in health economic modelling, uncertainty is handled by making assumptions. However if evidence becomes available which greatly invalidates an assumption, this should be considered. The present system of decision making and review is one in which there is no opportunity to have relevant material and up to date facts considered in any appeal. A more robust appeal process would allow consideration of the best available evidence.

  18.  There is a fear that such an appeal system could lead to a "never ending" process. NICE should consider appeals in other legal fields such as immigration or housing where these bodies continue to function and do not suffer from a "never ending" process by considering new data.

PUBLIC CONFIDENCE IN NICE

Whether public confidence in NICE is waning and if so why

  19.  Recently public confidence in NICE has been questioned due to decisions denying patients access to the only licensed treatment available for their condition for "cost effectiveness" reasons. This is the case with regards to bortezomib for multiple myeloma, pemetrexed disodium for malignant pleural mesothelioma, and cetuximab for the third line treatment of metastatic colorectal cancer.

  20.  The objectives of NICE to improve the quality of care are clearly defined in, "Social Value Judgements: Principles for the development of NICE guidance".[94] This report clearly states; "social value judgements relate to society rather than basic or clinical science; they take account the ethical principles, preferences, culture and aspirations that should underpin the nature and the extent of care provided by the NHS"94.

  21.  In a Health Technology Assessment, NICE assess the, "cost-effectiveness", of a technology by means of quality adjusted life years (QALYs) and relationship to cost. The QALY is a simple concept which takes into account quantity and quality of life, however this method is limited and does not capture the broad objective of the aforementioned NICE report or the added value of new innovative treatments. In addition the Cost/QALY calculation does not take into account the actual treatment setting such as at the end of life in which quantity and quality of life is already limited, but nonetheless valuable.

  22.  In an area such as oncology, if an expensive new treatment allows a terminal cancer patient to live three months longer, then it seems intuitively unfair that this should be ascribed the same low value-for-money rating (ie cost per-QALY threshold) as a treatment that gives three additional months of life to those with a non-life threatening disease. For patients with a poor prognosis, the absolute level of life-saved will likely be relatively low. The concept of ascribing higher cost-effectiveness thresholds to patients with lower life-expectancy is consistent with the "rule of rescue", which applies greater value to therapies for patients with poor prognosis and were there are few available alternatives which are life prolonging. Given that in the UK, cancer survival is an established national health priority (NHS Cancer Plan) it is reasonable to accept a higher threshold of cost effectiveness for this patient group.

  23.  When NICE is reviewing the only licensed treatment available for a disease state then cost effectiveness should not be the overruling driver of the decision making process. In these circumstances other factors such as whether the condition is life-threatening or whether there are any other direct treatment alternatives should be given equal consideration.

INCONSISTENT NHS IMPLEMENTATION OF GUIDANCE

The method in which NICE recommendations are implemented—both in technology appraisals and clinical guidance—and the reasons why guidance is acted upon or not

  24.  NHS implementation of NICE guidance is inconsistent across the UK. A number of factors contribute to this, the most important being poor NHS financial management, clinical resistance, and lack of sanctions against poor implementation. This is despite considerable efforts to improve this situation from the NICE Implementation team.

  25.  If such guidance from NICE is not followed, one could question the significant resources required to fulfil its function and meet its requirements. Implementation will be improved by stronger sanctions and in particular automatic inclusion of NICE approved medicines on local formularies.

Stephen J Ralston

Manager of Health Economics and Health Technology Assessment

Merck Serono

March 2007