1.  EXECUTIVE SUMMARY

  1.1  Johnson & Johnson is the world's most broadly based manufacturer in health care. With significant presence in the pharmaceutical, medical devices and diagnostics markets, Johnson & Johnson has potentially the most diversified experience of NICE. With an interest in ~19% of published Technology Appraisals, five more in progress, our interest includes appraisals of pharmaceuticals, medical devices and surgical procedures. We also have an interest in a similar proportion of Clinical Guidelines, including the management of urinary incontinence, surgical site infections, diabetes, bipolar disorder and smoking cessation.

  1.2  Summary of Issues: We recognise that NICE has made moves to reduce the time it takes to produce and release its guidance to the NHS.

—  We are concerned however that in reducing the development time of its guidance, stakeholder involvement and consultation has been eroded, resulting in inconsistencies and inaccuracies in guidance, (Terms of Reference (ToR) 1, 3, 4)

—  This has resulted in guidance being more frequently challenged, through an appeals system considered weighted heavily against the appellants (ToR 5)

—  We believe that Technology Appraisals are being rolled in to Clinical and Public Health Guidelines too quickly, without due consideration given to the potential implications of the context or wording of the new recommendations or the associated changes in funding status (ToR 3,7)

—  The Office of Fair Trading (OFT) report on the Pharmaceutical Price Regulation Scheme (PPRS) advocates that, for prescription medicines, NICE should adopt new powers in that they will have responsibility for price setting of products as an integral part of the health technology assessments that they conduct today. This document lays out some fundamental flaws in the activities of NICE in the way it operates today. We believe that it would be wholly inappropriate for NICE to adopt such new powers in the light of the evidence and observations outlined below.

  1.3  Recommendations to the HSC Review

—  All stakeholders to be given the opportunity to comment on the Evidence Review Group (ERG) report prior to the first Appraisal Committee meeting for an STA review

—  Manufacturers to be given the opportunity to address the Appraisal Committee in order to answer questions relating to the evidence submission

—  The mandatory funding direction of Technology Appraisals to be retained when they are incorporated in to Clinical and Public Health Guidelines, or they should remain "stand-alone" guidance

—  Re-introduction of an open call for evidence during the development of Clinical Guidelines.

—  Two stakeholder consultation periods to be reinstated in to the development of clinical guidelines

—  A review of the NICE Technology Appraisal appeals process and the introduction of a fair and truly independent appeals system.

—  NICE decision-making to be inclusive beyond cost/QALY, with transparency in explaining which factors drive the decision

2.  STAKEHOLDER INVOLVEMENT IN DEVELOPING NICE GUIDANCE

  2.1  Reduction in stakeholder consultation during process.

  2.2  The drive to speed up the publication of NICE guidance through the STA process has introduced inequities into the NICE technology appraisal process. First, the opportunity for stakeholders to comment on the output of the independent academic group has been removed. Under the Multiple Technology Appraisal (MTA) process, all stakeholders had the opportunity to comment on the Assessment Group's interpretation of the evidence prior to the 1st Appraisal Committee meeting. In the new STA process, that opportunity has been removed in an effort to shorten development times. This has removed a critical opportunity for stakeholders to comment on one of the key pieces of evidence the Committee considers in their deliberations. The absence of this critical step undermines many stakeholders' perceptions in the inclusive and consultative nature of the STA process for developing guidance.(ToR 3; Recommendation 1)

  2.3  Inequity of voice at the Committee meeting.

  2.4  A continuing failing of the NICE technology appraisal process is the lack of representation of the manufacturer at the Appraisal Committee meeting to answer questions or address issues that are identified during review, and this is more acute in the new STA process. Other key stakeholder groups are represented, but the one group, who are certain to hold the majority to the evidence base for technologies reviewed under the STA process, the manufacturers, continue to be excluded.

  2.5  It seems perverse that at a time when NICE is seeking to streamline its processes, that issues arising through the ERG or from the Committee on the day of the meeting cannot be clarified in real time by the presence of the manufacturer to address specific issues. The attendance of manufacturer representatives could be a significant positive step forward to reducing the development time for NICE guidance, for example, by reducing the number of occasions on which the Committee fails to reach a preliminary decision at its first meeting.(ToR 3; Rec. 2)

  2.6  Reduction in consultation in Clinical Guidelines Process

  2.7  In April 2006, following consultation under the banner of "improving the development process", NICE announced changes to the Clinical Guideline (CG) programme. Previously, NICE asked stakeholders to provide any evidence considered to be relevant to the development of the Clinical Guideline. Following the April 2006 amendments, NICE now asks the relevant National Collaborating Centre (NCC) to carry out the initial search for evidence and follow up with a "focused call" on a series of specific clinical questions. This raises the possibility of important information being missed during guideline development and we recommend that the original open call for evidence at the start of guideline development be reinstated.

2.8  Second, and possibly the most significant change to the development process was the reduction from 2 four-week consultation phases to 1 eight-week consultation period. This has a significant impact on how stakeholders can comment. It removes the iterative nature of the process, leaving stakeholders only one opportunity to provide feedback. There is therefore no opportunity to clarify misunderstandings of feedback, or opportunity to challenge changes to recommendations which, as a stakeholder, you may have approved in the original draft. There is also no right of appeal.

  2.9  This reduction in consultation has negatively impacted our ability to enter into meaningful dialogue with NICE during the development of two recent guidelines; Urinary Incontinence (CG40) and Heavy Menstrual Bleeding (CG44), discussed below as they involve the incorporation of Technology Appraisals (TA) into Clinical Guidelines.

  2.10  Furthermore, the decision by NICE to halt the development of the Clinical Guideline on the management of Surgical Site Infections in 2006 on the grounds that it may not have had appropriate stakeholder input also suggests that the Clinical Guideline Programme is attempting too much, too fast, without appropriate consultation or validation.(ToR 3, 7; Rec. 4, 5)

3.  INCORPORATION OF TECHNOLOGY APPRAISALS INTO CLINICAL AND PUBLIC HEALTH GUIDELINES

  3.1  The process of incorporating Technology Appraisals into Clinical or Public Health Guidelines appears to be ill thought-out, and raises a number of issues. We have experience of five such appraisals, which have either been included in guidelines, or are about to be, and each raises concerns. These can be categorised as 1) mandatory funding issues, and 2) impact on future technology development through the inconsistent application of evidence needs.

  3.2  Mandatory Funding of Technology Appraisals

  3.3  This has been identified as an issue for:

—  TA46: Surgery for Morbid Obesity into CG43: Obesity Guideline.

—  TA43: Atypical antipsychotics for schizophrenia into the update of CG1: Schizophrenia guideline (in progress).

—  TA39: NRT & bupropion for Smoking cessation into Public Health guideline on Smoking cessation (in progress).

  3.4  In each of these cases, the movement of the TA guidance already has or will impact patient access to the specific technology. This is perverse, as access to the original technology was clearly considered of high enough priority by the Department of Health to justify the original Technology Appraisal. Specific details with examples of each issue are presented in Annex 1

  3.5  The funding uncertainties for obesity surgery, atypical antipsychotics, and NRT for smoking cessation are clearly perverse, especially when each is addressing a high priority health issue for the NHS. These uncertainties therefore only serve to undermine confidence in the processes operating within NICE, and the ability of it to develop joined up guidance for the NHS.(ToR 3, 7; Rec. 3)

  3.6  Inconsistent Evidence Requirements

  3.7  This has been identified as an issue for:

—  TA78: Second Generation Ablation Techniques combined into CG44: Heavy Menstrual Bleeding guideline.

—  TA56: Tension free vaginal tape for stress urinary incontinence combined into CG40: Urinary Incontinence guideline.

  3.8  The publication of Clinical Guideline CG44—Heavy Menstrual Bleeding (HMB) has raised concerns within our organisation regarding the guideline development process and some of the objectives driving it. This is reinforced by previous recommendations in CG40—Urinary Incontinence.

  3.9  Our concerns are that the evidence based recommendations in the Technology Appraisals have been reduced to procurement recommendations, explicitly and implicitly, which are not evidence based. They have "genericised" the interventions without referral to appropriate evidence. We have examples of NHS Trusts interpreting the recommendations in this manner. Specific details are presented in Annex 2.

  3.10  These clinical guidelines serve to question the need to invest in evidence generation and justification in these areas. Whilst the Technology Appraisal recognises that each intervention has to prove its way before gaining a positive recommendation, the clinical guideline process appears to assume that all technologies are the same, and implies that evidence for one is evidence for all. Internally, questions are being asked as to the value of our randomised controlled clinical trials, as the cheaper, fast follower competitor offerings that are winning NHS tenders have no substantive evidence to support their devices.

  3.11  Both of these guidelines were published under the new process, with only one stakeholder consultation period. The recommendations of concern were not included as explicitly in the consultation drafts. Apart from in their own right being of concern regarding "dumbing down" appraisal recommendations and the potential impact of future research, they also serve as an example that further stakeholder consultation (such as a second consultation period under the old process), may have mitigated some of these issues. (ToR 3; Rec. 4, 5).

4.  RELIANCE ON "COST PER QALY" THRESHOLD IN TECHNOLOGY APPRAISALS

  4.1  NICE decisions give undue weight to cost per QALY estimates derived through computer simulation modelling. We acknowledge that cost-effectiveness is an important consideration in a NICE appraisal. However, it is not an appropriate basis on which to solely make a decision, which is increasingly the case in NICE decisions.

  4.2  An over-reliance on cost per QALY based decision-making is flawed for several reasons:

  4.3  Economic modelling provides an indicative direction of travel rather than a definitive answer.

  4.4  Cost-effectiveness ratios derived through computer simulation modelling are almost always estimates of what the future cost-effectiveness of the technology might be, rather than robust primary evidence. Despite the uncertainty inherent in simulation models, the answers they produce dominate the decision at the expense of other important factors such as the innovative nature of the technology, the level of unmet need and the disease under consideration.

  4.5  The burden of proof also appears to have shifted in the move from MTA to STA, where the onus is now on the manufacturer to prove cost-effectiveness before a product is considered for use. However, as appraisals are being undertaken earlier, there is less real-life experience to underpin regulatory trials, and the uncertainty in the cost-effectiveness evaluation is therefore greater, leading to the Appraisal Committee apparently being more cautious. As NICE moves to undertake reviews at an earlier stage, it also needs to recognise that less data will be available, and be more pragmatic in its decision making process, possibly with re-reviews scheduled on the delivery of new evidence.

  4.6  QALYs fail to consider the full range of factors which are of importance to patients and prescribers.

  4.7  Whilst NICE states that it considers a range of factors in the decision-making process, the weight given to these other factors is unclear and they are rarely if ever explained in the Final Appraisal Determination (FAD). Examples of issues which the QALY cannot readily capture, but which are critically important from a societal perspective, include the degree of unmet need, the innovative nature of the technology, and the severity of the underlying condition. A classical example of this is the Velcade (bortezomib) appraisal for multiple myeloma.

  4.8  QALY analyses provide a disincentive for companies to invest in areas with the highest levels of unmet need

  4.9  In conditions where few new treatments have been launched, new entrants into a class must compare against generic treatments which have been on the market for many years, rather than against other branded products. These are often the areas where innovation is most valued, but where achieving acceptable cost per QALYs can be most challenging. As an example, in the recent appraisal of VELCADE the main comparator (and only licensed alternative) was the generic drug dexamathasone. This situation arose because there are very few options for this patient group due to historic low levels of research and innovation. Dexamethasone costs around £80 per year making it almost impossible to achieve an acceptable cost per QALY, despite highly significant and impressive survival advantages with VELCADE being demonstrated in clinical trials. The £80 cost of dexamethasone is the cost of manufacture and distribution without any R&D element factored into the cost, as the patent has expired. Such comparisons present an impossibly unfair hurdle for comparative cost effectiveness assessments.

  4.10  The scope of £/QALY evaluations excludes societal costs

  4.11  The scope of costs considered in determining the cost per QALY for technologies is restricted to those incurred by the NHS & PSS. This excludes significant costs that can be incurred by patients and carers. An example of this is the review of Alzheimer's disease, where full-time institutional care costs funded by the patient were excluded from the calculation, resulting in an evaluation that inflated the cost per QALY for Alzheimer's drugs. The recommendation that resulted was based on this inflated QALY result, meaning that it was more cost effective to the NHS to let patients progress and be admitted in to institutional care earlier (as a proportion fund themselves), rather than use acetyl-cholinesterase inhibitors and delay the progression to full-time care. The transcript from the appraisal appeal hearing (13 July 2006, p221-229) elaborates this point. See OFT report on the PPRS, p81, Section 5.67.

  4.12  This over-reliance on cost per QALY thresholds may in part explain why English cancer patients are denied access to many important and life extending cancer treatments such as VELCADE, which are becoming standard of care across Europe. We believe that if NICE's decisions are to become more acceptable to the general public, it is imperative that the obsession with predictive computer modelling of potential future benefits be balanced with a more considered view on the wider societal and clinical benefits of the treatment. (ToR 3, Rec. 7)

5.  NICE APPEALS PROCESS

  5.1  Johnson & Johnson welcomes the fact that NICE's Technology Appraisal process includes an appeals procedure which allows stakeholders an opportunity to challenge the decisions made by the Appraisal Committee. However, we have fundamental concerns with the manner in which the current appeals process is administered.

  5.2  Most importantly, we believe that an appeals process should be truly independent. The current appeal process is administered by NICE itself and it has a vested interest in upholding the decisions that are made by its own appraisal committee. Specifically:

—  The appeal panel is always chaired by one of NICE's directors, often the Chairman of the Institute itself.

—  Of the five places on the appeal panel, at least two are always directors of NICE.

—  NICE controls membership of the appeals panel.

—  NICE has drawn up the grounds for appeal and makes a decision on the admissibility of appeal points before the hearing.

—  NICE administers the process and issues the appeal determination.

  5.3  In the two years since appeals have been held in public, it is striking that none has resulted in a change to section 1 of the guidance documents. The lack of balance in the appeals process was demonstrated in the Appeal lodged by Janssen-Cilag Ltd against the FAD for Attention Deficit Hyperactivity Disorder (ADHD). In this appraisal, the academic assessment group had failed to include the only high quality, randomised controlled trial comparing Concerta XL with atomoxetine in their evidence appraisal. Despite this omission, the appeal was rejected on the basis that the omission of this evidence did not change the overall decision. Given that the foundation of NICE decision-making should be based on high quality clinical evidence, this decision is nonsensical. Johnson & Johnson would strongly support a review of and the establishment of a fair and truly independent appeals system. (ToR 5; Rec. 6)

6.  CONFLICTS OF INTEREST

  6.1.  We recognise that NICE has published a new code of practice for declaring and dealing with conflicts of interests (November 2006). This document covers all stakeholders in the NICE process, from employees, manufacturers, advisory committees, and academics involved in NICE projects. We are particularly pleased to see the specific statement 3.5; "A personal non-pecuniary interest in a topic under consideration might include, but is not limited to: i) a clear opinion, reached as the conclusion of a research project, about the clinical and/or cost effectiveness of an intervention under review".

  6.2  We continue to be concerned over the involvement of the Liverpool Assessment Group in the ongoing review of coronary Stents, given the position communicated in their research paper published in Heart, 2005, before the current appraisal had started. They continue to be involved, developing new analyses for NICE at this time. Their latest analysis is due early April '07.  Our initial letter of concern to NICE, dated January 2006 in attached as Annex 3.[87]

  6.3  The continued involvement of this review group in the appraisal continues to undermine our and other stakeholders' confidence in the Institutes processes (ToR 2) 6.4.  6.5.  6.6.

Johnson & Johnson

March 2007

1.  EXAMPLES OF ISSUES ENCOUNTERED WITH MANDATORY FUNDING OF TECHNOLOGY APPRAISALS WHEN MOVING TO CLINICAL AND PUBLIC HEALTH GUIDELINES

  1.1  Surgery for morbid obesity

  1.2  The original guidance was issued in 2002. However it was exempt from the 3 month funding directive, as it required a degree of service re-configuration to implement the guidance. This however has been interpreted by the majority of the NHS (purchasers and providers) as an exemption to "ever implement". Uptake is currently well below that predicted by NICE. If the guidance had remained as a Technology Appraisal, when reviewed as part of a Core Standard there would at least be a drive to change current clinical practice. However, under the clinical guideline, the immediate need to develop a strategy for implementation is again deferred, and any negative impact on a Trust/PCT's assessment is removed, as in effect it has been shifted from a core standard to a developmental standard. An independent review carried out for NICE reported that 90% of all obesity surgery is focused in just 12 Trusts. Furthermore, the self-pay market in the UK significantly out-strips NHS activity, demonstrating that the clinical need is present, and it is patients who are losing out through NHS inactivity, supported by the change in NICE guidance.

  1.3  Atypical Antipsychotics

  1.4  NICE has decided to subsume the Technology Appraisal guidance for atypical antipsychotics (TA43) into the update on the guideline for Schizophrenia (CG1, in development). In communicating this decision, NICE made the following policy statement "At the time that the guideline updating the appraisal is issued, the existing appraisal guidance will be withdrawn, and from this point, the statutory obligation to provide funding for the technology will no longer apply. The NHS should have had ample time to fund the original guidance, and the case for a formal directive is substantially reduced." This statement is still to be found on the NICE website at: http://guidance.nice.org.uk/page.aspx?o=267029

  1.5  This decision means that patients' access to cost-effective medicines in this vulnerable patient group could be put at risk due to an unfortunate change in funding status of the guidance.

  1.6  Smoking Cessation

  1.7  Our confidence in the ability of NICE to run joined-up processes is further undermined when we consider what will happen to the existing Technology Appraisal on smoking cessation therapies (TA39). The guidance has been widely implemented, but has a resource impact on the NHS, not just in terms of prescribing, but also in additional support services. Much of the uptake has been underpinned by the mandatory nature of the guidance, in that PCTs have been bound to provide funding where physicians deem the intervention to be clinically appropriate for their patients, in line with funding directions issued by the DH to the NHS. We now have evidence of a PCT withdrawing these services for a period of time in an effort to help balance the end of year finances.

  1.8.  This may well be an isolated case, however we have been informed by NICE that the mandatory funding nature of the guidance will be lost once the new Public Health Guidelines on smoking cessation are published, as the recommendations contained within TA39 will be incorporated into and updated with the new guidance. PCTs will therefore have an effective "loop-hole" within which they will be able to legitimately withdraw such services without scrutiny from the HealthCare Commission or any other body, and, again, only patients will suffer. This could undermine the significant efforts to increase access to NRT made by the Government over recent years.

  1.9.  Furthermore, the Technology Appraisal programme is in the process of developing guidance on the use of varenicline which if approved, would attract mandatory funding. We could therefore be in a position where local funding is withdrawn from the proven technology NRT, and diverted to varenicline, if budgets are stretched. This may sound far-fetched, however this concern appears to also be held by both people within NICE and specialists within the smoking cessation field, giving some credence to the fears.

2.  EXAMPLES OF INCONSISTENT EVIDENCE REQUIREMENTS BETWEEN TECHNOLOGY APPRAISALS AND CLINICAL GUIDELINES

  2.1  In CG44 we are concerned by the recommendation:

1.5.7  Second-generation ablation techniques should be used where no structural or histological abnormality is present. The second-generation techniques recommended for consideration are as follows. Providers should ensure that when purchasing any of these that they buy the least expensive available option.

  2.2  The inclusion of what amounts to purchasing or procurement advice in the guideline is surprising, especially given that it reads as if it applies only to the acquisition cost of the device, and not to the total cost of delivery of the surgical pathway for the patient. Furthermore, by not discussing outcomes, it assumes that the patient outcomes are at best equivalent and at worst irrelevant: it fails to recognise that the patient's desired outcome should be a key consideration, such as either reduced menstrual bleeding or complete cessation of menstrual bleeding, as recognised in the original Technology Appraisal (TA78). It is also surprising that a focus on cost has been allowed in the final recommendations, whilst recommendations regarding patient safety and alternative operative options in surgical delivery have been omitted. For example, the comment recognising some options can be delivered via local anaesthetic rather than exposing patients to a potentially more risky general anaesthetic, present (and supported by us) in the draft, was removed from the final recommendations. Finally, there is also no recognition of the body of evidence (or lack of) that supports each technology now covered by the recommendation. Some of the cheaper devices available (and clearly more likely to be purchased under the above recommendation), have no RCT evidence to support their safety or efficacy, a hurdle that was required by the first three devices to market to achieve a positive outcome in TA78. This is therefore a perverse incentive to future research efforts, as the Clinical Guideline is, in effect, rewarding follow-on technologies on the basis of cheapness, and not on the basis of demonstrable patient safety or effectiveness.

  2.3  Similarly, with the guideline on urinary incontinence, CG40, a recommendation is that sub-urethral slings should be used, without recognising that different slings have different properties, and very different evidence bases to support their usage. An Interventional Procedures guidance was previously retracted on the evidence that one particular device had a very high failure rate. The recommendations now in the clinical guideline however imply that long term follow up evidence is available for all retropubic mid-urethral tape procedures using a "bottom-up" approach, a generalisation that is simply not true. Indeed, there is more evidence for some transobturator foramen approach devices than some retropubic mid-urethral tapes.

  2.4  We recognise that the Institute may be seeking to increase competition in the market through these guidelines, and that is an understandable objective where it is appropriate to do so. However, the manner and context within which this appears to have been undertaken in CG44 & CG40 will serve only to further reduce the incentive for evidence generation. The procurement recommendation may well have been well intentioned, but it has directly resulted in NHS Trusts now using it specifically to assist negotiating acquisition prices.