EXECUTIVE SUMMARY

  1.  Research and development of treatment for rarer diseases, including cancers, should not be compromised by NICE preventing access to new, innovative medicines through standard appraisal processes. A separate appraisal process should be set up for treatments of rarer diseases, including cancers, to ensure that innovation is encouraged.

  2.  All treatments for rarer diseases, whether designated as "orphan medicines" or not should be appraised through a separate process where the criteria are adjusted to account for clinical efficacy, unmet need, and total cost to the NHS, over and above cost-effectiveness.

  3.  The informal sub-category designated by NICE as "ultra-orphan diseases" should be removed as the facts used to define the need for this sub-category are fundamentally flawed (ie the assumption that most treatments for rarer diseases are not disadvantaged by using standard appraisal criteria is unfounded).

  4.  The time to issue appraisals through NICE has improved but is still not optimal. Patients with rarer diseases, including cancers, are still waiting too long for access to new treatments once they have been shown to be effective in clinical research or have received Marketing Authorisation.

  5.  Improving Outcomes Guidance should be issued by NICE as soon as possible for Rarer Cancers. Guidance should include clear recommendations for commissioners on funding treatments for rarer cancers, whether they have been appraised by NICE through the HTA or will not be appraised.

  6.  Clear guidance should be issued by NICE to commissioners in the interim period before final HTA appraisals are issued where treatments are already available in the NHS. This should also include clear guidance where treatments are already available in the NHS for an unlicenced indication of a medicine on the market that has not yet been appraised. This is common in cancers where initial licenses are usually gained in late stage disease and there is a time delay before Marketing Authorisation of a new indication and again before NICE Guidance. In addition, for rare diseases, guidance is required for commissioners for treatments that will not be reviewed at all by NICE.

  7.  There should be a clear link between guidance from NICE and the work done by the National Specialist Commissioning Advisory Group (NSCAG) and Regional PCT Specialist Commissioning Groups to ensure that treatments for rarer diseases, including cancers, are funded equitably across the UK, based on patient need as opposed to where a patient happens to live.

NICE'S EVALUATION PROCESS DISADVANTAGES PATIENTS WITH RARER CANCERS

  1.  Thousands of diseases and conditions exist that affect so few people that without special support it would be unlikely that any company would find it financially viable to develop a treatment or cure for them. Legislation on orphan medicinal products, Regulation (EC) No 141/2000 of the European Parliament and of the Council and Commission Regulation (EC) No 847/2000 entered into force in January 2000 and April 2000 respectively. This introduced a Community procedure for the designation of medicinal products as orphan medicinal products and incentives for their development and placement on the market. The European Commission was concerned about the equality of access to orphan medicines in the Member countries, and commissioned a survey (conducted by Alcimed) in 2004[120]. They perceived that there was a lack of homogeneity in:

—  Time between obtaining the Marketing Authorisation and commercialisation of these drugs.

—  Funding (reimbursement) of these products by each Member State.

  The European Agency for the Evaluation of Medicinal Products (EMEA), which has set up the Committee for Orphan Medicinal Products (COMP) to implement and monitor the regulations, published a chart commenting on individual country access to orphan medicines, which labelled the UK access as "slow" compared to other member states, and non-orphan medicines[121] (Appendix 1).

  2.  NICE claim that their current Health Technology Assessment (HTA) process is appropriate for the majority of treatments for rarer diseases, and that only a small percentage of these diseases (defined by NICE as an informal sub-category called ultra-orphan diseases) require a different process. However, evidence compiled by the Office of Health Economics (OHE) shows that appraisals of treatments for rarer diseases, including cancers, are statistically more likely to be rejected by NICE than standard treatments.

	Recommended	Restricted Use Only	Not Approved
16 EMEA/FDA* designated orphan medicines reviewed	3 (19%)	9 (56%)	4 (25%)
116 non-designated medicines	53 (46%)	56 (48%)	7 (6%)

  The distribution of the decisions made for orphan and non-designated medicines are statistically different (p=0.013). [122]In addition, there are six orphan designated medicines currently under review, with five not approved in the preliminary assessment released. Four of these appraisals have been appealed leading to further delaying patient access to highly effective medicines.

  3.  In November 2004, the NICE Citizen's Council considered and reported on access for patients to orphan medicines. NICE then made recommendations on the appraisal of orphan medicines in March 2006. [123]NICE suggested that there would only be problems with the appraisal of medicines for "very rare diseases" (defined as an informal sub-category by NICE as "ultra orphan drugs") having a prevalence of less than 1 in 50,000, and proposed to develop a process to evaluate these through an "Ultra-Orphan Drugs Evaluation Committee". The data provided by NICE upon which part of this decision was made is fundamentally flawed. For example:

—  Cancer medicines were included in the NICE analysis which are not for a rare disease (irinotecan, oxaliplatin, capecitabine and tegafur uracil for metastatic colorectal cancer).

—  Cancer medicines were included which NICE claimed are classified by the EMEA as orphan designated but are not on the register (topotecan, gemcitabine, temozolomide).

—  Cancer medicines were included which NICE claimed are classified by the FDA as orphan designated but are not on the register (topotecan, gemicitabine, irinotecan, oxaliplatin, capecitabine, tegafur uracil).

—  There are many other examples which are not specific to cancer. The analysis by the OHE shows that medicines for rare diseases, including cancers, are less likely to be approved by NICE than standard medicines, and therefore a separate appraisal process should be considered for these cases which are being disadvantaged. The rationale for a separate appraisal process for "ultra orphan diseases" is based on a flawed assessment and therefore should not be recommended as an informal sub-category.

  4.  It is important that all medicines for rarer diseases, whether they have applied for EMEA orphan designation or not, are assessed by a different set of criteria to medicines for common diseases. For example, Velcade, which is currently being assessed for multiple myeloma, is not designated as an orphan medicine as the company did not apply for this status, but the disease itself can be categorised as rare. Applying the same cost-effectiveness criteria will lead to most orphan medicines being denied to patients due to the high price. The price of orphan medicines may appear expensive when compared to other therapies. This needs to be put into context in terms of research and development costs. For example:

—  Clinical development costs are still high, even with fewer patients, as patients are more difficult to recruit and a wider number of centres may be needed.

—  Costs of research, pharmacovigilance, medical information and manufacturing are generally at least as high as for other medicines as there are less economies of scale.

—  There are small patient numbers, which make it more difficult for companies to earn a return on investment.

    In order to continue to encourage research and development into treatment of rarer diseases, the criteria for approval of innovative treatments should adjusted to account for clinical efficacy, unmet need, and total cost to the NHS, over and above cost-effectiveness. This would meet with the requirements of the European Commission to encourage access to medicines for rarer diseases.

THE SPEED OF PUBLISHING GUIDANCE CAN BE IMPROVED

  5.  The time to issue appraisals through NICE has improved, particularly with the development of the Single Technology Assessment (STA) process, but is still not optimal. Patients with rarer diseases, including cancers, are still waiting too long for access to new treatments once they have been shown to be effective in clinical research or have received Marketing Authorisation. For example:

—  Velcade for multiple myeloma was initially granted Marketing Authorisation in April 2004, and received positive opinion for the expanded indication in March 2005, and the NICE guidance on the expanded authorisation has still not been issued. In the meantime, patients are dependent on decisions made by local PCTs based on budgets only which has led to inequality of access across the UK.

  6.  In the UK, high per-patient costs for medicines for rarer diseases, including cancers, can produce budget issues for local providers. This can be dealt with through specialist commissioning or top-sliced funding which works well through the National Specialist Commissioning Agency (NSCAG) for very rare diseases where a centralised budget is maintained. However, there is no guidance for the majority of treatments of rare diseases, which are decided at PCT level through local commissioning processes leading to inequality of access for patients.

  Improving Outcomes Guidance should be issued by NICE as soon as possible for Rarer Cancers. Guidance should include clear recommendations for commissioners on funding treatments for rarer cancers, whether they have been appraised by NICE through the HTA or will not be appraised.

  Clear guidance should be also issued by NICE to commissioners in the interim period before final HTA appraisals are issued where treatments are already available in the NHS. This should also include clear guidance where treatments are already available in the NHS for an unlicenced indication of a medicine on the market that has not yet been appraised. This is common in cancers where initial licenses are usually gained in late stage disease and there is a time delay before Marketing Authorisation of a new indication (eg Herceptin) and again before NICE Guidance. In addition, for rare diseases, guidance is required for commissioners for treatments that may not be reviewed at all by NICE. (for example Sutent for Gastro Intestinal Stromal Tumors and late stage kidney disease.

Penny Wilson-Webb

Rarer Cancers Forum

March 2007

121   http://ec.europa.eu/health/ph_threats/non_com/docs/EMEA_chart_en.pdf Back

122   OHE Working paper by the OHE : "HTA for orphan drugs: A review of the Issues and of NICE and SMC Decisions". Back

123   http://www.nice.org.uk/page.aspx?o=296850 Back