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The Official News & Technical Journal Of The International Society For Pharmacoeconomics And Outcomes Research
ECONOMIC EVALUATION

Pharmacoeconomics and Market Access in Europe: Case Studies in Scotland and The Netherlands

Keith Tolley MSc, Director, Market Access Unit Mapi Values, Macclesfield, UK, and Maarten Postma, University of Groningen, Groningen, The Netherlands


(This paper is based on the Workshop that the authors organised during the last European Conference of ISPOR in Florence (6-8 November 2005). Maarten Postma is a member of the Dutch ”Commissie Farmaceutische Hulp” (CFH), Keith Tolley is an economic assessor for the New Drugs Committee of the Scottish Medicines Consortium (SMC). The CFH advises on the reimbursement of new drugs, whilst the SMC issues guidance on the use of new drugs and indications to the National Health Service in Scotland. The views expressed in this article are the responsibility of the authors and not do necessarily represent the opinions of the CFH or NDC/SMC.)

Introduction
Pharmacoeconomics has become established as a valuable aid to drug reimbursement, pricing and market access decisions for new drugs in many European countries. However, to be useful for such purposes, the methods used should be robust and the results of pharmacoeconomic evaluations timely. To aid robustness, guidelines for the conduct of pharmacoeconomic studies have been produced in numerous countries - many of these guidelines have been summarised and are available on the ISPOR website [1]. Timeliness for market access decisions means that pharmacoeconomic evidence is required at or around launch of a new product.

 In this article we provide an overview of two established European agencies that use pharmacoeconomics as part of a system of rapid technology appraisal to aid reimbursement and market access decisions for new drugs at launch: the Scottish Medicines Consortium (SMC) and the Netherlands ”Commissie Farmaceutische Hulp” (Committee for Pharmaceutical Help; CFH).

Scottish Medicines Consortium
The Scottish Medicines Consortium came into being in 2002. It provides guidance and recommendations to Health Boards in Scotland on the use of all new pharmaceuticals, covering new chemical entities and new indications for existing licensed drugs (launched since 2002). The SMC appraisal represents a two-stage process.

The first stage involves a company submission to the New Drugs Committee (NDC) of the SMC of the clinical and health economic data supporting the new product/indication. This submission is reviewed in detail by an NDC review team consisting of a clinical assessor, an economic assessor and a lead assessor (the latter is the only one of the three who is a full member of the NDC). Final draft guidance on the clinical and costeffectiveness of the product, and a recommendation on use (which can be one of accepted for use, accepted for restricted use, or not accepted) is drawn up by the NDC. The NDC stage involves only consideration of the clinical and cost-effectiveness evidence supporting the drug.

The second stage of the process involves consideration of the draft guidance by the SMC Committee including a response by the manufacturer (who are sent the draft guidance after the NDC meeting), but also taking into account other factors such as budget impact, level of unmet need or innovativeness of the drug, precedence regarding earlier decisions for drugs in the same class/patient group, and patient advocacy submissions. The final guidance is issued by the SMC and posted on the SMC website about a month later.

It is not the intention here to go into detail about the process involved in an SMC submission - this is adequately covered on the SMC website at: www.scottishmedicines.org.uk. However, a number of observations can be made about the NDC and SMC process and the methods/ approaches adopted for pharmacoeconomic analysis.

The SMC review at least provides a test bed for the health economic analyses, and the first indication of the strength of the economic case for the product.

Firstly, the whole process takes about 4 months to complete from receipt of manufacturer submission to final guidance being issued on the SMC website (assuming no appeal). This rapidity has the advantages of timeliness associated with delivery of guidance to the health boards in Scotland soon after the introduction of a new drug, and allows manufacturers with positive recommendations rapid access to the market (especially as manufacturers can submit prior to launch and plan to receive guidance straight after launch). The downsides are the limitations of clinical data at launch for pharmacoeconomic analysis producing high uncertainty in the cost-effectiveness results, a greater risk of false negatives or false positives due to speed of appraisal, and the possibility that cost-effectiveness of a product can change over time i.e. generally improve, for example due to dose reductions over time, or new clinical/economic evidence. Although not currently undertaken, this latter concern could be somewhat addressed via the use of a formal review period, whereby the original recommendation is reviewed by the SMC say 2-3 years later if there are reasons to do so (e.g. new evidence).

Secondly, whilst the process is rapid, it does not mean it lacks robustness in the technical requirements for the pharmacoeconomic submission. The guidelines for the pharmacoeconomic submission are available on the SMC website and are based on (but do not completely follow) NICE methodological guidance [2]. The preference is for net cost per QALY data for the new product (although other forms of economic evaluation are accepted if appropriate), with choice of comparator(s) representing the drugs most likely to be displaced in Scotland. If, as typically occurs, there is a lack of head to head data against such comparators this has to be overcome through the use of indirect comparisons involving systematic review, meta analysis or other forms of evidence synthesis. In addition, the time horizon has to be appropriately specified and, if lifetime, adequately modelled from the shorter term data. Resource utilisation and utility data should be robustly collected and sufficiently relevant to the Scotland/UK context, and a full and transparent sensitivity analysis should be conducted. Adherence to good decision analytic/ modelling practice (e.g. in the use of Markov models) is also very important. There should be a clear link between the clinical evidence submitted and the economic evidence. Currently, NDC requirements are (arguably) not as stringent as NICE, for example, probabilistic sensitivity analysis is not mandatory and there is not a set reference case that needs to be followed. However, unlike NICE, if no economic case is submitted the product will get an automatic negative recommendation.

Thirdly, the onus is placed on the submitting manufacturer to be convincing and transparent in the pharmacoeconomic case presented. Rejection of the economic case is generally on one of two grounds:

a) The submission is transparent and pharmacoeconomic submission of good quality, but the incremental cost per QALY is considered too high (i.e. typically above £25-35,000 per QALY, although no formal threshold applies). Not surprisingly, this reason for rejection is relatively uncommon, and

b) There are flaws or a lack of transparency in one or more key aspects of the pharmacoeconomic submission, such that the assessor cannot determine the actual cost-effectiveness of the product. Most rejections are on this ground (i.e. the economic case has not been demonstrated).

Hence, it is important for the manufacturer to make sure they are using sufficiently robust pharmacoeconomic methods (but not over-complex) and following SMC guidelines. There is likely to be sympathy to limitations in data faced by manufacturers, but this should not preclude efforts to produce a sufficiently robust pharmacoeconomic model for the submission. Planning early can help overcome some of these problems.

Figure 1 presents the recommendations issued by the SMC over the period Jan-October 2004. The impact of the two stage process can be clearly seen with just less than 70% of drugs reviewed over this period receiving a positive recommendation, but only 42% being accepted on the clinical and economic evidence presented at the NDC stage. As mentioned other factors come into play at SMC stage, but also some of the changed decisions may have come about as a result of improved clarity in the pharmacoeconomic case on the part of the manufacturer.

 

It is not currently clear what impact SMC guidance is having on clinical practice even in Scotland (although this is being investigated in a research project due to report in 2007), let alone outside of Scotland. However, anecdotally it appears to be having an impact. As the UK is often the first to launch market, the SMC is likely to be the first HTA type body a manufacturer of a new drug will have to submit to. Hence, the SMC review at least provides a test bed for the health economic analyses, and the first indication of the strength of the economic case for the product. This means it is important for the manufacturer to be prepared with a robust economic model, especially with the advent of the NICE single technology appraisal programme likely to raise the stakes in the UK and beyond.

Commissie Farmaceutische Hulp (CFH), The Netherlands
From January 1st 2005 in the Netherlands, a favourable cost-effectiveness result has become a further criterion for reimbursement, after quality (good laboratory practices), safety, and effectiveness have been established. In particular, manufacturers of new drugs who claim added “therapeutic value” for their product must, in addition to a therapeutic file, submit an economic file to the Council for Health Insurance (”College voor Zorgverzekeringen”; CvZ). These drugs aim for a listing on section 1B of the Dutch reference pricing system (”Geneesmiddelen VergoedingsSyteem; GVS). If newly registered drugs are deemed comparable to existing drugs, they are clustered in section 1A and a fixed maximum price applies. An economic submission is not required for such drugs, which are typically ”me-too's” and generics. However, to attain 1B listing an economic submission is required - which should consist of a cost-effectiveness or cost-utility analysis with preferred outcomes in net costs per life-year gained or QALY gained, but not a costminimisation analysis. The ”Commissie Farmaceutische Hulp” (CFH), advises CvZ on reimbursement issues and pharmacoeconomists have participated on the CFH for several years now.

 The “cost-effectiveness” 4th hurdle that was erected in The Netherlands in 2005 was not a sudden event. For some years previously an arrangement had been in place whereby manufacturers were free to add an economic file to their reimbursement claim. However, this was not mandatory. Nonetheless, in many cases manufacturers took the opportunity to submit a pharmacoeconomic case. For example, economic files were submitted prior to 2005 to underpin reimbursement claims for clopidogrel (Plavix®) and pimecrolimus (Elidel®). These voluntary submissions enabled all parties (the manufacturers, CvZ and CFH) to gather experience on how to handle the pharmacoeconomic aspect of reimbursement submissions.

In dealing with the economic files, CFH and CvZ have made use of 19 guidelines for pharmacoeconomic research, derived from the Institute for Medical Technology Assessment in Rotterdam that were developed in 1999 [3]. Important guidelines include the use of an appropriate perspective, the choice of appropriate comparator, the discount rate to be used, and the need for an adequate time horizon. CFH/CvZ determine an overall score based on adherence to these guidelines, which contributes to the final assessment of the quality of the pharmacoeconomic claim. For example, the company submission for the anti-platelet drug clopidogrel adhered to more than 60% of the guidelines. Ultimately, it is the CvZ who advise the Ministry of Health -on the basis of the CFH-advice - on the quality of the pharmacoeconomic file submitted. In principle, this could mean an advice to the Minister to intepret the economic file as adequate (for example, adhering to all important guideline items), even if the evidence for the drug is that it is not sufficiently cost-effective. For the latter consideration, there are only informal thresholds used in the Netherlands, often around c =20,000 per life-year or QALY gained.

The pharmacoeconomic guidance of the CFH/CvZ can be found on www.cvz.nl, but is only available in the Dutch language.

The main similarity between the CFH model and the NDC/SMC approach is in the timing of the assessment, with the pharmacoeconomic evaluation being based on the clinical data available at or soon after registration. Given this timing, in both countries only Phase III clinical studies are usually available to judge the clinical and cost-effectiveness of new drugs, which is opposite to the situation for full NICE appraisals which may be conducted several years post registration when observational data on drug utilization and outcomes is more likely to be available.

In addition, some of the key differences and similarities of the systems applied by CvZ/CFH- and NDC/SMC are:

  • Both operate with a pharmacoeconomic checklist and use explicit “state of the art” guidelines for pharmacoeconomic research, although with some differences in content;

  • For both the time from starting the assessment to actual advice being issued is 3-4 months;

  • SMC-guidance is intended as a recommendation to local authorities in Scotland on the use (and indirectly the funding) of a new drug, whereas CvZ/CFH advice is specifically for determination of the reimbursement status of new drugs;

  • SMC evaluates all new drugs and indications (whether hospital or non-hospital), whereas CvZ/CFH is primarily directed at the non-hospital market, and within this only those drugs that claim added value compared to the existing drugs for a specific indication;

  • For CvZ/CFH a user-friendly electronic version of the pharmacoeconomic model is required, whereas NDC/SMC does not typically request the manufacturers electronic model;

  • CvZ/CFH only advises on the quality of the economic file, whereas NDC attempts an assessment of whether the drug can be considered costeffective or not;

  • SMC may be overruled later by guidance from a full NICE appraisal, so in a sense it may be perceived as a preliminary recommendation; CvZ/CFH provide a final advice unless the manufacturer re-appeals; and

  • SMC allows input from experts and patient advocacy groups, whilst this only occurs in exceptional circumstances for CvZ/CFH.

Of course, both the CvZ/CFH and the SMC can issue negative recommendations. This may not be due to the pharmacoeconomic submission alone. The clinical evidence may be limited to show therapeutic benefit, often due to weak study design, too small numbers or absence of evidence on “hard endpoints”, i.e. mortality and clinically relevant morbidity. Furthermore, the evidence in the clinical studies is not against the comparator drug or technology used in actual practice, leading to problems reconciling the clinical and pharmacoeconomic sections. Also, all assumptions (e.g. for resource use) in the economic model should be based on robust, ideally published data sources, which is not always the case.

Table 1 shows the outcomes of the evaluations for 3 selected drugs with economic files for CvZ/CFH, SMC and NICE. This illustrates how, due to a range of factors (both evidence based and other factors), outcomes can vary even across decision making bodies that have a similarly high technical standard for pharmacoeconomic submissions.

The status of the CvZ/CFH-advice is changing as a new health insurance system is being adopted in the Netherlands from January 1st 2006, with more independence in decision making being given to individual health insurance companies. Indeed, a number of individual insurance companies have already “overruled” CvZ/CFH advice and reimbursed methylphenidate OROS. Additionally, an extension of the reimbursement system to require pharmacoeconomic files for in-patient drugs to show added value is expected in The Netherlands.

Conclusions
Recent developments at NICE is a new programme of rapid single technology appraisals of new drugs/indications at launch [4]. This has started in 2006, initially for selected anti-cancer drugs. It is therefore interesting, and also to provide learnings for NICE, to assess experiences at SMC and CFH regarding the use of pharmacoeconomics as part of a process of rapid technology appraisal. Also, one of our aims in the original ISPOR workshop was to assess similarities and differences between the SMC and CFH, and so we have attempted to cover this objective in this article.

References
1. www.ispor.org/peguidelines/index.asp. Last accessed March 27, 2006.
2. NICE: Guide to the methods of technology appraisal, NICE, April 2004.
3. CvZ: Guidelines for Pharmacoeconomic Research. Amstelveen: CvZ, 1999. 4. NICE: NICE to issue faster guidance to the NHS, NICE Press Release, Nov 3rd, 2005.


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