Bpz.gov.pl

TNO report
2002.024
A review of health technology assessmentmethods in the field of pharmaceuticals HTA and pharmaceutical coverage decisions Standard of health services purchased in the national health insurancesystem (contract nr. 3.4.1.41) - Poland All rights reserved.
Copyright: Ministry of Health, Office for Foreign Aid Programs in Health Care, Poland 2002.
This report is part of a project that was financed through World Bank Loan 3466-POL In the transition of the Polish health care system to a social insurance system similar tothat of many Western European countries, many issues have arisen. A number of suchissues concern the basic of making decisions in Polish health care.
Under the Soviet model of health care, decisions were made based on socialist ideologyand central planning. A new basis is needed. Following the lead of other Europeancountries, Poland wishes to gain information on how decisions can be guided by healthtechnology assessment. Some key problems in Poland include: 1 Attempts to set standards on safety and quality;2 The basis of coverage, that is, the definition of the benefits package;3 Payment for highly qualified services.
Health policy makers in European Union countries (and Switzerland) have addressedthese and related problems, especially using Health Technology Assessment (HTA) andlinking it to regulatory and reimbursement decisions. Using HTA actively would resultin standards being based on effectiveness and cost-effectiveness, coverage decisionsbeing based (in part) on systematic evidence of effectiveness, and highly qualifiedservices being regulated and reimbursed based on effectiveness. This working paperdeals with the issue of definition of pharmaceutical benefits based on HTA.
Health Technology Assessment
HTA may be defined as “a structured analysis of a health technology, a set of relatedtechnologies, or a technology-related issue that is performed for the purpose ofproviding input to a policy decision” (Banta, EUR-ASSESS glossary).
HTA is a form of policy research that systematically examines short- and long-termconsequences of the application of health technologies. The goal of HTA is to provideinput to decision making in policy and practice. The essential properties of HTA are thisorientation to decision making and its multidisciplinary and comprehensive nature(Banta, Introduction to EUR-ASSESS).
Health technologies are the drugs, devices, procedures, and the organisational andsupport system within which health care is delivered.
HTA takes a broad view of technology and of technological change and carries outanalyses of such issues from a number of perspectives. The field includes studies ofethical and social consequences of technology; factors speeding or impedingdevelopment and diffusion of health technology; the effects of public policies ondiffusion and use of health technology and suggested changes in those policies; andstudies of variation in use of technologies. The most prominent part of HTA is todetermine, insofar as possible, the benefits and financial costs of a particular technologyor group of technologies. The main goal of such studies is to improve “value formoney” in health care.
Given this broad context, HTA is not defined by a set of methods but by its intent. Atechnical assessment of a pharmaceutical or medical device carried out by a program as part of a regulatory decision can be considered HTA. Likewise, an ethical analysisconcerning gene therapy done to clarify its implications before deciding whether toprovide it can be considered an HTA. The most frequent activity in HTA is a synthesisor systematic review of available information, especially on efficacy and cost-effectiveness, to assist different types of policy decisions. A prospective randomisedclinical trial or prospective cost-effectiveness study done for policy reasons, as in theNetherlands or the United Kingdom, is also a technology assessment. On the otherhand, clinical research or even clinical trials done solely for the purpose of increasingscientific knowledge are not technology assessments.
Technology assessments are useful to a wide range of decision makers in health care,including government policy makers, insurance companies and other payers, industry,planners, administrators, clinicians, and patients. This report concerns the use of HTAin making policy decisions concerning pharmaceuticals (drugs), especially regulatoryand payment decisions.
This report includes a “Methodological Appendix” which discusses the basics andmethods of HTA in some details. The Methodological Appendix is background forWorking Papers 2,3 and 4 and will be provided with each of those reports. Therefore,these Working Papers will only deal with HTA at a general level in their text.
Assessment of Pharmaceuticals
Probably more information is available on the efficacy and safety of pharmaceuticals(drugs) than of any other technology. The main reason that this is true is because of theregulation of pharmaceutical products. At the same time, drugs have been subject tomuch attention as a contributor to health care costs and as a technology whose risks,benefits, and cost-effectiveness must be considered carefully.
It has been said that the only relatively complete, organised system for HTA is thatcarried out under the supervision of drug regulatory agencies (Banta and Luce, 1997, p.
177). It continues to be true, despite much progress in HTA, that many technologieshave not been carefully assessed, while a great deal of information is available ondrugs. This may explain, in part, why coverage decisions concerning pharmaceuticalsare generally more explicit than other health technology coverage decisions.
Traditionally, clinical trials of drugs have been randomised controlled trials (RCTs) inwhich a drug is tested against placebo or, less commonly, an alternative drug. A numberof the earliest health technology assessments carried out in the 1930s and 1940sinvolved drugs such as penicillin, sulfonamides, antimalarial drugs, and anti-tuberculosis drugs (Banta and Luce, p. 1977). Another visible form of pharmaceuticalassessment concerns cancer chemotherapy, where clinical trials have been an integralpart of drug development since the 1950s.
Adverse consequences (side effects) of drugs have also been prominent in assessment.
All drugs have side effects, so balancing risks versus benefits is very important in thisfield. RCTs are not so useful in assessment of side effects, so other types of studies,such as epidemiological surveillance, are often necessary.
Other types of assessment are less common in the pharmaceutical field. Economicassessment is still relatively uncommon, although some drug regulatory and reimbursement programs are now demanding economic data. Examples includeAustralia and the Canadian provinces of Ontario and British Columbia. Cost-effectiveness studies concerning drugs are becoming more common.
Other types of assessments of drugs are less common. Assessments seldom compareequivalent drugs for relative efficacy or cost-effectiveness, for example, but focusinstead merely on demonstrating efficacy. Even here, information is often faulty, oftenrelying on “surrogate endpoints” such as lowered blood pressure or improved urineflow without actually dealing directly with patient outcome (Liberati et al, 1997)Relatively little attention is paid to indications of use of the pharmaceuticals, which is avery important issue, since physicians often use drugs for indications that are notdemonstrated to be efficacious.
Regulation of Pharmaceuticals
A landmark in pharmaceutical regulation was the passage of the US Food and DrugAmendments of 1962, which required proof of safety and efficacy from well-designedclinical trials before the pharmaceutical product could be marketed in the USA. Thetrials are actually organised and/or paid for by industry. The US Food and DrugAdministration (FDA) supervises this process and approves the drugs for marketing.
This model has been generally followed in most countries of the world.
In the European Union (EU), the European Commission has pushed toward a singlemarket for pharmaceuticals. It has created a multistate procedure for marketingapproval of drugs. The procedure is administrated by the European MedicinesEvaluation Agency (EMEA), located in London. While the system of pharmaceuticalregulation in the European Union is still being developed, Member States of the EUhave no option but participation in the European system. In short, centrally registereddrugs are in effect registered throughout the EU. Drugs registered in a Member State gothrough a “mutual recognition” procedure in which drug registration is beingharmonised throughout the EU.
Therefore, Member States of the European Union have less and less influence overpharmaceuticals available in their market. Pressures from the European Commission,the EMEA, and the industry will inevitably lead to greater and greater harmonisation ofthis “internal market”.
Poland has a pharmaceutical registration process analogous to that of other Europeancountries. In theory, that process is carried out on the basis of evidence of efficacy andsafety. However, Polish experts have been quite critical of decisions in this process,which seems to need improvements. In any case, when Poland becomes a member ofthe EU, it will be required to follow the decisions of the EMEA.
Coverage of Pharmaceuticals
There are no European regulations or directives dealing with health care issues relatedto coverage for health care provision in general or pharmaceuticals specifically. Anumber of issues have encouraged European countries to make more explicit decisionsconcerning pharmaceutical coverage. These issues include: 1 the visibility and costs of pharmaceuticals, which make up about 15% of health care 2 issues of efficacy and safety with many drugs, which arise continually;3 extensive evidence of overuse and misuse of pharmaceuticals;4 the relative ease of identifying and assessing pharmaceuticals, compared with many Therefore, coverage decisions concerning pharmaceuticals are already explicit inessentially all members of the European Union (and in Poland, for that matter). Thisarea is considered by the European Commission to fall within the “competence” of eachMember State. Pharmaceuticals can be placed on a “positive list”, a “negative list”, orboth. The European court has explicitly held that negative lists, pharmaceuticals thatwill not be reimbursed in a particular Member State, are legal, since Member Stateshave a legitimate interest in controlling the health budget. However, evolving Europeanlaw requires that the basis for such decisions must be transparent, objective andverifiable. Therefore, HTA plays an increasingly important role in such decisions.
Coverage decisions go far beyond just listing products that will be paid for or not paidfor, however. Member States also retain substantial autonomy in the area of pricingreimbursement, and user charges. All Member States wish to control pharmaceuticalexpenditure. A variety of mechanisms have been adopted with this aim in view,operating on patients, doctors, and the industry. Such mechanisms have stimulated thedevelopment of cost and cost-effectiveness studies in HTA, in the field that is generallynow referred to as “pharmaco-economics”.
Introduction — 7
Assessment of Pharmaceuticals — 8
Regulation of Pharmaceuticals in Europe — 10
Coverage of Pharmaceuticals in Europe — 12
Use of Pharmaceuticals — 15
Paying for New, Expensive Pharmaceutical Products — 17
The Case of Switzerland — 18
The Case of the Netherlands — 20
Introduction: History and Recent Developments Regarding Reimbursement ofPharmaceuticals — 20 Current Process of HTA in Relation to Coverage of New Pharmaceuticals — 22 Discussion — 28
References — 29
Appendices
Fout! Geen inhoudsopgavegegevens gevonden.
AppendicesA Positive and Negative Lists for Pharmaceutical Coverage in Selected European Other reports have described the background of Poland and the Polish health caresystem, so this report will not repeat that material.
What is very clear is that the Polish health care system has changed dramatically inrecent years. The main change has been to move away from the centralised model of theSoviet system and the development of decentralised administration. With this change,the role of the Ministry of Health has also changed dramatically, so that it is becomingan instrument for policy development and leadership rather than the head of acentralised health care bureaucracy. A great deal of decision-making is now delegatedto other parts of the health care system.
To develop its new role, the Ministry of Health needs sources of information that willguide future developments. Health technology assessment (HTA) is such a source ofinformation. It is because of this that the Polish Ministry of Health has asked TNO toadvise it on how to link HTA with different policy areas, focusing on health benefitscoverage. This report focuses on a related area, those decisions that are still made in theMinistry of Health, or those decisions that may be made in the future.
A great deal of information is available concerning the efficacy and safety of drugs. Themain reason that this is true is because of the regulation of pharmaceutical products,which requires manufacturers to test drugs rigorously before they can be marketed. Atthe same time, other organisations, such as research organisations, focus on theassessments of drugs. HTA agencies pay an increasing amount of attention to drugs.
As indicated, the traditional focus of pharmaceutical assessment is efficacy and safety.
Traditionally, clinical trials of drugs have been randomised controlled trials (RCTs), inwhich a drug is tested against a placebo or an alternative drug. Pharmaceuticalassessment is a well-established part of research and of HTA.
While efficacy and safety information is more available in the field of drugs than inother areas of health technology, the system is far from perfect. A number of problemscan be identified:1 Clinical trials do not often involve the comparison of similar drugs. Therefore, the clinician lacks fundamentally important information in making choices of drugs forpatients.
2 The focus of clinical trials is demonstrating efficacy. There is less attention paid to the question of efficacy under what circumstances. One critical aspect under-emphasised in trials is indications for use. A drug is often only efficacious for certainindications, but most drugs are used for indications that have never been the subjectof trials.
3 The end-point of efficacy trials is often “surrogate endpoints” that is, endpoints that may not be directly related to an improvement in patient health outcome (Liberati etal, 1997). Those arguing for surrogate endpoints say correctly that a trial todemonstrate effects of health outcome is more difficult to organise and usually willtake longer than a drug based on surrogate endpoints. However, many surrogateendpoints have not been shown to be associated with better health of patients.
4 Other types of information, such as costs and cost-effectiveness, are less often assessed. Nonetheless, such assessment information is growing rapidly, stimulated byconcerns about the costs of drugs. Likewise, assessments of quality-of-life are stillnot very common.
The widespread availability of information on efficacy and safety has simplified thetask of regulators and payers for care enormously. In many cases, prospective studiesare not necessary to determine whether or not a drug is useful.
Pharmacoepidemiology. The field of pharmacoepidemiology is a field dedicated to the
study of the use and effects of drugs in large numbers of people (Strom, 1989). It
incorporates what was previously called “post-marketing surveillance”. As the name
implies, the field is a blend of clinical pharmacology and epidemiology. The field is
particularly concerned with the study of drug effects and adverse reactions (side
effects).
The need for post-marketing studies is due to several reasons. First, pre-marketingstudies are very limited and cannot answer many questions. They tend to be rather smalland of limited duration. They are conducted in artificial environments (“idealcircumstances”) where patients tend to be homogenous in age and sex and are less likely to have complicating medical conditions that might confound the results of thetrial. And, as already noted, they tend to compare a new drug to a placebo instead of toanother active drug. The strength of prospective trials is their high internal validity, butthey can be difficult to apply in the “real world”.
Post-marketing studies tend to be observational rather than experimental, and aretherefore aimed at examining effectiveness (as compared with efficacy) and, especially,safety, in the real world of medical practice. They are useful in learning about drug-drug interactions; about effects in previously untested population such as the elderly,children, and patients with multiple diseases; effects of overdoses; and many otheraspects of everyday practice, including prescribing patterns.
Post-marketing studies are generally more useful for studying safety than clinical trialsfor one simple reason: side effects are generally not common. A side effect that appearsin 1 in 100 patients may not be noticed in a clinical trial, but such a side effect may beextremely important when the drug is used in millions of people. Therefore, post-marketing studies play a very important part in the assessment of drugs.
Quality of Life Assessments. There has been a clear trend toward including health-
related quality-of-life within clinical trials, especially those sponsored by the
pharmaceutical industry. The first such studies were carried out in the mid- to late-
1980s, but are becoming more and more frequent. The pharmaceutical industry, in
particular, shows strong interest in including quality-of-life as part of the outcomes in
drug clinical trials. One important reason that such studies are important is that
improved quality of life is in fact an important goal of medical care.
A number of scales, both specific and general, are available for measuring quality-of-life in pharmaceutical trials. One comprehensive discussion of quality-of-lifemeasurement in clinical trials is presented in Revicki (1997).
Economic Assessments of Pharmaceuticals. Experience with assessing the economic
consequences of drugs is relatively recent. However, since about 1975, when the costs
of health care began to become an important policy issue, costs and cost-effectiveness
studies have become increasingly common. Since the mid-1980s, the number of cost-
effectiveness studies of drugs has out-stripped studies of other types of technologies.
The main reason that this is true is industry support for such studies, and for the “new”
field of pharmacoeconomics. Governments that require economic information in drug
regulatory process and coverage bodies that seek economic information give further
impetus to this process. There seems little doubt that clear evidence of cost-
effectiveness of drugs is actively sought by such public programs in Europe.
Industry often argues that a drug, especially a new drug, is cost-effective, by which itfrequently means “cost-saving”. This argument is inherently appealing, because drugscan often prevent more expensive interventions, such as hospitalisation. However, as inall forms and uses of HTA, such claims must be carefully examined on a case-by-casebasis.
The system of regulation of pharmaceuticals can claim to be the only relativelycomplete, organised system for health technology assessment. In the optimal situation, aseries of studies is required to be carried out under the supervision of the drugregulatory/registration agencies and programs. When a company has a drug that itwishes to put on the market, it must support clinical trials. However, before tests inhumans, the company must submit laboratory and animal data to the regulatory toobtain a license for human testing. At the end of the process, the regulatory programsynthesises the laboratory, animal and human data to decide whether the drug can beapproved for marketing or not.
All countries regulate pharmaceuticals in an analogous manner. However, in manysituations, the decisions are based on information that is not based on clinical trialscarried out in that particular country. Decisions can be based on published articles,information in databases, decisions in other countries, and so forth. Ordinarily, theregulatory agency responds to requests from the industry, which is then required topresent the information sought by the agency. This is the case in Poland, by and large.
Such processes should be transparent and based on clear-cut criteria. Otherwise,consumers and physicians cannot have confidence in their results. However, in manycases, the processes are not transparent. Therefore, even if the criteria are clear-cut, itcannot be clear to others how rigorously these criteria are applied in practice. In such acase, the only way of evaluating the outcome is to examine the results; that is, whatpharmaceuticals have been admitted to the market, compared to other countries. ThePolish system looks adequate on paper, but many informants in Poland have criticised itfor its outcomes (as is also the case in reimbursement, see below).
While all countries have developed such regulatory programs, the case of Europe isspecial. The European Commission, supported by the pharmaceutical industry, hassought to develop one internal market for pharmaceuticals in Europe. The EuropeanCouncil Regulation of 1990 established the European Community procedures for theauthorisation of drugs for the European market and for the supervision of medicinalproducts and established the European Medicines Evaluation Agency (EMEA), locatedin London.
The present program does not regulate all aspects of pharmaceutical marketing. Furtherbarriers such as lack of standards for package sizes, dosages, and names of productsmarketed under different names in different countries would need to be addressedbefore a single market becomes a reality. The greatest problem with furtherdevelopments in this area is the jealousy of Member States concerning their ownsovereignty. This again points out the differing motivations of the EuropeanCommission and the Member States in pharmaceutical regulation.
Furthermore, a truly single market would require standardising the systems ofregulation of prices/profits. In terms of insurance (see below), there would have to bealignment of how much patients pay for medicine and what drugs are covered by healthinsurance. It is doubtful if industry would welcome moves to align drug costs, and it iscertain that Member States of the EU are not prepared to harmonise the lists of drugscovered.
It is worth noting again that the main impetus in this “Europeanisation” ofpharmaceutical regulation was not public health or public protection, but economicdevelopment and efficiency (and in addition, pharmaceutical innovation). Theregulation of pharmaceuticals is the result of the interplay of decisions taken at the levelof the European Union (EU) and the decisions of each state. The relationship betweenthese two different levels is subtle and complex. States are concerned with publicprotection and public health, but are also deeply concerned about containing the costs ofpharmaceutical consumption (Cranovsky et al, 1997). The central aim of the EuropeanUnion is to remove barriers to the free movement of goods while at the same timeencouraging research and development to promote new products, develop industry, andgain exports. At the European level, and in many of the Member States, thepharmaceutical industry is viewed as one of Europe’s best performing high-technologysectors. This is highlighted by the fact that, generally, biotechnology products areregulated at the central level.
Nonetheless, the European program of regulation remains highly decentralised. Thereare three registration procedures for pharmaceutical products:1 A centralised procedures, reserved for innovative products and leading to a single community-wide authorisation valid for all 15 Member States; 2 A decentralised procedure, which will eventually apply to the majority of products, based on the principle of mutual recognition (accepting the decisions of otherMember States concerning registration); and 3 A national procedure limited in principle to applications of local interest concerning The model of EMEA then has relatively little resemblance to country pharmaceuticalregulation, depending as it does on a complex structure of committees, mechanisms ofseeking advice, and decisions taken first at the national level. The actual functioning ofthis program is not of great concern for this project. The important point is that whenPoland joins the European Union, it becomes a member of this program. The decisionsby EMEA are binding on all Member States. Drugs admitted to the market based oneither the centralised procedure or the decentralised procedure will be admitted to themarket of all Member States, without choice. Poland has already developed proposedlegislation to reform its pharmaceutical regulatory process to conform to that of the EU.
This legislation will go into effect on Poland’s accession to the European Union.
Coverage of pharmaceuticals is determined by every country in the world by its ownindependent processes. While countries certainly learn from each other in this area,there is no international program for pharmaceutical coverage. In Europe, in contrast topharmaceutical regulation, coverage of pharmaceuticals remains almost entirely anissue for each Member State of the European Union.
There are no European regulations or directives dealing with health care issues relatedto coverage for health services provision. The only EU policy document dealing withthis issue is a 1992 Council recommendation that proposed that Member States shouldestablish positive and negative lists and organise the role of social protection inpreventing illness and in treating and rehabilitating the persons concerned so as to meetthe following objectives under conditions determined by each State: to ensure that allpersons resident within the territory of the State have access to necessary health care aswell as to facilities seeking to prevent illness and to maintain and, where necessary,develop a high-quality health care system geared to the evolving needs of thepopulation, and especially those arising from dependence of the elderly, to thedevelopment of pathologies and therapies and the need to step up prevention (EuropeanCouncil, 1992). In short, it is the responsibility of the Member States to define anddevelop specific policies for high-quality health care.
In an important case (Case 238/82 Dephar), the European court considered the legalityof a negative list, excluding certain expensive products from reimbursement by healthinsurance institutions. The court held that such schemes might be legal and compatiblewith EU policy, recognising that Member States have a legitimate interest in controllingthe health budget.
Another development concerning Europe and its influence on pharmaceutical paymentis that arguments between governments and providers have increasingly involvedcitations to European rules. The European Court of Justice has ruled that consumers canlegally import cheaper over-the-counter drugs from another country, provided that thedrug is approved in their own country (Jacobzana, 2000). The Court has also ruled infavour of parallel imports, in which a cheaper version of the drug may be imported fromanother country. Recent decisions have concerned the right to receive and bereimbursed for care or health services in another country, but these cases have no directapplication to pharmaceuticals (until now).
Pricing and Reimbursement Policies Toward Pharmaceuticals. As has already been
made clear, pricing and reimbursement policies remain under the autonomous control of
the Member States of the EU. In December 1988, the European Council adopted a
directive relating to the transparency of measures regulating the pricing of medicinal
products and their inclusion in the scope of national health insurance schemes
(Directive, 1989). The “Transparency Directive” acknowledged that the Directive was
an initial step toward harmonisation and that further measures should take place
progressively. The Directive requires that national authorities adopt transparent,
objective, and verifiable criteria when deciding on price or profit regulations or the
setting up of limited and positive lists of drugs. If defines a time limit of 90 days for
national authorities to agree or set a price on newly introduced products and requires
that they state the reasons if they fix a price different from that sought by the company.
It is worth emphasising that such “objective” and “verifiable” criteria could beimportant produce of HTA.
With this Directive, and with the formation of the EMEA, the issue of reimbursement ofpharmaceuticals took centre state. Up until that time, countries depended mainly onpharmaceutical regulation to control drugs and drug expenditures. That is no longerpossible. During the last 10 years, more and more companies have taken active steps touse pharmaceutical reimbursement as an important policy tool to meet differentpurposes, including assuring the cost-effectiveness of pharmaceutical treatment.
Member States have adopted a variety of measures to control pharmaceuticalexpenditure. These measures concern patients, doctors, and the industry. Cost-sharing(co-payments) is intended to influence patients’ behaviour. Attempts to influencephysicians’ behaviour include positive and negative lists, encouraging genericprescribing, monitoring doctors/ prescribing, giving budgets to each doctor, and othermechanisms. Finally, regulating or influencing prices operates at the industry level.
The implementation of the EURO seems certain to influence reimbursement policiestoward pharmaceuticals. Price-transparency will certainly increase.
Positive and Negative Lists. A very limited positive list is in effect 100% cost-sharing
for those products excluded from it. Italy’s decision in 1994 to narrow its list from more
than 4,000 to 771 clearly had this effect. The most common policy is to have a positive
list, that is, a list of drugs that are paid for, or partially paid for. In this case, there is also
an implicit negative list, drugs that are not paid for, although some countries have both
a positive and a negative list. Table 1 shows countries with a positive and a negative list
in selected European countries (see Annex A).
Ideally, such lists are made up guided by a process of HTA. That is certainly the case inSwitzerland, described below. However, the reimbursement decision is considerablymore complicated that the regulatory decision, which is generally only based on safetyand efficacy considerations. The reimbursement decision probably always includessome consideration of cost, although it may often be implicit. Again, the Swissexperience gives some insight into this issue. To be sound, lists need to be revisedperiodically. Most countries revise their drug lists several times a year (Jacobzana,2000). Countries that emphasise HTA, mainly an analysis of cost-effectivenessinformation, include the Netherlands, the United Kingdom, France, and Portugal.
Countries that explicitly refer to the use of such formal analysis as part of a nationalprocess of guideline development for pharmaceutical use include Finland and Italy.
In Poland, although acknowledgement is given to the idea of basing coverage decisionsfor Poland’s positive list, the implementation of this idea seems faulty. The process ofplacing a product on the list, and of deciding whether it should be fully or partiallyreimbursed, is not transparent. Again, one must rely on analysis of the list itself todetermine if sound criteria are being followed.
As described in the report from Working Paper 1, TNO contracted with the Frenchpharmaceutical journal La Revue Prescrire to analyse the Polish list. The full report isavailable as an annex of that report. In summary, Prescrire stated that the lists are notbased on any priority decisions than can be deduced from examining them. Mostnecessary drugs are presumably those that should be fully reimbursed. However, while many drugs on list 1 do meet this test, others do not. For example, iron salts are on list2, while this treatment is essential for treatment of iron deficiency anemia. The oldestand cheapest of anti-hypertensive drugs are on list 2, while beta-blockers, which aremore expensive and are not the first line treatment, are on list 1. Many other examplescan be cited. Important drugs are not found on any of the lists. These include oralopiates (for pain); anti-epileptics; anti-Parkinson drugs; unfractionated heparins for anti-coagulation. On the other hand, many drugs are on the lists although they have noknown efficacy. Such drugs include vasodilators, treatments for functionalgastrointestinal disorders, treatments for diarrhea, and drugs for pulmonary complains.
Obsolete drugs are found on the lists as well. In short, the Polish pharmaceutical listurgently needs reform.
At the same time, the Polish situation continues to evolve rapidly. One recent change isan explicit approach to imported drugs. In an agreement of late 2001, the Ministry ofHealth, the Ministry of Finance, the Ministry of Economy, and the Sickness Fundsagreed to evaluate imported drug pricing with a view to making recommendations oncoverage of foreign drugs. The mandate is as follows: 1 To consider pharmaceutical prices in countries with similar GDP as Poland;2 To consider market factors such as price competition, the level of supply, and the 3 To consider the efficacy of the pharmaceutical;4 To consider the importance and nature of the treatment.
Generic Prescribing. Member States have made attempts to influence the prescribing
behaviour of physicians. One popular policy is to encourage generic prescribing, that is,
not to use the brand-name product. Such a policy can be implemented by giving the
pharmacist legal authority, which is limited in most cases, to substitute a generic
product when a brand name is use on the prescription. Incentives for pharmacists can
also be favourable with generic prescribing, as in the Netherlands and the United
Kingdom. Finally, physicians can be encouraged by various means to use generic
prescribing.
Other Methods of Regulating or Influencing Prices. Every Member State of the
European Union regulates or influences prices. This subject is outside the bounds of this
paper. In brief, pharmaceutical prices are set using some standard, usually the average
or lowest prices in selected countries.
Although policies developed to control and channel pharmaceutical development anduse sketched above are complex, they are not actually the main determining factor inpharmaceutical use. Naturally, if a drug is not admitted to the market, it generally is notavailable. If it is not admitted to the reimbursement list, its use will be discouraged.
However, the key decisions are generally made by physicians who recommend drugs topatients and write prescriptions for their use. This is the main problem for health caresystems; the most important person in the process neither uses nor pays for the product.
Furthermore, the patient (or consumer) generally pays only a fraction, often only asmall fraction, of the cost. In Europe, most patients have rather complete coverage ofimportant pharmaceuticals. Patients are therefore not very sensitive to the costs ofpharmaceuticals, neither to themselves nor in the aggregate. Furthermore, theknowledge of physicians concerning efficacy and safety of drugs is limited and quitesubject to pharmaceutical industry promotion; the physicians may have inadequateconcern about the safety and efficacy of the products that they prescribe. Patients alsolack the ability to transform information on drugs into knowledge concerningappropriate use.
At best, the decisions concerning whether the long-term consequences of newmedicines are positive or negative are difficult. No medicine is safe; it may be relativelysafe in relation to the benefits gained. The degree of uncertainty can be reduced byHTA and related studies, but the available studies often do not address the questionsthat physicians might appropriately ask. For example, few studies give guidance toanswering the question, under what circumstances can this drug contribute to the healthof this particularly patient? This problem is confounded by the stance of industry, which is fundamentallymotivated by profits. The main issue for industry, aside from profits, is innovation,which allows the company to sell its products at a high price (in early years). Therefore,the information furnished to physicians by industry is not reliable. It is biased in favourof a particular product or products of that company. Safety and efficacy are secondaryconsiderations.
Government, physicians, insurance companies, and others have responded to thissituation by attempting to develop systems of changing physician behaviour, especiallyprescribing practice. Almost all countries are involved in developing some sort ofguidelines for pharmaceutical use and prescribing (Kanavos, 1991). Particularly activecountries, using guidelines to link HTA to prescribing practice, include the Netherlandsand the United Kingdom (Kanavos, 1991). Monitoring of prescribing practice is alsoincreasing. Peer reviews are the main method for determining if physicians areconforming to guidelines. Feedback and co-operation with physicians may change theirprescribing behaviour (Jacobzana, 2000). A combination of printed materials, one-on-one education, special seminars, and feedback seems to be the method with the bestresults. In some countries, such as the Netherlands, physicians and pharmacists havetaken the initiative to work together to develop pharmaceutical guidelines to improvepractice.
Finally, cost-effectiveness of prescribing can only be improved by involving patients(Jacobzana 2000). Patients need to be involved and to approve such moves. Providing better information to patients and encouraging them to use it for decision-making is alargely future challenge for HTA and for better pharmaceutical use.
Paying for New, Expensive Pharmaceutical Products The issue of paying for new, expensive pharmaceutical products is quite visible inEurope, and has generated a significant controversy. As stated above, the main concernof the European Commission is innovation, and the main concern of industry isinnovative linked to profits. Entry to the market is often determined centrally for suchdrugs. However, the price of new products is very often quite high, and countries withto control such prices or costs. Several countries have developed special pricing,reimbursement, and delivery policies for this class of drugs.
A particularly visible case was that of a new AIDS treatment (Cranovsky et al, 1997). InFrance, the high potential costs triggered a national debate. The National AIDS Councilproposed that the choice of recipient be made by national lottery. The NationalAdvisory Ethics Committee stated that a lottery scheme should be the last resort andheld only at the local hospital level when choice could not be made on the basis ofmedical criteria. The visible outcry by AIDS groups is perceived to have led the PrimeMinister to openly oppose the lottery idea. A committee of experts was set up to defineeligibility criteria. While AIDS groups are particularly influential, this case illustratesthat it is often quite difficult to limit access to drugs primarily on grounds of costs.
Several countries have set up specific policies for the use of B-interferon 1b, a new drugapproved for treatment of multiple sclerosis. Several countries set up specific policiesfor B-interferon. In some cases, those were based on HTA. In Denmark, for example,the Ministry of Health decided in December 1995 that B-interferon would be restrictedto hospital dispensing (Cranovsky et al, 1997). In making this decision, the Ministryconsidered the views of the Multiple Sclerosis Society, the Danish Society for Researchin Multiple Sclerosis, and the Danish Neurological Society. In early 1996 a unit of theMinistry produced an HTA report recommending a number of criteria concerning theuse of B-interferon in multiple sclerosis. The report emphasised that there was stilllimited knowledge of the drug’s effectiveness and no knowledge at all of its long-termeffectiveness. Subsequently, the Ministry launched a reference program for B-interferon. The program includes the guidelines for eligibility criteria for treatment withB-interferon, practice guidelines for doctors prescribing the drug, and the establishmentof a national clinical database. This linkage of HTA and decisions by the Ministry ofHealth and the development of a reference program for one drug was visible in Europe,and may set important precedents for the future, both in Denmark and in othercountries. Simultaneously, the Ministry of Research had established a committee todevelop a national strategy for Danish health research. In its report, the committeeexplicitly mentions HTA and some international experiences. The experience with b-interferon 1b was widely known in Denmark and probably was a contributing factorleading to the formation of a national agency for HTA in 1997 (Jorgensen et al, 2000).
The Swiss system of defining the health benefits package using HTA has beendescribed in working papers 1 and 4. The system for defining pharmaceutical benefitshas some additional organisations and principles.
As already described, the federal commission on health insurance benefits (ELK) makesthe actual coverage decisions, after presentation of documentation developed under theleadership of the Swiss Federal Office of Social Security (SFOSS). In the area ofpharmaceuticals, the Federal Drug Commission advises the SFOSS in the choice ofpharmaceuticals to be reimbursed. The FDC is a body that is composed of 28 membersrepresenting physicians, pharmacists, sickness funds, compulsory accident insurers,laboratories, and hospitals. The FDC is split into two subcommittees, one of whichdeals with scientific matters and consists of scientific experts, while the other deals witheconomic matters, and has representatives of physicians, pharmacists, sickness funds,compulsory accident insurers, and hospitals (Cranovsky, 2000).
Pharmaceutical companies develop applications for coverage of a new pharmaceutical.
Each application is examined by the two committees separately and then the entirecommittee decides whether or not to recommend coverage of the drug. Therecommendation is transmitted to the SFOSS. Requests to the SFOSS for priceincreases are also examined by the FDC, but in this case only by the subcommittee oneconomic matters.
Drugs, which come to be SFOSS for a coverage decision, have already been examinedfor efficacy and safety and admitted to the market by the Swiss pharmaceuticalregulatory agency (IOCM). IOCM is main concerned with the risk/benefit ratio. TheFDC also examines the same scientific material as was submitted to the IOCM, but theFDC is mainly concerned with cost-effectiveness.
The following criteria are used in determining if a pharmaceutical is cost-effective(Cranovsky, 2000):1 Therapeutic efficacy in relation to other drugs for the same indication or with a 2 Cost per day or per course of treatment, in comparison with costs for drugs for the same indication or with a similar mode of action; 3 Cost for research work, clinical trials, and introduction on the domestic market, in the 4 Price structuring in Switzerland and abroad.
After the subcommittee has made its determination, the subcommittee for scientificquestions meets. It classifies each pharmaceutical into one of four categories, accordingto the medical need it meets, its therapeutic value, and the guarantees it offers in termsof efficacy and composition:1 Indispensable;2 Important;3 Conditionally necessary; and4 Unnecessary.
If a drug is classified in category 1 or 2, the price is of little importance, because thefirst consideration is taken to be access by patients with serious health conditions.
Preparations in category 4 are not placed on the reimbursement list. The final decisionis made by a plenary assembly of the FDC, which transmits it to the SFOSS.
As in other cases, the Swiss experience shows how principles concerning coverage canbe put into operation in a real life situation. At this moment, Poland has analogous tasksand committees, and can profit from the Swiss experience. However, with accession tothe European Union, Poland will participate in the European system of drug regulation.
Nonetheless, the experience of the Swiss coverage process for pharmaceuticals will stillbe relevant.
Introduction: History and Recent Developments Regarding Reimbursement of
Pharmaceuticals
The case of the Netherlands has been described in general terms in Working Paper 1.
Coverage of pharmaceuticals is similar, but is further developed, partly because of thefield of pharmaceuticals is easier to deal with (all pharmaceuticals are registered, andthereby identified, the number of pharmaceuticals in finite, the evidence is generallymore complete). This case will describe the Dutch system for reimbursement ofpharmaceuticals.
Regarding new pharmaceuticals, two important procedures exist: market approval ofpharmaceuticals and the reimbursement of registered pharmaceuticals. During the lastyears, an increasing number of pharmaceuticals have been are registered on theEuropean level through the centralised procedure, which means through the EuropeanUnion program. This means that the pharmaceutical is registered in all member states.
For this purpose, a European drug regulatory office has been set up in London, calledthe European Medicines Evaluation Agency (EMEA) (Bos, 2000). The Committee forProprietary Medicinal Products (CPMP) supports this agency. Since 1998, nationalregistration of a drug is possible only when the drug is registered in one specificmember state of the European Union (EU).
In addition to the national registration procedure, mutual acknowledgement ofregistration is possible (‘decentralised procedure’). In principle, this means that anational registration of a drug is acknowledged by all other member states. For certaindrugs (e.g. vaccines) a European registration is obligatory (Health Care InsuranceBoard, 2000).
In the Netherlands, the Board for the Evaluation of Drugs (College ter Beoordeling vanGeneesmiddelen - CBG), which is comparable to the CPMP on a European level, isresponsible for registration of all pharmaceutical products. The CBG registers drugsbased only on safety and efficacy; cost-effectiveness plays no role in these decisions.
Traditionally, approval of pharmaceutical products by the Dutch Board led to an almostautomatic reimbursement by health insurance companies and sickness funds. However,listing of pharmaceuticals for reimbursement is more and more based on effectivenessand cost-effectiveness (Bos, 2000).
In 1991, the Drugs Reimbursement System (Geneesmiddelen Vergoedingen Systeem -GVS) was introduced. The aim of this system is to limit costs and encourage a morerational use of drugs. In this system, reimbursement is limited with regard to drugs thathave cheaper alternatives (Bos, 2000).
In addition, in 1995 the Health Care Insurance Board introduced a decision-model forpharmaceuticals (Beslismodel extramurale farmaceutische hulp), which forms the basisof the current evaluation procedure of pharmaceuticals within the GVS. This modelconsists of the following criteria: ‘necessary care’, ‘efficacy’, ‘effectiveness’,‘therapeutic value’, ‘cost-effectiveness’ and ‘own responsibility’. (This scheme is similar to that put forward by the Dunning Commission and described in WorkingPaper 1. See Figure 1). From these criteria, the criterion ‘necessary care’ is used forgroups of pharmaceuticals (e.g. to exclude the group of homeopathic drugs from thebenefit package).
Figure 1. Decision criteria.
T e c h n olo g y
C o v e ra g e
The remaining criteria are used for the evaluation of specific pharmaceuticals: Efficacy. The effect is studied under ideal conditions in a homogeneous group of
patients, often using intermediate outcomes. This criterion is already evaluated in
relation to the pre-market approval.
Effectiveness. The effect is studied in practice, using a heterogeneous group of
patients. Therapy (non-) adherence plays a role, and the focus is on final outcomes, such
as a reduction in morbidity.
Therapeutic value. The sum of the evaluation of all properties of a pharmaceutical
that are relevant to the treatment, which together determine the place of the drug in
therapy compared with other available treatment options. To determine therapeutic
value the following aspects are evaluated: efficacy, effectiveness, side effects,
experience, applicability, user satisfaction and influence on the quality of life.
Primarily, therapeutic value is determined by the balance between effectiveness and
side effects of the pharmaceutical compared to standard treatment.
Cost-effectiveness. A pharmaceutical is cost-effective if it is efficacious and the
relationship between the therapeutic value and the costs is favorable in comparison with
other forms of therapy. This criterion is tested by means of a simple evaluation of the
consequences for macro costs.
Own responsibility. A pharmaceutical will be paid out of pocket when this is feasible
for the patient, the costs are insurable, and exclusion of reimbursement does not lead to
undesirable substitution. This criterion is used in one case only: exclusion of
pharmaceuticals to stop smoking (nicotine substitution, bupropion (Zyban) (Toenders,
2001; Health Care Insurance Board, 1999).
In the current procedure, a decision about inclusion of a new pharmaceutical in thebenefit package is largely dependent on therapeutic value and efficacy (Health CareInsurance Board, 1999).
In 1997, the Minister of Health asked the Health Care Insurance Board to formulateguidelines for pharmaco-economic evaluation. Pharmaco-economic research shouldprovide a reliable, producible and verifiable insight into the therapeutic value of a drug,the cost of using the drug and possible cost-savings compared with other drugs and/ortreatments (Health Care Insurance Board, 1999).
The resulting 19 guidelines are based on Canadian pharmaco-economic guidelines andfocus on target groups, the perspective of study, indications, methods of analysis,definition of costs, methods for measuring costs, determination and valuation of qualityof life, outcome measures, reliability, validity and results. According to theseguidelines, a cost-effectiveness analysis should be performed on those pharmaceuticalsfor which the manufacturer claims added value compared with existing treatmentoptions. The responsibility of performing pharmaco-economic research lies with themanufacturer. This means that a manufacturer needs to demonstrate information oncost-effectiveness of the new pharmaceutical before claiming additional value of thisnew pharmaceutical compared to existing interventions.
In 2002, manufacturers are being asked to start using these guidelines, to gainexperience. The aim is that pharmaco-economic evaluation will become part of theprocedure of evaluating pharmaceuticals in 2005 (Toenders, 2001).
In 2001, the Council of Ministers agreed to the proposal of the Minister of Health toinclude the results of pharmaco-economic evaluation in the procedure of the GVS. Thisproposal needs to be approved by the Council of State (Raad van State) (websiteMinistry of Health: http//www.minvws.nl/infotheek.html). In addition to more emphasison cost-effectiveness data, the health insurance companies and sickness funds will havea prominent role in regulating pharmaceuticals in the coming years.
Current Process of HTA in Relation to Coverage of New Pharmaceuticals
The Health Care Insurance Board (College voor zorgverzekeringen - CVZ) plays animportant task in the HTA process related to coverage of pharmaceuticals. This Boardaims to stimulate more evidence-based use of social health insurance resources. TheBoard advises the government which health interventions, including pharmaceuticals,should be reimbursed under the current health insurance system (Ten Velden, 1998).
To process of judging whether a pharmaceutical will be reimbursed under the socialhealth insurance, consist of 3 parts: Official request of manufacturer for inclusion in the GVS to the Minster of Health.
The Minister of Health asks advice of the Committee for Pharmaceutical Aid
(Commissie Farmaceutische Hulp - CFH), which is part of the Health Care Insurance
Board.
Ministerial decision. Final decision by the Minster of Health within 90 days of
receiving the application (Health Care Insurance Board, 2001a).
Evaluation. Evaluation of pharmaceuticals by the CFH should be distinguished into
two parts:
Generic judgments, which focus on groups of indications or of pharmaceuticals, such ashomoeopathic drugs.
Specific judgments of individual pharmaceuticals, which has the following aims.

To evaluate therapeutic value and effectiveness according to which the Minister of Health can decide to reimburse the pharmaceutical or not. The consequences for thecosts on macro level will also be included. This analysis include data on: incidenceand prevalence figures, groups of patients for which the pharmaceutical is indicatedand the expected effects of substitution, usage of the pharmaceutical (dose andduration of treatment), price of pharmaceutical and total treatment costs.

To publish the results in the "Pharmacotherapeutical Compass" (Farmacotherapeutisch Kompas). The Compass is published by the Health CareInsurance Board and is updated yearly. In the Compass, the CFH gives guidanceabout treatment of diseases, with an emphasis on available pharmaceuticals. TheCompass presents information on the appropriate use of pharmaceuticals in practiceand summarizes scientific information on the therapeutic value and/or economicconsiderations of individual products. The Compass is available free to generalpractitioners, pharmacists, and medical professionals, who live in the Netherlandsand for Dutch universities. This guide, which is available as a book and/or CD, isincreasingly linked to coverage and reimbursement decisions and has considerableeffect on the prescribing patterns of general practitioners (Health Care InsuranceBoard, 1999, 2001b, p. 42; Bos, 2000).
Pharmaceutical aid. Pharmaceutical aid encompasses those registered drugs that have
been singled out by the Minister. These drugs can be placed on List 1 (Bijlage 1) of the
Pharmaceutical Aid Regulation (Regeling farmaceutische hulp 1996), which is a
positive list and more specifically on:
List 1A with a reimbursement limit. Inclusion on List 1A is applicable forpharmaceuticals that can be substituted by pharmaceuticals with the same therapeuticgoal (‘onderling vervangbaar’). The criteria for substitutability are:
Similar field of application (indications)
Identical route of administration (e.g. oral, intravenous)
Generally intended for the same age group and absence of clinically relevant differences applying to the whole patient population, such as side effects.
For each cluster of substitutable pharmaceuticals, a reimbursement limit is calculatedwith prices on a reference year (Autumn 1998). If the price of a drug exceeds thereimbursement limit, the difference has to be paid by the patient (Health CareInsurance Board, 2001a).
List 1 B without a reimbursement limit. There are two options with regard to List 1 B.

The pharmaceutical is equivalent, but not substitutable: when the pharmaceutical leads to similar or lower costs it can be placed on List 1B. Higher costs means that itwill not be reimbursed.

The pharmaceutical is not equivalent, but has therapeutic added value. Additional requirement may be added before it will be reimbursed only when the pharmaceuticalleads to higher costs. If and when the pharmaceutical will be included on List 1B ispartly dependent on the budget available.
List 2 when extra conditions apply to the provision of a pharmaceutical. Apharmaceutical will be placed on List 2 if there is a chance that the pharmaceutical willnot be appropriate used, when specific knowledge or expertise is necessary, or when thepharmaceutical is extremely costly. Conditions could focus on such issues as a specificpatient population, treatment protocol, or approval of the insurance company (e.g.
Rivastigmine for treatment of Alzheimer patients and cholesterol loweringpharmaceuticals for patients with familial hypercholesterolaemia or high-risk patientsfor coronary artery disease).
The pharmaceutical has no added therapeutic value: It will not be reimbursed, unlessspecial circumstances justify reimbursement.
There is insufficient data to judge the therapeutic value and effectiveness of apharmaceutical: It will not be reimbursed (Health Care Insurance Board, 1999; 2000).
List 1C. In relation to the implementation of pharmaco-economic guidelines, a List 1Cis being developed. This List will reimburse new pharmaceuticals that are notsubstitutable and for which further evaluation is needed (Health Care Insurance Board,2000, 2001b, p. 56).
The positive list is available (in Dutch only) at the website of the Health Care Insurance
Board (www.cvz.nl - ‘positieve lijst geneesmiddelen’).
As described in the introduction, the pharmaco-economic evaluations will have a moreprominent role in the procedure of the GVS in the coming years. The Minister of Healthneeds information about efficiency mainly for pharmaceuticals eligible for inclusion onList 1B of the Pharmaceutical Aid Regulation. This means that if a manufacturer claimsadded value of a pharmaceutical, the results of pharmaco-economic evaluations need tobe included in the judgement procedure.
The efficiency of a pharmaceutical will then be judged including the trade-off betweentherapeutic value and additional costs. If the new pharmaceutical has an equaltherapeutic value compared to existing pharmaceutical, it can be included in List 1A. Atthis moment, the Health Care Insurance Board is implementing the pharmaco-economic guidelines in their judgement procedure. The goal is to complete the inclusion in theexisting procedure in 2005 (Toenders, 2001; Health Care Insurance Board, 1999).
Examples of Evaluation
In 2001, the following pharmaceuticals were evaluated by the CFH: Abacavir/ lamivudine/ zidovudine (Trizivir®) - treatment of HIV (indication)Calcium carbonate / colecalciferol (Calcium-D-Sandoz®) -treatment of insufficientvitamin D3, calcium (elderly)Desloratadine (Aerius®) - treatment of allergic rhinitisDexibuprofen (Seractil®) - treatment of arthritisEthinylestradiol/drospirenon (Yasmin®) - hormonal contraceptivePioglitazon (Actos®) - treatment of diabetes mellitus IIRisedroninezuur (Actonel®) - treatment and prevention of postmenopausal osteoporosisTestosteron (Virormone®) - substitution therapy of insufficient testosterone in adultmenEstradiol nasal (Aerodiol®) - treatment of insufficient estrogen in postmenopausalwomenLevetiracetam (Keppra®) - treatment of epilepsyLopinavir/ritonavir (Kaletra®) - treatment of HIV1 (adults and children > 2 years)
 Replagal®) - treatment of Fabry disease
  Fabrazyme®) - treatment of Fabry diseaseAlginaat/antacida (Rennie Duo®)- treatment of gastro-esophageal reflux complaintsand hyperacidityAlprostadil urethraal (Muse®) - treatment of erection dysfunctionTegafur/uracil (UFT®) - treatment of colorectal cancerTobramycine (Tobi®) - treatment of lung infections of CF-patientsAlmotriptan (Almogran®) - treatment of migraineEletriptan (Relpax®) - treatment of migraineNateglinide (Starlix®) - treatment of diabetes mellitus IIOlanzapine intramusculair (Zyprexa i.m. ®) - treatment of schizophreniaDarbepoetine alfa (Aranesp®) - treatment of anemia (chronic kidney disorder)Pilocarpine oral (Salagen®) - Sjögren patients, treatment of xerostomy afterchemotherapy in patients with throat/neck tumorsVenlafaxine (Efexor/Efexor XR®) - treatment of depressionAtovaquon/proguanil (Malarone®) - treatment of malariaEthinylestradiol/levonorgestrel (Fem7 Sequi®) - treatment of insufficient estrogen inmenopausal women after ovarian removalLutropine alfa (Luveris®) - treatment of stimulation of egg cells.
Capecitabine (Xeloda®) - treatment of colorectal cancerCelecoxib (Celebrex®) - treatment of rheumatic arthritisEstradiol/dienogest (Climodien®) - treatment of insufficient estrogen in menopausalwomen after ovarian removalImatinib (Glivec®) -treatment of chronic myeloid leukemiaMenotrofine (Menopur®) - treatment of infertilityKetotifen for the eye (Zaditen®)- treatment of allergic conjunctivitisEstradiol oral (Estreva®)- treatment of insufficient estrogen in menopausal women afterovarian removalTemozolomide (Temodal®) - treatment of malign brain tumors Estradiol/dydrogesteron (Femoston®) - treatment of insufficient estrogen andprevention of postmenopausal osteoporosisOctreotide (Sandostatine®) - treatment of acromegaly and carcinoid syndromeFormoterol/budesonide (Symbicort®) - treatment of asthmaLamotrigine (Lamictal®) - treatment of epilepsy and additional treatment of Lennox-Gastaut syndromeFusidin/hydrocortison (Fucidin Hc®) - treatment of eczemaMacrogol/elektrolyten (Klean Prep®) - cleaning of intestinesTemozolomide (Temodal®) - treatment of malignant gliomaSirolimus (Rapamune®)- kidney transplants (resistance of organ) For all these pharmaceuticals, a report has been prepared by the CFH, which isavailable at the website of the Health Care Insurance Board (www.cvz.nl). The reportwas sent to the Minister of Health, who uses the report to decide whether or not toinclude the pharmaceutical in the GVS. As an example of the different decisions thatthe Minister can make according to the positive list of drugs the followingpharmaceuticals are selected: List 1A: Formoterol/budesonide (Symbicort®) - treatment of asthma
Formoterol/budesonide, is known as Symbicort® Turbuhaler and is indicated as a
maintenance treatment of asthma. Symbicort® Turbuhaler is a combination of two
existing drugs, which are already listed in the GVS. This means that Symbicort
®Turbuhaler can substitute for the two existing drugs (‘onderling vervangbaar’). At
this moment, Symbicort ®Turbuhaler is included in List 1A of the Pharmaceutical Aid
Regulation. The reimbursement of Symbicort® Turbuhaler is calculated on the basis of
the reimbursement limit of both separate existing drugs that are substitutable.
List 1B: Therapeutic added value and higher costs: Tegafur/uracil (UFT®) -
treatment of colorectal cancer
Tegafur/uracil, also known as UFT® , is indicated for treatment of malignant
colorectal cancer in combination with foline-acid. UFT® is an oral cytostatic drug,
while the standard intravenous treatment (fluorouracil – 5FU, in combination with
foline-acid) is given as daycare in a hospital. UFT® has an added value compared to the
standard intravenous treatment: the effectiveness is the same, but UFT ® is less toxic.
In addition, UFT® is not substitutable by 5FU. Reimbursement under the GVS will lead
to higher costs (maximum of about 25 million EURO a year, and a decrease of the
hospital budget of 9 million EURO a year).
List 1B: Therapeutic added value and no additional costs: Calcium carbonate/
colecalciferol (Calcium-D-Sandoz®) - treatment of insufficient vitamin D3,
calcium (elderly)
Calciumcarbonaat/colecalciferol is indicated for the correction of insufficient calcium
and vitamin D3, and also as an additional treatment of osteoporosis in patients with a
lack of calcium and vitamin D3. The CFH judged Calcium-D-Sandoz®as having a
potential added value for a specific group (elderly with low mobility). Reimbursement
under GVS will not influence the costs enormously.
List 2:
 Replagal®) - treatment of Fabry disease
is indicated for chronic enzyme-substitution treatment of patients with adiagnosis of Fabry disease. Information about clinical efficacy and effectiveness islacking. This implies that no judgment can be made about the therapeutic value of Replagal®). The CFH advised to set additional requirements in relation tothe provision of  No therapeutic added value: Celecoxib (Celebrex®) - treatment of rheumatic
arthritis:
Celecoxib is indicated for symptomatic treatment of pain and inflammation of
rheumatic arthritis and arthrosis. The manufacturer asked for a new judgement in this
case. The CFH concluded that Celebrex® has no therapeutic added value compared to
other treatment options of high-risk patients for gastro-intestinal complications such as
elderly and patients with gastro-intestinal ulcers. Celebrex® has remained in the current
cluster of pharmaceuticals.
The case of coverage of pharmaceuticals is a good one to point out some of thecomplexities for linking HTA to coverage decisions. It is also the area of health carethat has the longest and most extensive experience3 with basing coverage decisions onHTA.
The first point is that HTA information on pharmaceuticals is more complete than thatfor other health technologies. The main reason that this is true is that society concernsabout pharmaceuticals preceded serious concerns about other health technologies bysome years. Pharmaceuticals have been increasingly regulated for efficacy, for example,since the early 1960, while general HTA began in the mid-1970s. Fostered by problemsof safety and efficacy of drugs, governmental regulation has developed to assure afavourable benefit/risk ratio in pharmaceutical use.
The special status of drugs as a product certainly fostered this development. The publicin general, and government policy makers in particular, have been favourable to theidea that industry products must be regulated in the public interest. It has been farharder to develop analogous approaches to physician practice. Physicians areprestigious professionals, generally trusted by the public and policy makers.
The 40 years experience with pharmaceutical regulation, along with the model of basingdecisions on controlled clinical trials (as well as an HTA-type process), has led to awealth of information on drugs, especially concerning their safety and efficacy. In fact,assessment of drugs has stimulated the development of the general field of HTA. It hasshown that research can guide policy decisions.
There is little different in the actual assessment of drugs for regulatory purposes. Themethods discussed in the Methodological Appendix are generally quite applicable.
With increasingly visible problems of all health technologies and rising costs of care,other policies have been sought. Reimbursement has been seen as an important toolsince 1980 or so. Here, again, pharmaceuticals have led the way. The defined list ofpharmaceuticals on the market, and the generally available information on their safetyand efficacy, has stimulated use of reimbursement mechanisms, especially coverage. Ashas been discussed in other reports from this project, most areas of health care practiceremain largely undefined and largely unassessed. That is not true in the case ofpharmaceuticals.
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Appendix A.1/1
Table 1: Positive and Negative Lists for
Pharmaceutical Coverage in Selected European
Countries
Positive
Negative
Source: Cranovsky et al, 1997; Panavos, 2001.

Source: http://www.bpz.gov.pl/old/file/TNOeng2.pdf