Author byline as per print journal: Robert Janknegt, PharmD, PhD, Niels Boone, PharmD, Frans Erdkamp, MD, PhD, Victor Zambon, MD
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Abstract: |
Submitted: 10 April 2014; Revised: 29 July 2014; Accepted: 11 August 2014; Published online first: 25 August 2014
Prostate cancer
Prostate carcinoma is, after lung carcinoma, the most frequent form of cancer in men [1]. About 8,000 new patients are diagnosed with prostate cancer in The Netherlands each year [2]. The diagnosis of localized prostate cancer has increased considerably, probably because of the measurement of prostate specific antigen (PSA), which is useful in the detection of early stage prostate cancer [1]. A detailed description of the treatment of all stages of prostate cancer falls outside the scope of this manuscript. The reader is referred to the Dutch national guideline for a full overview of the treatment of prostate cancer [1].
Androgens stimulate the growth of both normal and cancerous prostate cells. Androgen deprivation therapy (ADT) is the primary treatment for patients with advanced prostate cancer [2]. Gonadotropin-releasing hormone (GnRH), also known as luteinising hormone release hormone (LHRH) is secreted by the hypothalamus and stimulates the hypophysis to secrete LH, follicle stimulating hormone (FSH) and adrenocorticotropic hormone (ACTH). LH activates the testes to produce testosterone. Chronic administration of GnRH agonists (analogues) blocks the secretion of LH, FSH and ACTH by the hypophysis. This results in a reduction of circulating testosterone levels. GnRH agonists increase survival as effectively as bilateral orchiectomy or treatment with oestrogens [2].
Androgen deprivation therapy (ADT) is a palliative and not a curative treatment of advanced or metastatic prostate cancer. It can normalize serum levels of PSA and can produce objective tumour responses. This antitumour activity can improve quality of life in patients with metastatic prostate cancer by reducing bone pain as well as the rates of complications, such as pathologic fracture, spinal cord compression, and ureteral obstruction. The duration of response to ADT for patients with metastatic disease is highly variable, and most prostate cancer patients eventually experience disease progression despite treatment. Patients who have progressed while on ADT are said to have castration-resistant disease [2].
Patients with high-risk or locally advanced prostate cancer should be treated with external beam radiotherapy plus hormone treatment for at least two years.
Neoadjuvant GnRH agonists are recommended for four to six months in patients receiving radical radiotherapy for high-risk disease and should be considered in patients with intermediate-risk disease. Adjuvant hormonal therapy for two to three years is recommended for men receiving neo-adjuvant hormonal therapy and radical radiotherapy who are at high risk of prostate cancer mortality [1]. The drugs are indicated in the treatment of advanced or metastatic prostate cancer. GnRH agonists are the drugs of choice in metastatic prostate cancer, although a recent guideline from the European Society of Medical Oncology (ESMO) stated that antagonists could be an alternative [1]. Combined androgen depletion (GnRH agonists + ochiectomy) does not offer advantages over chemical or surgical castration only [1].
Guidelines for the treatment of prostate cancer do not specify a medicine of choice within the drug classes. There are no published tools available that could aid therapy choice. In this article the SOJA method was applied to both GnRH agonists and antagonists in order to make a transparent and rational selection of the most suitable medicines.
The SOJA method is a model for rational drug selection for formulary purposes [3]. See [2] for a detailed description of the methodology. The outcome of this study should be seen as the basis for discussions within formulary committees and not as the absolute truth. The present score is specific for the European situation.
The selection criteria and the relative weights that are assigned by the authors are shown in Table 1. For drugs included in this analysis, see Table 2.
Efficacy
Improved overall survival should be the aim or all cancer treatment but this requires very large scale and long-term studies to establish. Also, both relapse-free survival and disease-free survival are used alternative endpoints in the judgement of clinical efficacy. Relapse-free survival is probably a more relevant endpoint than disease-free survival, because death unrelated to prostate cancer or its complications is included in the latter endpoint.
Outcomes that have been used in trials to establish the role of hormonal therapy in men with advanced prostate cancer include overall survival, measurable tumour response, changes in serum PSA, skeletal-related events, and quality of life (QoL). Complicating the interpretation of results, many studies were conducted prior to the routine use of serum PSA testing in screening and monitoring of disease and therefore these studies do not reflect typical contemporary patient populations or current practice patterns [4].
The prolonged natural history of advanced prostate cancer, its occurrence in older men who often have substantial comorbidity, and the heterogeneity of disease between patients complicate the use of overall survival as an endpoint in assessing response to treatment. The standard classifications of complete response, partial response, stable disease, and progressive disease are inadequate to evaluate response in most men with metastatic prostate cancer. Measurable disease is present in a small fraction of patients. Bone metastases are the most common site of disease, and bone involvement is difficult to measure objectively. Bone scan interpretation is variable, and there is a long healing time when lesions do respond to treatment [4].
PSA levels as a measure of efficacy
The appropriate use of serum PSA as a response endpoint for hormone therapy has not been well studied. The rate of PSA decline following initial hormone therapy relative to the rate of rise prior to initiation of hormone therapy is highly predictive of the time to prostate cancer-specific death [4]. The median survival of those with low PSA levels (< 0.2 ng/mL) was much longer than those with PSA levels of above 4 ng/mL [4].
Inclusion and exclusion criteria
In most cases, we have only used double-blind randomized studies to judge clinical efficacy of drugs included in SOJA analyses. The SOJA model is an instrument that enables users of the programme to determine, on the basis of agreed criteria, an order of merit for the various medicines available in a specific category [3]. This was not done in this SOJA score, because very few double-blind studies have been performed. For this reason, open, randomized phase III studies were included in the analysis. Non-randomized studies and studies comparing GnRH agonists with the addition of a drug such as flutamide or placebo were not included in the analysis, as these studies investigated the effects of the drug added to the GnRH agonist. Studies including a minimum of 25 patients per treatment arm were included in the analysis. Studies with short acting GnRH agonist formulations or nasal formulations were excluded. Similarly, studies in which hormonal treatment was not distinguished from orchiectomy in the same treatment arm were excluded, as well as studies that did not specify the GnRH agonist by name [5].
Direct comparative studies
Few direct comparative studies between GnRH (ant)agonists were identified. One retrospective study was excluded [6] as well as two other studies with a very small number of patients [7, 8] and one non-comparative study [9].
Abarelix versus leuprorelin
One study compared abarelix to leuprorelin. As could be expected testosterone surge was not seen in the abarelix group and did occur in the leuprorelin group [10].
Degarelix versus goserelin
Two studies compared degarelix and goserelin. Testosterone levels decreased more rapidly in the degarelix arm than in the goserelin arm, at eight weeks the levels were similar [11]. The effects of prostate volume and PSA levels were similar at 12 weeks [12]. At the same time point, more patients reported a > 3 point decrease in the International Prostate Symptom Score on degarelix than on goserelin: 36% vs 27% [12].
Degarelix versus leuprorelin
One study compared leuprorelin with degarelix 240 mg (n = 201). The testosterone response rates were comparable at one year. PSA levels declined more quickly in the degarelix group. The final reductions at 364 days were similar in the treatment groups [13–15].
Goserelin versus leuprorelin
A double-blind study compared goserelin 3.6 mg every 28 days (n = 540) and leuprorlin (n = 273) in patients with stage D2 (metastatic) prostate cancer. Both drugs were given in combination with either bicalutamide or (50 mg once daily) or flutamide 250 mg tid. The median follow-up was 160 weeks. The effects on time to progression and survival were similar [16].
Leuprorelin versus triptorelin
Two studies compared leuprorelin and triptorelin in patients with advanced prostate cancer. The effects on testosterone were identical. LH and PSA levels fell to a similar extent in both medicines [17, 18].
Studies with individual drugs
Buserelin
In one study buserelin depot was compared to polyestradiol phosphate (PEP). A more favourable effect of buserelin on disease progression was observed after three years of treatment [19]. This study is difficult to interpret because the comparator is not approved in The Netherlands.
Goserelin
Localized prostate cancer
Many studies were performed with goserelin. The medicine was studied as add-on to radiotherapy [20–44], showing lower PSA failure [28, 32, 34], increased five years disease-free survival [21, 31, 33, 36, 40] and 10 years [32] and lower degrees of local progression [23, 26, 33], better progression-free survival [26] and lower disease specific mortality at 10 years [23, 28, 33]. There was no effect on overall survival in the majority of the studies. Only one study showed an effect on overall survival at five and 10 years [37, 38].
Advanced prostate cancer
Six studies compared the monthly 3.6 mg and the 10.8 mg dose given every three months of goserelin in patients with advanced prostate cancer. The effects on testosterone levels were similar in the studies [45–50].
Other studies compared goserelin (3.6 mg monthly) to various medicines, such as polyestradiol phosphate (PEP) [51], diethylstilbestrol [52–54], bicalutamide [55–57] and orchiectomy [58–61]. Another study compared intermittent and continuous ADT [62].
Goserelin resulted in a longer time to progression [51], objective response rate [52, 53, 58] or no differences in clinically relevant endpoints [54–57, 59–62].
Metastatic prostate cancer
Several studies compared ADT with goserelin with or without flutamide with surgical orchiecomy in patients with metastatic prostate cancer [63–69], resulting in similar effects on objective response rates, time to disease progression and overall survival.
The EORTC 30853 study compared orchiectomy [n = 161] with a combination of goserelin (3.6 mg monthly) plus flutamide (250 mg tid orally, n = 163) in patients with metastatic prostate cancer. Significantly more favourable effects on objective progression and death from cancer were seen in the ADT group [70–74]. The time from objective progression to death was however longer in the orchiectomy group [72]. At longer follow-up (7.2 years) the advantages of ADT were maintained [75].
Other studies compared combinations of goserelin, flutamide and finasteride [76], goserelin versus extramustine [77], goserelin versus cyproterone acetate [78]. No differences were found in the first two studies, a longer time to progression was found for goserelin compared to cyproterone acetate [78].
Leuprorelin
Localized prostate cancer
Several studies were performed with leuprorelin: three versus eight months of neoadjuvant therapy with leuprorelin [79], as add-on to surgery [80]. The medicine was also studied as add-on to radiotherapy [20, 81, 82].
PSA was reduced compared to surgery alone. Positive surgical margins and lymph node involvement were seen more often in the group with surgery alone [80]. A higher overall survival was seen compared to radiotherapy alone [81]. Another study showed no positive effects on quality of life [82].
Advanced prostate cancer
One study investigated the effects of leuprorelin or oral bicalutamide on bone mineral density (BMD). The results were more favourable for bicalutamide [83].
Studies comparing one and three months formulations showed no relevant differences concerning effects on testosterone levels and PSA [84–87]. This was also the case for a comparison of three and six months formulations in a mixed population [88].
Leuprorelin prior to radical prostatectomy was compared to no pretreatment by a US study group. This study showed no differences in clinical relapse-free or PSA relapse-free survival rates between the groups [89, 90].
Triptorelin
Localized prostate cancer
One study compared preoperative triptorelin with no hormonal treatment in patients with localized prostate cancer. Triptorelin did not show favourable effects on postoperative PSA or skeletal events [91].
Advanced prostate cancer
One study compared triptorelin (+flutamide) with PEP. The primary endpoint was overall survival. No differences in mortality were observed at shorter or longer follow-up [92–94]. The 28 days and 3 months formulations showed similar effects on testosterone, LH and PSA levels [95]. Use of triptorelin prior to prostatectomy resulted in a lower rate than the control group, but there was no effect on progression-free survival [96–97].
Metastatic prostate cancer
Triptorelin was as effective as orchiectomy regarding effects on metastases and pain scores [98].
Although the levels of evidence were quite variable, no clinically meaningful differences were identified in clinical efficacy among buserelin, goserelin, leuprorelin and triptorelin in localized, advanced or metastatic prostate cancer. The clinical efficacy of goserelin and leuprorelin are much better documented than the other drugs.
It is not yet clear whether or not intermediate therapy with GnRH agonists is as safe and effective as continuous therapy [5].
All medicines are awarded 80%.
Safety
The incidence of severe adverse reactions was low for all compounds. Very few direct comparative studies between GnRH agonists and antagonists were identified. Agonists in general may induce depression, which can be severe. The incidence of severe adverse events was low to moderately high in most studies. The duration and size of most studies was insufficient to make firm statements concerning relative safety in the long term. There are no indications for major differences between the drugs concerning safety, with the exception of abarelix, which shows anaphylactic reactions at a higher rate than is the case with the other drugs.
Abarelix is awarded 60%, whereas the other medicines are awarded 70%.
Tolerability
Gonadotropin-releasing hormone (GnRH) agonists were associated with frequent, but harmless side effects. The side effects in direct comparative studies that are most relevant are summarized in Table 3.
The most common side effects result from the mechanism of action of the drugs, leading to impotence, decreased sexual drive and hot flushes. When GnRH agonists are given as monotherapy, testosterone surge may occur in the early phases of treatment.
Dosage frequency
A low dosage frequency is convenient to the patient and may increase compliance with therapy. The highest score (100%) was awarded to the lowest dose frequency (every six months), the lowest score (20%) was awarded to the highest dose frequency (every week). Scores for different dosage frequecies are given in Table 4. Leuprorelin was awarded 90%, because the generic formulation was included in the analysis. Six months formulations of goserelin and leuprorelin are not available in The Netherlands, but these are approved in other European countries. The dosage frequency of the agonists is more favourable than the antagonists.
User-friendly dosage forms
A user-friendly dosage form which is easy to store and handle is convenient to the patient and the caregiver. User-friendly scores ranged from 30% for drugs stored at room temperature to 15% for drugs stored in a refrigerator, and 0% for drugs stored below 0°C. Drugs that required no reconstitution had a score of 30%, drugs that needed complicated reconstitution had a score of 10%. Ease of administration ranged from 40% for easy, to 10% for complex. Score for different drugs are shown in Table 5.
The hybrid generic implant formulation of leuprorelin was used for calculation of the score. Eligard is not ready for use and needs to be reconstituted and kept in the refrigirator.
All agonists are given subcutaneously in a depot formulation. No independent studies comparing the ease of use of the implants are available. The ease of administration is better for the antagonists, as no implant has to be injected.
Drug interactions
No specific studies were performed. There are almost no known interactions with any of the GnRH agonists. Buserelin and goserelin may lower glucose tolerance, which could lead to decreased efficacy of antidiabetic medication.
Special precautions
Data were collected from the summaries of product characteristics (SPCs) for each drug. The warnings and precautions of the GnRH agonists are summarized in Table 6.
More special precautions are applicable to abarelix and degarelix. These drugs are awarded 60%. Although there are differences in the SPCs of the GnRH agonists, it is unclear whether this reflects real differences between the drugs. These medicines are given a score of 70%.
Documentation
The score for this criterion is divided into four sub-criteria: (1) number of randomized comparative studies; (2) number of patients in these studies; (3) number of years marketed; and (4) number of patient days worldwide.
The first two of these sub-criteria are indicative of the overall clinical documentation of the drugs in randomized controlled clinical studies. A large number of clinical studies and a large number of patients included in these studies leave no doubt about the clinical efficacy and safety of this drug in the studied population. The latter two criteria are indicative of the overall clinical experience with the drug. These sub-criteria may introduce a bias to the advantage of older drugs, but this is done intentionally. The safety of a newly introduced drug cannot be guaranteed from the results of clinical studies, in which only a relatively small number of patients were included and most patients at risk for the development of adverse reactions (e.g. patients with diminished renal function) were excluded. Both the number of patients that have been treated on a worldwide basis and the period that a certain drug has been available are of importance, as it may take time until adverse reactions occur. For a summary of these data, see Table 7.
The overall SOJA score is presented in Table 8.
There is currently no major need to make formulary choices within the GnRH agonists and antagonists in most countries. The drugs are usually not included in the hospital formulary because they are primarily used outside the hospital. In The Netherlands, many expensive drugs will be transferred to the hospital budget in January 2015. This will lead to discussions concerning formulary selection, because the cost of these drugs will be the responsibility of the hospital. Therefore, there is a need for tools to aid formulary choices. We have not included the criterion acquisition cost, to allow for a pre-selection only on quality aspects. Only the drugs with the highest scores will be considered as options for the treatment of patients with prostate cancer. After completion of the study, it turned out that the medicines in the present analysis would not be transferred to the hospital budget in 2015.
The weighting of the selection criteria reflects the opinion of the authors. Of course, such opinions are always open for debate. Therefore, all existing SOJA productions are available on the Internet (www.tablet.sojaonline.nl), allowing each user of the method to assign his/her own relative weight to each criterion, thereby calculating a personal score [101]. None of the SOJA productions is financially supported by pharmaceutical companies.
Goserelin and leuprorelin show the highest scores. The main advantage compared with buserelin and triptorelin is the better documentation for the treatment of prostate cancer. Because the differences in score between goserelin and leuprorelin (and possibly triptorelin) are limited, these drugs are acceptable as first-line therapy. Clearly the judgement of the authors concerning the properties of the medicines has an impact on the final outcomes. There are however few indications that there are clinically relevant differences between the agonists regarding clinical efficacy, safety and tolerability.
It should be noted that the studies with leuprorelin were performed with various formulations, whereas this was not the case for the other medicines. A specification of the applied formulation was only provided in a few studies: Lupron [17, 83], Enantone [18] and Sandoz generic formulation [87]. The 16 other studies did not specify the formulation, although the vast majority of studies used a dose of 7.5 mg per 28 days or 22.5 mg per three months [10, 13, 16, 20, 79, 81, 86, 99, 102]. The 3.75 mg or 11.25 strengths were used in two studies [80, 89].
Acquisition cost plays a key role in the final selection of the drug of choice. The recent introduction of a generic leuprorelin implant formulation, which does not need reconstitution and can be stored outside of a refrigerator [87], and which is at least as effective as previously used leuprorelin formulations and was well tolerated in a relatively large group of patients (n = 818) [103] may be a good starting point for a renewed discussion on drug selection for the treatment of prostate cancer. Major cost savings might be applicable, because the acquisition cost of the various drugs has always been quite high. It seems likely that the need for a careful economic evaluation of drugs in oncology will increase throughout Europe.
Table 9 provides an overview of prices of the various agents in countries throughout Europe. The generic formulation is less expensive than the other medicines in most countries, with the interesting exception of The Netherlands. Prices are also quite different between countries, prices in Belgium are considerably lower than in other counties. Prices may be lower after negotiations between hospitals and companies.
The GnRH antagonists, degarelix and abarelix, show considerably lower scores than the GnRH agonists. Based on current data, these drugs should not be considered as first-line therapy for the treatment of prostate cancer. Their acquisition cost is also higher than those of (the already expensive) GnRH agonists. The 2013 guideline for the treatment of prostate carcinoma of the European Association of Urology assigned a limited place to GnRH antagonists: ‘Overall, this new family of agents seems appealing, but their advantages over GnRH agonists are far from proven. The use of GnRH antagonists is limited by a monthly formulation. Suppression of the initial flare-up with monotherapy is only clinically relevant in a few, symptomatic, metastatic patients’ [104].
Competing interests: Dr Rob Janknegt is the Deputy Editor-in-Chief and member of the Executive Editorial Board of the Generics and Biosimilars Initiative Journal (GaBI Journal). Niels Boone has nothing to declare. Dr Frans Erdkamp has participated in clinical trials funded by AstraZeneca. Dr Victor Zambon has nothing to declare.
Provenance and peer review: Not commissioned; externally peer reviewed.
Robert Janknegt, PharmaD, PhD, Hospital Pharmacist
Niels Boone, PharmD, Hospital Pharmacist
Frans Erdkamp, MD, PhD, Oncologist
Victor Zambon, MD, Urologist
Orbis Medisch Centrum, 1 Dr H van der Hoffplein, NL-6162 BG Sittard-Geleen, The Netherlands
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Author for correspondence: Rob Janknegt, PhamD, PhD, Hospital Pharmcist, Clinical Pharmacologist, Orbis Medisch Centrum, 1 Dr H van der Hoff plein, NL-6162 BG Sittard-Geleen, The Netherlands |
Copyright © 2014 Pro Pharma Communications InternationalDisclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Source URL: https://gabi-journal.net/gnrh-agonists-and-antagonists-in-prostate-cancer.html
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Abstract: |
Submitted: 23 March 2011; Revised manuscript received: 29 September 2011; Accepted: 9 October 2011
The increased use of generic medicines is one of the most important elements in terms of the creation and maintenance of sustainable healthcare systems in Europe. Generic medicine prescribing by physicians in European countries has been supported by a variety of initiatives. However, despite these efforts, the use of generic drugs is still limited in many countries. Policymakers, insurers, and governments have focused on the low cost of generic drugs, but most physicians do not consider cost to be an important criterion; they want to prescribe a drug which is primarily effective and safe.
Prescribing is a complex process and, ideally, should be a rational process based on evidence-based criteria such as clinical efficacy, safety, tolerability, drug interactions, dosage frequency and ultimately cost. However, in practice, numerous other factors can play a role in medicine prescribing including emotional factors, the influence of pharmaceutical companies, personal financial interests, and unconscious criteria [1]. As a result, the medicine prescribing process is not always evidence based, transparent or reproducible.
In the last 20 years, matrix models have been developed to inform decisions in medicine prescribing in a transparent and reproducible way [2]. A matrix model, in essence, is an interactive computer program that identifies the most appropriate medicine to prescribe, taking into account clinically relevant and evidence-based selection criteria. Such matrix models have been implemented in The Netherlands [2] and in Northern Ireland, UK [3].
As the introduction of matrix models is likely to have an impact on the prescribing of originator and generic medicines, the aim of this paper is to describe the design of available matrix models and to assess the experience with these models to date. This will aid physicians, health insurance companies, and policy makers to gain a better understanding of both how matrix models can support generic medicine prescribing and how they can be used as a tool to support further population health improvements whilst optimising pharmaceutical expenditure.
Two matrix models have been developed in The Netherlands: the System of Objectified Judgement Analysis (SOJA) [2] and InforMatrix [4]. These matrix models are used for assessing medicines within a certain pharmaceutical class.
The SOJA matrix model
The SOJA matrix model defines a number of selection criteria for a given group of medicines and scores the extent to which each individual medicine fulfills the requirements for each criterion. The most important selection criteria are: clinical efficacy, documented effects on clinically relevant endpoints, incidence and severity of side effects, tolerability, dosage frequency, drug interactions, costs, and documentation. Each criterion is given a relative weight, i.e. more important selection criteria are assigned a higher relative weight.
The scores of a medicine on each selection criterion are determined by a panel of experts in the field. The scores of all medicines are compared to the hypothetical ‘ideal’ medicine from that group, which is assigned the full relative weight for each criterion. This ideal medicine will be 100% effective in all patients, have optimal effects in terms of clinically relevant endpoints and quality of life, have no side effects, is given once daily, shows no drug interactions, is well documented concerning randomised double-blind comparative clinical studies, has a very low acquisition cost, and there must be extensive clinical experience with the drug. The scores for the other medicines for each selection criterion are expressed as a percentage of the relative weight for that criterion. One medicine may therefore score 70% on efficacy, 80% for side effects, 100% for dosage frequency, 30% for medicine interactions, and 20% for cost, as compared with the ‘ideal’ medicine that is used as a reference.
In the published SOJA scores, 1,000 points are divided over the criteria that are considered to be relevant for a particular group of medicines. An example of a SOJA score for antipsychotics in the treatment of schizophrenia is presented in Table 1. Once generic olanzapine becomes available, this drug will also perform well in a future SOJA update.
Interactive program
In the interactive program, the percentages scores for each medicine per criterion have been determined by a panel of experts, but users of the program, e.g. physicians, pharmacists, are free to assign their own relative weight to each criterion. The program then computes the ranking scores for the medicines in the group.
The InforMatrix model
The InforMatrix model was developed in the early 1990s [5]. The InforMatrix model is an instrument that enables the users of the program to determine, on the basis of agreed criteria, an order of merit for the various medicines available in a specific category. The criteria used are: effectiveness, safety, tolerability, ease of use, applicability, and costs. Safety refers to the incidence of severe to life-threatening side effects and tolerability the incidence of mild to moderate side effects, such as nausea, headache or skin reactions. Relative weights are applied to these six criteria by the users of the program. Next, the medicines are compared to each other per criterion. This evaluation of the medicines is informed by data from the literature and by clinical experience. The weighted score of a medicine per criterion is determined by multiplying the score of a medicine for the criterion by the relative weight of the criterion. To compute the final score of a medicine, the weighted scores are totalled across the six criteria. The most important differences and similarities of both methods are summarised in Table 2.
Validation
Various validation steps are used for matrix productions. For InforMatrix, a standard set of criteria is used in all productions. The same is true for SOJA, although extra criteria may be added when this is considered relevant, such as risk of development of resistance to antibiotics.
All matrix authors are asked to provide information on links with pharmaceutical companies or other conflicts of interest, which may affect their judgement. All discussions with individual authors are visible to all other authors in order to improve a transparent decision-making process.
Matrix models are a step towards objective medicine prescribing, but it should be noted that there is still some subjectivity involved in these models. For example, although there is usually agreement on the fact that medicine A has a lower incidence of side effects than medicine B as proven in clinical trials, any assessment of the importance of the observed difference, as is done in SOJA, is subjective. Therefore, a number of peer reviewers critically assess the evidence integrated in the matrix model. The matrix productions are sent to all pharmaceutical companies that are marketing drugs in that specific drug class (including generics) for their comments on the scientific correctness and completeness. All articles are then published in peer reviewed journals, necessitating comments by independent reviewers.
How SOJA and InforMatrix can influence generics prescribing
SOJA is designed for use in primary care and for drug classes with large numbers of randomised clinical trials, allowing judgement of the relative efficacy and safety. Informatrix is used primarily in hospital care and for drug classes for which few or no direct double-blind comparative studies have been performed, such as for the tumour necrosis factor-alpha blockers, which have only been compared to placebo, but not between the drugs.
The experience with the SOJA and InforMatrix models suggests that users of the program usually assign high relative weights to criteria such as clinical efficacy, documented effects on clinical endpoints, safety, and dosage frequency. Medicines that perform well on these criteria therefore show a high score for almost all users. In general, generic medicines score very well in the SOJA and InforMatrix models. Their high scores do not originate from their low cost—as physicians and pharmacists do not consider cost to be an important criterion, but instead from their proven clinical efficacy, proven effects on clinically relevant endpoints— morbidity and mortality, extensive and long-term clinical experience with the medicine, and documented long-term safety. Examples of pharmaceutical classes where generic medicines perform well in the most recent updates of published SOJA scores are presented in Table 3. These scores are based on the weightings assigned by the authors of the original publications.
As physicians tend to have few incentives to prescribe generic medicines in most European countries, this paper has identified matrix models to be an instrument to support generic medicine prescribing. Matrix models provide a tool to facilitate rational and evidence-based medicine prescribing. Such models can be applied by physicians, pharmacists, formulary committees in hospitals, health insurance companies, and policymakers to inform medicinal selection.
Matrix models ensure that medicine prescribing is founded upon multiple rational and evidence-based criteria; other non-rational selection criteria do not play a role in the decision-making process. As a result, medicine prescribing becomes transparent and reproducible as the criteria and weightings on which decisions are based are known. A matrix model also avoids the situation where a decision is taken solely on one criterion and therefore supports a comprehensive approach towards medicine prescribing. The use of matrix models in The Netherlands and Northern Ireland suggests that this method for medicine prescribing greatly aids discussion in pharmacotherapy audit meetings between general practitioners and/or pharmacists, local or regional formulary committees, pricing, and reimbursement negotiations.
Matrix models allow the active participation of physicians, pharmacists and other stakeholders in informing medicine prescribing. These models tend to integrate ‘top-down’ and ‘bottom-up’ methods of decision making. The ‘top-down’ contents of matrix models, i.e. assessment of medicines based on a thorough evaluation of the evidence, are combined with the high compliance of the ‘bottom-up’ decision-making process as the final decision is made by, for example, the formulary committee in a hospital. This is likely to increase the acceptability of the matrix model’s outcome—namely the identification of the most appropriate medicine to prescribe.
Matrix models suffer from a number of limitations; they are time-dependent in that the evidence on the efficacy, safety, costs, pharmacokinetic and pharmaceutical aspects of medicines change continuously. Also, new products are introduced over time and older products are withdrawn from the market. Regular updates of the information needed by matrix models are therefore necessary. For instance, the Dutch SOJA matrix model is updated every six months.
It could be argued that matrix models may inhibit the introduction of innovative medicines due to the limited documentation of evidence on such medicines. If a new medicine has no added benefit as compared to existing medicines in terms of the selection criteria used in matrix models, it will almost certainly show a low score because of its poorer documentation and usually higher acquisition cost. However, such medicines are not innovative, but are in essence ‘me too’ medicines. Generically available drugs will show higher scores compared to the ‘me too’ drugs. A truly innovative medicine would exhibit an added benefit compared to existing medicines, thus generating a high score in a matrix model, especially when effects on clinically relevant endpoints have been documented.
The operation of matrix models in practice—based on unpublished results from hundreds of interactive sessions in The Netherlands and Northern Ireland—shows that users of the program tend to assign high relative weights to the clinical efficacy, documented effects on clinical endpoints, safety and dosage frequency of medicines. Pharmaceutical factors, pharmacokinetics and acquisition cost are usually given a low relative weight. During these sessions, generic medicines showed favourable overall scores because they have the same quality, safety, and efficacy as originator medicines, but have a lower cost. Compared to newer drugs from the same class, they have the advantage of wider clinical experience, documented effects on clinical endpoints and better documentation concerning randomised controlled clinical trials.
Other scores such as for erythropoiesis-stimulating factors and granulocyte colony-stimulating factor showed favourable results for drugs, which are also available as biosimilars. Again, the preference for these drugs is based on quality aspects instead of cost. Therefore, matrix models may also be useful to promote the use of (good quality) biosimilars.
A variety of interactive tools are available on the Internet [6], which allow active participation of physicians and pharmacists in the preparation of the score. The existing programs are specific for the Dutch and UK situation. Several adjustments to criteria need to be made to make these programs suitable for use in other countries such as available formulations, trade names, approved indications, dosage frequency, and acquisition cost. These adjustments can be made in a couple of hours per program, so country-specific matrices can be made at very short notice. Besides this, it is highly recommended to use a local expert group in each country to increase ‘ownership’; translation into the local language is also recommended for most countries.
Matrix models may serve as an instrument to support generic medicine prescribing. The experience of The Netherlands and Northern Ireland indicates that generic medicines perform well in matrix models. In Northern Ireland, generic drugs showed the highest scores for the first five drug classes—statins, proton pump inhibitors, ACE inhibitors, angiotensin II antagonists, and selective serotonin reuptake inhibitors—investigated by the matrix methodology [7]. In the Dutch situation, generics showed the highest scores for many pharmaceutical classes. The main advantage of matrix models is that the high scores for drugs available as generics are based on clinically relevant criteria, such as efficacy, documented effects on clinical endpoints, safety and dosage frequency of medicines and not solely on acquisition cost. Therefore the outcomes of matrix models are accepted much better by physicians, rather than choosing generic drugs on the basis of cost. All matrices are available in an interactive format, thereby allowing active participation of physicians and pharmacists.
Use of generic drugs instead of patented drugs can save major amounts of money. However, many physicians do not consider cost an important selection criterion. This paper describes interactive matrix models to promote rational drug selection within a drug class, based on criteria such as efficacy, safety, tolerability, dosage frequency, drug interactions, documentation and cost. When all these criteria are taken into consideration and weighted, generic drugs are very interesting alternatives to much more expensive patented drugs.
References
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Author: Robert Janknegt, PharmD, PhD , Director of Pharmacy and Clinical Pharmacology, Orbis Medisch Centrum, 1 Dr H van der Hoffplein, NL-6162 BG Sittard-Geleen, The Netherlands |
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Source URL: https://gabi-journal.net/how-matrix-models-can-support-generic-medicine-prescribing.html
Copyright ©2024 GaBI Journal unless otherwise noted.
