British Journal of Clinical Pharmacology
DOI:10.1111/bcp.12456
Patient representatives’ contributions to the benefit–risk assessment tasks of the European Medicines Agency scientific committees
Correspondence
Rosemarie D. L. C. Bernabe, Ghislaine J. M. W. van Thiel & Johannes van Delden
Received
Julius Center for Health Sciences and Primary Care, Utrecht University Medical Center, Str. 6.131, PO Box 85500, 3508GA Utrecht, The Netherlands
27 June 2014
Dr Rosemarie D. L. C. Bernabe PhD, Julius Center for Health Sciences and Primary Care, Utrecht University Medical Center, Str. 6.131, PO Box 85500, 3508GA Utrecht, The Netherlands. Tel.: +31 88 756 8367 Fax: +31 88 756 8099 E-mail: [email protected] -----------------------------------------------------------------------
Keywords benefit–risk assessment, European Medicines Agency, patient participation, patient representatives, scientific committees -----------------------------------------------------------------------
8 October 2013
Accepted Accepted Article Published Online 4 July 2014
In the European Medicines Agency (EMA), the involvement of patients has been increasingly recognized as valuable and necessary. Specifically in scientific committees, patients through patient representatives are actively involved in deliberations and decision making processes. These scientific committees are meant to ensure that licensed medicines have a positive benefit–risk ratio in favour of the patients and users. To investigate what the contributions are of patient representatives in benefit–risk assessment, we interviewed 15 scientific committee members, 10 of whom are/were EU-state regulatory representatives and five are/were patient representatives. We asked the participants questions related to the benefit–risk assessment tasks of their committees, the connection between patient representatives and the patient perspective, and the contribution of patient representatives in the various benefit–risk assessments tasks. We found that the contribution of patient representatives benefit–risk assessment may be a variable of the benefits and the risks involved in the drug such that the necessity of their contribution is strongly felt when both benefits and risks are high, when benefits are almost equal or are equal to risks and when both benefits and risks are low. In terms of the various benefit–risk tasks, patient representatives contribute to benefit–risk analysis by providing criteria that help define the benefit–risk picture. In benefit–risk evaluation, patient representatives aid in providing a specific basis for the values and weights given to specific benefits and risks and in decision making, they provide what may be a crucial patient perspective in terms of the acceptability of risks. Hence, patient representatives provide a specific expertise in these scientific committees.
Introduction In the European Medicines Agency (EMA), scientific committees are meant to ‘ensure that medicines have a positive benefit–risk balance in favour of patients and users of these products once they reach the marketplace’ [1]. Currently, there are seven scientific committees: the Committee for Medicinal Products for Human Use (CHMP) which is responsible for the preparation of the opinion of the EMA on a human medicinal product, the Pharmacovigilance Risk Assessment Committee (PRAC) which is responsible for the assessment and the monitoring of safety issues of human medicines, the Committee 1248
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for Medicinal Products for Veterinary Use (CVMP) which is responsible for preparing the EMA’s opinion on veterinary medicines, the Committee for Orphan Medicinal Products (COMP) which is responsible for reviewing applications for ‘orphan-medicinal-product designation’, the Committee on Herbal Medicinal Products (HMPC) which is responsible for the preparation of the opinion of the EMA on herbal medicines, the Committee for Advanced Therapies (CAT) which is responsible for the assessment, in terms of quality, safety and efficacy, of advanced therapy medicines and the Paediatric Committee (PDCO) which is responsible for assessing and providing opinions on ‘paediatric investigation plans [1]. Within © 2014 The British Pharmacological Society
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the CHMP, PRAC, COMP, CAT and PDCO, patients are involved either as experts who provide testimony advice and/or as patient representatives who are full committee members. The involvement of patients has been increasingly recognized as valuable and necessary. In the EU Roadmap to 2015, for example, patients are said to contribute to benefit/risk considerations by ‘enrich(ing) regulatory decisions by complementing them with the views of those directly affected by regulatory decisions’ [2]. At the same time, the inputs of patients contribute to transparency, trust and mutual respect between the regulators and the community of patients [3]. Hence, at least in the EMA, the value of the ‘experiential knowledge’ of patients in clinical trials and decision making is now largely acknowledged. This is reflected in the literature as well [4, 5]. Rather, the current debate is, ‘how to achieve more structured involvement of patients in the Agency’s work’ [2]. This study specifically looks at the contribution of patient representatives in the benefit–risk assessment tasks of scientific committees. In the process of doing so, we hope to contribute to the structuring of patients’ involvement in terms of the assessment of benefits and risks done by these committees. Within the CHMP, there are scientific advisory groups that provide advice on specific medicines or treatments [6]. In a report entitled, Outcome report on pilot phase for participation of patient representatives in Scientific Advisory Groups, results show that ‘patient representative contribution to the scientific advisory group (SAG) meetings is . . . variable’, and the variability would depend on the type of questions addressed in the SAG meetings and the selected patients to attend [7]. Though the report focused on SAGs, we believe the results may very well be applied to scientific committees, especially that some members of these scientific committees were or are also members of SAGs. As such, we shall assume the variable findings of the report and we hope to identify further the factors related to such variability within the sphere of benefit/risk assessment.
Aim This research aims to provide a preliminary exploration of the thoughts of EMA committee members on the role of patient representatives in the assessment of benefits and risks of scientific committees. To achieve this aim, we shall respond to the following questions: a For the committee members, do scientific committees assess benefits and risks, and if so, what does this assessment consist of? b What is the connection between patient representatives and the patient perspective?
c How do patient representatives contribute in the assessment of benefits and risks?
Methodology Sample Members or former members of any of the six EMA scientific committees on human therapeutic products were eligible to be participants. In December 2012, invitations to participate via email were sent randomly to 54 committee members who either are/were EU-state regulatory representatives or are/were patient representatives. In total, 15 committee members agreed to participate. The views expressed by the interviewed experts are their personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or working parties. Five of the participants are/were patient representatives (two are/were patients themselves; three represent/ represented patients1) while 10 are/were regulators/ scientists. Committee membership experience ranged from 1 year to more than 10 years, the average committee experience being 4.9 years. Average EMA participation, i.e. their participation in all EMA groups including working parties, was 5.7 years. Seven of the participants were female and eight were male. Participants were either from the CHMP, COMP, CAT, PDCO or PRAC.
Data collection Invitation letters via email were randomly sent to scientific committee members. From January to March 2013, the participants were interviewed once via phone and were asked to elaborate on the benefit–risk evaluation tasks of their committees, the incorporation of the patient perspective in such evaluations, their perceived added value of the patient representatives’ contributions in such evaluations and their level of satisfaction with the involvement of patient participants in such evaluations. For the participants who consented to the recording of the interview, the recordings were transcribed. For those who did not give their consent, data were written down as notes.
Data analysis The methods of grounded theory [8] were used to analyze the data. Because in grounded theory, a ‘theory emerges through a close and careful analysis of the data’ [9], the researchers considered this method as most appropriate 1
In spite of this distinction, the researchers decided to treat the patient representatives as homogenous since (a) the number of patient representatives was too small to make such a distinction validly and (b) there was no marked discordance among their responses. Br J Clin Pharmacol
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for this research. Due to lack of sufficiently similar literature, verifying an existing hypothesis on the subject matter is not possible. The researchers need to begin on the ‘ground,’ so to speak, to understand the process and allow a theory to emerge on the contributions of patient representatives in the benefit/risk assessment tasks of scientific committees. After data collection, both RB and GvT went through the data to do open coding and then axial coding afterwards. Discrepancies were resolved through joint discussions. NVivo 10 was used to aid the researchers in the coding process. For the final interpretation of the data, joint meetings between RB, GvT, and JvD were held for the purposes of consensus. Patient representatives were coded as A and regulators as B. Since some committees are younger than the others, it may be more interesting to know the years of EMA experience of the participants. Participants with ≤5 years of EMA experience at the time of the interview were coded as A and those with >5 years of EMA experience at the time of the interview were coded as B. Thus, a patient representative with 4 years of EMA experience will be coded as [A,A]. This research was organized chronologically according to the research aims. To analyze the data on patient representatives’ contribution in the weighing of risks and benefits, we used the risk studies framework [10–12]. In this framework, the weighing of benefits and risks consists of the following tasks: analysis, evaluation, treatment and decision making. Benefit–risk analysis refers to the ‘systematic use of information to identify initiating events, causes, and consequences of these initiating events, and express risk (and benefit)’ in a benefit–risk picture [10]. Benefit–risk evaluation refers to the process of comparing benefits and risks against a given criteria to determine benefit and risk significance. Risk treatment refers to the process of modifying risks. Finally, decision making refers to the process of judging whether the risks of a treatment, a dossier, a protocol etcetera are acceptable given the benefits, i.e. if risks do not outweigh benefits. We shall use this framework to categorize and organize the responses of the participants. Note that the third step, i.e. risk treatment, is irrelevant for us in the sense that none of the responses address this task. As such, we shall skip this step.
According to Dutch law, no ethics committee approval was needed.
Findings The participants’ perception of the benefit–risk assessment task of scientific committees All the participants agreed that their committees do a benefit–risk assessment of some sort. Thus, all members, including patient participants, ought to be engaged in these assessments as well. Though explicit benefit–risk assessment is attributed to the CHMP and PRAC, other committees are said to weigh benefits against risks, or efficacy against safety in one form or another. According to a committee member who does not belong to either CHMP or PRAC, . . . risk benefit is always a very important part when we decide whether we are going to give a positive opinion or a waiver to a product if it is of significant benefit, or if it is not of benefit to the patients, or if there are safety concerns . . . [B,B] Though all participants were of the opinion that their committees did a benefit–risk assessment, there were various definitions of what this meant. It is noteworthy that only one of the participants mentioned using a methodology from the EMA Benefit/Risk Methodology project [13], a 3 year project initiated by a working group of the CHMP which is meant to aid the agency in standardizing its benefit/risk methodology and in making the act of balancing as consistent and transparent as possible. For many of the participants, benefit–risk assessment meant following the set procedure:
Ethical considerations
But what is done then is that these two rapporteurs independently from each other provide an assessment of quality, safety and efficacy, and make a recommendation already at the first round of review on the approvability or non-approvability of . . . a therapy. And this is then circulated to the members, they can comment like agree, disagree or we want this question or we want that question to the company, and then there is a formal discussion at the plenary meeting . . . So you could say that this is a very formalized process, well-defined in the legislation and in the rules of procedure . . . [B,B]
The participants’ agreement to participate in our study was asked via email. Those who agreed to participate were then asked if they consented to the recording of the interview as well. In cases when participants declined on the latter, notes were taken. The recorded interviews were all deleted after they had been transcribed. The transcribed interviews were anonymized and were saved in a password-protected computer.
Depending on the committee, the various committee members mentioned different benefit–risk criteria. For example, a member of COMP mentioned ‘significant benefit’ as the benefit–risk criterion, a PRAC member mentioned ‘good pharmacovigilance practice’ and process maps and a CAT member mentioned ‘good clinical practice’.
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The patient perspective and the patient representatives The ‘patient perspective’ is a common theme for the majority of participants. Several participants summarized this perspective through the questions, ‘what would patients think or feel?’ and ‘would patients accept this risk considering these benefits?’ It is the majority assumption that patient representatives either (a) have a personal and direct access to their own experiences as patients or, (b) have a relatively easier access to this perspective. The latter perspective, i.e. that patient representatives have easier access to the patient perspective, referred either to the ability and the practice of patient representatives to ‘collect information from their network (i.e. their patient organizations among others)’ [A,A] or from what this patient representative referred to as an EMA database of patient contacts, the patient representatives’ intimate access to patients (such as the parents of sick children, for example), and/or their access to some consensus opinion from a group of patients. It is noteworthy that for some participants, these two perspectives are not exclusive. One regulator said, The primary way that patients are involved is in the individual level. So it is the individual patient sitting there and giving her view. But you can often see that patients then kind of discuss the items with other patients or even make surveys, you know. They have their ways of getting, or supporting their opinion with other people’s opinion. [B,B] The patient perspective is a major justification for patient participation in these scientific committees. First, patients are the end-users of the drug. As such, the usefulness and the economic possibilities of a drug depend on how these users value it. Second, the patient perspective is important since according to a number of participants who are regulators, patients give something that they (i.e. the regulators) do not have, which is the experience with the disease and some other medications. This allows for the discussion to be heterogenized, which, according to one regulator, provides some sort of focus on the agenda of the discussion. Third, the patient perspective provides some sort of political legitimization to the regulatory process that these committees have. It is interesting and important to note that apart from the majority opinion that patient representatives are needed in scientific committees, most of the participants agree that the participation of patients (who are not patient representatives) is necessary, at least in terms of giving information and advice. As regards the nature of the inputs that patient representatives provide, variability was noticed. One patient representative characterized her/his contribution as ‘objective’, which s/he further defined as being well-informed and going beyond personal experiences. Another patient representative on the other hand
saw her/his contribution as something that comes from her/his personal experience, an experience that other members do not necessarily have.
The participants’ perception of patient representatives’ contributions in the benefit–risk assessment task of scientific committees The risk–benefit tasks It is the opinion of a number of participants that patient representatives bring in something new or original to the discussion. One regulator called this original contribution the ‘non-medical aspect,’ i.e. that aspect that is meta-medical (beyond what is strictly ‘medical’) and meta-scientific (beyond what is strictly ‘scientific’). We shall in the following pages elucidate what this original contribution in the various benefit– risk tasks may mean. Benefit risk analysis In the creation of a benefit–risk picture during analysis, committee members consider various aspects and/or considerations to include in that picture. One regulator participant, for example, mentioned the following aspects that s/he considers during benefit– risk analysis: In respect to benefits we consider the obvious things . . . duration, the generalizability of the evidence of efficacy, alternative treatment, all kinds of things. On the risk side we also consider clinical importance, the nature of the toxicity, predictability, reversibility . . . [B,B] However, for the majority of the participants, this list is incomplete without the meta-medical aspects. Another regulator referred to the contribution of patient participants as providing an experiential picture of the pathology in question: I mean you have the broader view of the pathology when you talk with patient representatives because when you get out of the clinics, you have a different view, you find that it is important talking with patients. [B,A] According to another regulator, the meta-medical contribution of patient representatives in benefit–risk analysis is not only in the provision of aspects that are beyond the list of aspects that regulators regularly look at, but in including aspects that regulators would probably consider as negligible. I suppose the patient perspective is important in that context because some of the side effects that may not seem as risk drivers might be actually important in terms of the impact on the patient and certain impact Br J Clin Pharmacol
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on patient compliance and willingness to use a medicine. [B,B]
understanding of risks and benefits. One patient representative expressed this point as follows:
Thus, these meta-medical aspects, combined with the aspects that regulators generally consider as necessary, form part of the benefit–risk picture that scientific committees look at. It is noteworthy that it is the minority opinion that patient representatives should be limited to benefit–risk analysis, i.e. that they ought not to be included in benefit– risk evaluation and decision making. For one regulator, for example, patients who participate in committees should aid committee members in evaluation and decision making by answering questions, providing data, stating their opinions and narrating their experiences, but not to do anything beyond this.
If you’re a pathologist or a statistician or you know, a regulatory professional, you can calculate, you can look at the numbers, you can work out whether you think this is a sensible scientific rationale. What you can’t do in the same way is say, yeah but how important is it? How significant is it? [A,B]
Benefit risk evaluation It is the majority opinion that patient representatives rightfully ought to go beyond the task of being information providers and consultants. This is an affirmation of the existing system wherein of all the six committees relating to human medicinal products, only two are not mandated to have patient representatives (i.e. the CHMP and the HMPC). This means that for the majority, patient representatives should participate in discussions and be part of the decision making process. According to one patient representative, . . . the message or the assumptions underpinning that framing of the committee (i.e. the CHMP) were that it was a mechanical process, if you feed in the ingredients at one end and turn the handle, you get a judgment at the other end. And the purpose of the committee was simply to make sure that all the evidence, all the ingredients were fed in at the one end, and the handle was turned in a timely manner. But as things evolved, so it was realized that this was essentially an over-simplistic interpretation of the situation and patient perspectives actually were an important part of the process because they’re able to give that insight into the benefits of the proposed intervention. [A,B] For this patient representative, the assessment of benefits and risks cannot be satisfactorily done homogenously and mechanically. In this instance, the mechanical aspect springs from the homogenous. Since the system is assumed to be homogenous, the process becomes monotonous and therefore mechanical. Rather, for this patient representative, committees need the input of another set of stakeholders, i.e. the patients through the patient representatives. The meta-medical contributions of patient representatives allow for more heterogeneity and hopefully, for a less monotonous process. It is the notion of the majority of the participants that patient representatives allow for a specific and concrete 1252
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A regulator gave the example of quality of life scores to illustrate this same point: Another typical question is when there is a quality of life score, which is more of a subjective score, then one could ask the patients if this makes sense in the way that it is assessed and evaluated, and also if this is relevant from the kind of symptoms that are put there. [B,B] Another patient representative cited the necessity of actual patient involvement by giving the example of her/ his experience in one committee’s discussion on the significant difference between being able to walk 20 m as opposed to 40 m: And that is really something you should ask the patients themselves. In those kinds of cases, we brought in these patients and asked, what does it mean, what is the difference for you if you could walk 20 m or 40 m? And then all of a sudden this stupid 20 m which for you and for me would make no difference at all, does make the difference, because it means you can reach your car, and by reaching your car you can drive to wherever you want. You can drive to your work, or maybe also, by walking 40 m you can reach your office and you can do your job. [A,B] In this instance, this difference meant a real impact on this group of patients’ lives (at the very least, the lives of patients who were consulted), and hence the specificity aided in the valuation of the significance of the benefits and the risks. Since patient representatives aid in the appreciation of the significance of the benefits given the condition, and the significance of adverse events and the uncertainties, to a certain extent, patient representatives aid in providing a concrete basis for the values and weights given to specific benefits and risks. This valuation and the weighing of benefits and risks constitute benefit–risk evaluation. Decision making In final decision making, committee members are asked to judge (to grant marketing authorization, for example), or at the very least, are asked to endorse or not to endorse a proposal. For all the committee members, the act of judging or coming up with
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a decision is reached most of the time by consensus, and only in very few instances do committees resort to voting. In the process of reaching a consensus, patient representatives, just like the other committee members, participate in discussions leading towards consensus. However, apart from this generic role that patient participants share with all the other members, there are very specific roles that seemingly only patient participants could fill. First, patient participants, through their contribution to what the patient perspective is, are truly helpful in coming up with a consensus or a decision especially when the benefit–risk margin is narrow, i.e. in moments of uncertainty. One regulator expressed this point this way: Are we clear what the correct action to take, and of course we might want to change behaviour, but if there is uncertainty, if we’re not clear as to what’s the best action for every individual out there, well then I think that’s a situation where we really need to get the input of patients, to explain to us what the patients’ values and judgments might be, how that might impact individuals and decisions . . . [B,B] This regulator, along with a few other participants, cited a specific therapy (which we call therapy A) as an example where the benefit–risk margin is narrow, and hence making the patient perspective explicit through patient representatives was necessary for the final decision making. I can think about an obvious example, the (therapy A) example concerning progressive multifocal leukoencephalopathy life threatening adverse reaction, very rare, and then a very effective drug to treat a very debilitating and very progressive disease. But then it’s the value judgments there, do the patients worry more about being in a wheelchair or do they really worry about their cognitive function and adverse reaction that might affect their brain? So it’s trying to get those value judgments. [B,B] In this situation where risks are high and benefits are high, the concrete expression of the patient perspective through the patient participants seemed to be the focal point in decision making in the sense that after all deliberations and discussions, the final decision making could only be achieved once the patient perspective has been clearly expressed. At this point, regulators want some proof that their decision is, according to another regulator, indeed ‘consistent with the patients’ judgment’ [B,B]. Second, in the act of providing the patient perspective on what level of risk is acceptable given the benefits, patient participants seem more accepting of risks than regulators, especially in life-threatening or severely disabling diseases. Since patient representatives may be more tolerant of risks in certain situations, this latter level of acceptable risk may act as a balance against the level of
acceptable risk for regulators and, in difficult decisions, this patient perspective on acceptable risk may even provide confidence. A patient participant expressed this as follows: I think the patient representative’s role in the committee is to kind of give the regulatory professionals who are there from national competent authorities or other interested groups, you know the commission, the agency whatever, give those people the confidence to be able to make a judgment whether there is probably a significant degree of uncertainty [A,B]. In those moments of regulatory uncertainty, the differing level of acceptable risk for patient participants becomes one of the elements not only to make the decision but to be confident about it.
Discussion In the introduction, we mentioned that according to the Outcome report, the contributions of patient representatives are variable, depending on the questions being addressed and the patients who were selected to attend. Our results provide some clarification on this variability, at least within the area of benefit–risk assessment. Our results agree with the Outcome report that variability may be accounted for by who is invited to attend. In section on ‘the patient perspective and the patient representatives’ we saw that there was variability with how the contributions of patient representatives were characterized, i.e. it could either be primarily an opinion that goes beyond personal experiences, or it could be something very personal. These differences on how contributions are characterized may also account for variability in terms of how patient representatives view what sort of preparation and inputs are required of them. On top of the ‘who’ aspect, the variability that was earlier mentioned in terms of patient representative contribution, specifically within the assessment of benefits and risks, may also be explained by aspects such as the amount of uncertainty in the benefits and the risks, narrowness of the benefit–risk margin and the amount of specificity of actual life situation needed to make the decision, among others. Hence, the more uncertain regulators are (either because of the degree of uncertainty on the medicine in question or because of the narrow benefit–risk margin), the more pressed they would be to get a grip of the ‘patient perspective’, which in turn makes the presence and the task of patient representatives more urgent. The opposite is also true: if the benefit–risk margin is wide and/or if there are not many uncertainties on therapeutic effects and on the necessity of the drug, then the less need there is to validate what the patient perspective is. Patient representative participation is unambiguously necessary during benefit–risk assessment when both benBr J Clin Pharmacol
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Table 1 Summary of the contributions of patient representatives in the benefit– risk assessment task of scientific committees
Benefit–risk tasks
Contributions of patient representatives
Benefit–risk analysis
Additional inputs in the benefit–risk picture, such as experiential information regarding the pathology or some other aspects that regulators might find negligible but may in fact be important from the patient’s perspective Providing a concrete basis for the values and weights given to specific benefits and risks by concretizing and making explicit the significance of these benefits and risks (by providing real-life impact of certain interventions on patients, for example)
Benefit–risk evaluation
Decision making
Especially within areas where the patient perspective is necessary or pressing, validating that the risks of an indication are indeed acceptable for the patients considering the benefits (i.e., provide extra confidence on the decision)
efits and risks are high (such as therapy A above), when benefits are almost equal or are equal to risks (i.e. narrow margin), and when both benefits and risks are low (which may boil down to the question, would patients want and need this drug due to economic or other reasons?). In cases when risks are high and benefits are low, or when risks are low and benefits are high, the necessity for patient representative participation may not necessarily be that pressing. Now we do not in any way say that patient representatives ought to be present in committees only when both benefits and risks are high, when benefits are almost equal or are equal to risks, and when both benefits and risks are low; rather, during these situations, the patient perspective is unambiguously necessary in these sense that reasonable decision making is impossible without it. Not only is the presence of patient representatives pressing during the above-mentioned situations but, in what follows, the patient representatives’ tasks and contributions in the various benefit–risk tasks are also clearly set out, many times irrelevant of whether benefits and risks are high or low (see Table 1). It is interesting that though our study is the first we know that deals with patient representatives’ contributions on the benefit/risk assessment task of scientific committees, our findings accord with recent literature on patients’ contribution in other settings. Notwithstanding the limitations of the comparability, in terms of the conclusion that patient representatives aid in formulating a richer benefit–risk picture, the study by Avery et al. on the patient participation on the UK Yellow Card Scheme [14] concludes the same. In this study, Avery et al. conclude 1254
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that patient reporting could potentially enrich pharmacovigilance since patients report ‘reactions different from those reported by health care professionals, generating new potential signals . . .’. Avery et al.’s conclusion also supports our findings that patient representatives aid benefit–risk evaluation. Earlier, we saw that patient representatives contribute by providing a specific basis for the values and weights given to specific benefits and risks. In Avery et al.’s study, they conclude that patients ‘describe suspected ADRs in enough detail to provide useful information or likely causality and impact on patients’ lives’ [14]. Lastly, that patient representatives’ contributions may be crucial for decision making, especially in a nonstraightforward situation, accords with the findings of Arnardottir [15]. In chapter 7 of her PhD thesis, Arnardottir explored the comparability of the values that regulators, doctors and patients attach to the benefits and risks of an oral anti-diabetes drug and found that regulators, doctors and patients may value major benefits and risks in the same way. She concludes the chapter by stating that the inputs of doctors and patients on individual care can aid regulatory decision making, especially in nonstraightforward situations [15]. We earlier stated that the level of acceptable risk for patient participants may act as a balance against the level of acceptable risk for regulators, and that the patient representatives’ level of acceptable risk may provide confidence in difficult decisions. In this sense, patient participants’ acceptable risk may ease the ‘cautious regulator’ problem, i.e. the ‘progressive lowering of risk tolerance of regulatory agencies’ [16], which incidentally was named as one of the main causes of increased drug development cost and decreased drug development efficiency [16, 17]. Thus, though the intensity and the need for patient participant contribution in benefit–risk assessment may be variable depending on the situation (such as the levels of risks and benefits), the presence of patient participants is obviously an asset in these interdisciplinary scientific committees. They provide an ‘expertise’ that no other member could provide. As such, their inclusion as full members, and hence as co-holders of power, is not only wanted for political reasons. The elaboration of the patient perspective by the patient representatives is an integral part of the existence of such scientific committees and by default, of their procedures such as benefit–risk assessment. Within this study, we touched upon some areas that need further research, such as the characterization of what patient perspective is, the distinction between the inputs of patient representatives who are patients themselves and those who represent patients but are not patients, who the patient is, the inclusion of patient representatives in the CHMP and HMPC, the necessity and the manner of consultation with patients and patient organizations as inputs for scientific committee discussions and the need for more training, support and compensation for patient representatives, among others. We hope that this study
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would aid in providing the initial impetus for future studies within the area of patient participation in scientific committees.
Limitations of the study The number of participants, especially the number of patient representatives (i.e. five), is an obvious limitation of this study. The manner of collecting data also poses its own limitation.
Conclusion The contribution of patient representatives in benefit–risk assessment is a variable of the benefits and the risks involved in the drug. The necessity of the patient representatives’ contribution is strongly felt when both benefits and risks are high, when benefits are almost equal or are equal to risks and when both benefits and risks are low. We also saw that the contribution of patient representatives in benefit/risk assessment can be specifically defined as follows. In benefit–risk analysis, their criteria help define the benefit–risk picture; in benefit/risk evaluation, patient representatives aid in providing a concrete basis for the values and weights given to specific benefits and risks by making specific and explicit the significance of these benefits and risks and in decision making, they provide what may be a crucial patient perspective in terms of the acceptability of risks. Hence, patient representatives provide a specific expertise in scientific committees.
Competing Interests All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare RDLCB and GJMWvT received support from the Dutch Top Institute Pharma for the submitted work and RDLCB received a PhD grant from the Dutch Top Institute Pharma in the previous 3 years. JJMvD has no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years. This study was performed in the context of the Escher project (T6-202), a project of the Dutch Top Institute Pharma, Leiden, The Netherlands.
REFERENCES 1 European Medicines Agency. Committees, working parties and other groups. [online]. Available at http://www.ema
.europa.eu/ema/index.jsp?curl=pages/about_us/general/ general_content_000217.jsp&mid= (last accessed 19 June 2014). 2 European Medicines Agency. Roadmap to 2015: the European Medicines Agency’s contribution to science, medicines, and health. 16 December 2010 [online]. Available at http://www.ema.europa.eu/docs/en_GB/document _library/Report/2011/01/WC500101373.pdf (last accessed 19 June 2014). 3 European Medicines Agency. The role of patients as members of the EMA Human Scientific Committees. 2011 [online]. Available at http://www.ema.europa.eu/docs/en _GB/document_library/Other/2011/12/WC500119614.pdf (last accessed 19 June 2014). 4 Patient Partner. Patient involvement in clinical research: a guide for sponsors and investigators. 2011 [online]. Available at http://www.patientpartner-europe.eu/en/ project-outcomes/sponsors-guide (last accessed 19 June 2014). 5 van Thiel G, Stolk P. Background paper 8.5: patient and citizen involvement. World Health Organization, 10 June 2013 [online]. Available at http://apps.who.int/ medicinedocs/documents/s20234en/s20234en.pdf (last accessed 19 June 2014). 6 European Medicines Agency. CHMP: working parties and other groups. [online]. Available at http://www.ema.europa .eu/ema/index.jsp?curl=pages/about_us/general/general _content_000102.jsp (last accessed 19 June 2014). 7 European Medicines Agency. Outcome report on pilot phase for participation of patient representatives in Scientific Advisory Group (SAG) meetings. 15 September 2011 [online]. Available at http://www.ema.europa.eu/docs/en _GB/document_library/Report/2011/12/WC500119201.pdf (last accessed 19 June 2014). 8 Boeije H. Analysis in Qualitative Research. London: Sage, 2009. 9 Lingard L, Albert M, Levinson W. Grounded theory, mixed methods, and action research. BMJ 2008; 337: 459–61. 10 Aven T. Risk Analysis: Asssessing Uncertainties beyond Expected Values and Probabilities. Chichester: Wiley, 2008. 11 Vose D. Risk Analysis: A Quantitative Guide, 3rd edn. Chichester: Wiley, 2008. 12 Bernabe RD, van Thiel GJ, Raaijmakers JA, van Delden JJ. The risk-benefit task of research ethics committees: an evaluation of current approaches and the need to incorporate decision studies methods. BMC Med Ethics 2012; 13: 1–9. 13 European Medicines Agency. Benefit-risk methodology. [online]. Available at http://www.ema.europa.eu/ema/ index.jsp?curl=pages/special_topics/document_listing/ document_listing_000314.jsp&mid=WC0b01ac0580223ed6 (last accessed 19 June 2014). 14 Avery AJ, Anderson C, Bond CM, Fortnum H, Gifford A, Hannaford PC, Hazell L, Krska J, Lee AJ, McLernon DJ, Murphy E, Shakir S, Watson MC. Evaluation of patient Br J Clin Pharmacol
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reporting of adverse drug reactions to the UK ‘Yellow Card Scheme’: literature review, descriptive and qualitative analyses, and questionnaire surveys. Health Technol Assess 2011; 15: 1–234. 15 Arnardottir AH. Regulator benefit risk assessment: different perspectives. 2013 [online]. Available at http://www .tipharma.com/fileadmin/user_upload/Theses/PDF/Arna _Hrund_Arnardottir_T6-202.pdf (last accessed 19 June 2014).
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16 Tafuri G. Exploring the regulatory decision-making process for medicines. Utrecht University PhD Dissertation, 2013. 17 Scannell JW, Blanckley A, Boldon H, Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov 2012; 11: 191–200.
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DOI:10.1111/bcp.12456
Patient representatives’ contributions to the benefit–risk assessment tasks of the European Medicines Agency scientific committees
Correspondence
Rosemarie D. L. C. Bernabe, Ghislaine J. M. W. van Thiel & Johannes van Delden
Received
Julius Center for Health Sciences and Primary Care, Utrecht University Medical Center, Str. 6.131, PO Box 85500, 3508GA Utrecht, The Netherlands
27 June 2014
Dr Rosemarie D. L. C. Bernabe PhD, Julius Center for Health Sciences and Primary Care, Utrecht University Medical Center, Str. 6.131, PO Box 85500, 3508GA Utrecht, The Netherlands. Tel.: +31 88 756 8367 Fax: +31 88 756 8099 E-mail: [email protected] -----------------------------------------------------------------------
Keywords benefit–risk assessment, European Medicines Agency, patient participation, patient representatives, scientific committees -----------------------------------------------------------------------
8 October 2013
Accepted Accepted Article Published Online 4 July 2014
In the European Medicines Agency (EMA), the involvement of patients has been increasingly recognized as valuable and necessary. Specifically in scientific committees, patients through patient representatives are actively involved in deliberations and decision making processes. These scientific committees are meant to ensure that licensed medicines have a positive benefit–risk ratio in favour of the patients and users. To investigate what the contributions are of patient representatives in benefit–risk assessment, we interviewed 15 scientific committee members, 10 of whom are/were EU-state regulatory representatives and five are/were patient representatives. We asked the participants questions related to the benefit–risk assessment tasks of their committees, the connection between patient representatives and the patient perspective, and the contribution of patient representatives in the various benefit–risk assessments tasks. We found that the contribution of patient representatives benefit–risk assessment may be a variable of the benefits and the risks involved in the drug such that the necessity of their contribution is strongly felt when both benefits and risks are high, when benefits are almost equal or are equal to risks and when both benefits and risks are low. In terms of the various benefit–risk tasks, patient representatives contribute to benefit–risk analysis by providing criteria that help define the benefit–risk picture. In benefit–risk evaluation, patient representatives aid in providing a specific basis for the values and weights given to specific benefits and risks and in decision making, they provide what may be a crucial patient perspective in terms of the acceptability of risks. Hence, patient representatives provide a specific expertise in these scientific committees.
Introduction In the European Medicines Agency (EMA), scientific committees are meant to ‘ensure that medicines have a positive benefit–risk balance in favour of patients and users of these products once they reach the marketplace’ [1]. Currently, there are seven scientific committees: the Committee for Medicinal Products for Human Use (CHMP) which is responsible for the preparation of the opinion of the EMA on a human medicinal product, the Pharmacovigilance Risk Assessment Committee (PRAC) which is responsible for the assessment and the monitoring of safety issues of human medicines, the Committee 1248
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for Medicinal Products for Veterinary Use (CVMP) which is responsible for preparing the EMA’s opinion on veterinary medicines, the Committee for Orphan Medicinal Products (COMP) which is responsible for reviewing applications for ‘orphan-medicinal-product designation’, the Committee on Herbal Medicinal Products (HMPC) which is responsible for the preparation of the opinion of the EMA on herbal medicines, the Committee for Advanced Therapies (CAT) which is responsible for the assessment, in terms of quality, safety and efficacy, of advanced therapy medicines and the Paediatric Committee (PDCO) which is responsible for assessing and providing opinions on ‘paediatric investigation plans [1]. Within © 2014 The British Pharmacological Society
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the CHMP, PRAC, COMP, CAT and PDCO, patients are involved either as experts who provide testimony advice and/or as patient representatives who are full committee members. The involvement of patients has been increasingly recognized as valuable and necessary. In the EU Roadmap to 2015, for example, patients are said to contribute to benefit/risk considerations by ‘enrich(ing) regulatory decisions by complementing them with the views of those directly affected by regulatory decisions’ [2]. At the same time, the inputs of patients contribute to transparency, trust and mutual respect between the regulators and the community of patients [3]. Hence, at least in the EMA, the value of the ‘experiential knowledge’ of patients in clinical trials and decision making is now largely acknowledged. This is reflected in the literature as well [4, 5]. Rather, the current debate is, ‘how to achieve more structured involvement of patients in the Agency’s work’ [2]. This study specifically looks at the contribution of patient representatives in the benefit–risk assessment tasks of scientific committees. In the process of doing so, we hope to contribute to the structuring of patients’ involvement in terms of the assessment of benefits and risks done by these committees. Within the CHMP, there are scientific advisory groups that provide advice on specific medicines or treatments [6]. In a report entitled, Outcome report on pilot phase for participation of patient representatives in Scientific Advisory Groups, results show that ‘patient representative contribution to the scientific advisory group (SAG) meetings is . . . variable’, and the variability would depend on the type of questions addressed in the SAG meetings and the selected patients to attend [7]. Though the report focused on SAGs, we believe the results may very well be applied to scientific committees, especially that some members of these scientific committees were or are also members of SAGs. As such, we shall assume the variable findings of the report and we hope to identify further the factors related to such variability within the sphere of benefit/risk assessment.
Aim This research aims to provide a preliminary exploration of the thoughts of EMA committee members on the role of patient representatives in the assessment of benefits and risks of scientific committees. To achieve this aim, we shall respond to the following questions: a For the committee members, do scientific committees assess benefits and risks, and if so, what does this assessment consist of? b What is the connection between patient representatives and the patient perspective?
c How do patient representatives contribute in the assessment of benefits and risks?
Methodology Sample Members or former members of any of the six EMA scientific committees on human therapeutic products were eligible to be participants. In December 2012, invitations to participate via email were sent randomly to 54 committee members who either are/were EU-state regulatory representatives or are/were patient representatives. In total, 15 committee members agreed to participate. The views expressed by the interviewed experts are their personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or working parties. Five of the participants are/were patient representatives (two are/were patients themselves; three represent/ represented patients1) while 10 are/were regulators/ scientists. Committee membership experience ranged from 1 year to more than 10 years, the average committee experience being 4.9 years. Average EMA participation, i.e. their participation in all EMA groups including working parties, was 5.7 years. Seven of the participants were female and eight were male. Participants were either from the CHMP, COMP, CAT, PDCO or PRAC.
Data collection Invitation letters via email were randomly sent to scientific committee members. From January to March 2013, the participants were interviewed once via phone and were asked to elaborate on the benefit–risk evaluation tasks of their committees, the incorporation of the patient perspective in such evaluations, their perceived added value of the patient representatives’ contributions in such evaluations and their level of satisfaction with the involvement of patient participants in such evaluations. For the participants who consented to the recording of the interview, the recordings were transcribed. For those who did not give their consent, data were written down as notes.
Data analysis The methods of grounded theory [8] were used to analyze the data. Because in grounded theory, a ‘theory emerges through a close and careful analysis of the data’ [9], the researchers considered this method as most appropriate 1
In spite of this distinction, the researchers decided to treat the patient representatives as homogenous since (a) the number of patient representatives was too small to make such a distinction validly and (b) there was no marked discordance among their responses. Br J Clin Pharmacol
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for this research. Due to lack of sufficiently similar literature, verifying an existing hypothesis on the subject matter is not possible. The researchers need to begin on the ‘ground,’ so to speak, to understand the process and allow a theory to emerge on the contributions of patient representatives in the benefit/risk assessment tasks of scientific committees. After data collection, both RB and GvT went through the data to do open coding and then axial coding afterwards. Discrepancies were resolved through joint discussions. NVivo 10 was used to aid the researchers in the coding process. For the final interpretation of the data, joint meetings between RB, GvT, and JvD were held for the purposes of consensus. Patient representatives were coded as A and regulators as B. Since some committees are younger than the others, it may be more interesting to know the years of EMA experience of the participants. Participants with ≤5 years of EMA experience at the time of the interview were coded as A and those with >5 years of EMA experience at the time of the interview were coded as B. Thus, a patient representative with 4 years of EMA experience will be coded as [A,A]. This research was organized chronologically according to the research aims. To analyze the data on patient representatives’ contribution in the weighing of risks and benefits, we used the risk studies framework [10–12]. In this framework, the weighing of benefits and risks consists of the following tasks: analysis, evaluation, treatment and decision making. Benefit–risk analysis refers to the ‘systematic use of information to identify initiating events, causes, and consequences of these initiating events, and express risk (and benefit)’ in a benefit–risk picture [10]. Benefit–risk evaluation refers to the process of comparing benefits and risks against a given criteria to determine benefit and risk significance. Risk treatment refers to the process of modifying risks. Finally, decision making refers to the process of judging whether the risks of a treatment, a dossier, a protocol etcetera are acceptable given the benefits, i.e. if risks do not outweigh benefits. We shall use this framework to categorize and organize the responses of the participants. Note that the third step, i.e. risk treatment, is irrelevant for us in the sense that none of the responses address this task. As such, we shall skip this step.
According to Dutch law, no ethics committee approval was needed.
Findings The participants’ perception of the benefit–risk assessment task of scientific committees All the participants agreed that their committees do a benefit–risk assessment of some sort. Thus, all members, including patient participants, ought to be engaged in these assessments as well. Though explicit benefit–risk assessment is attributed to the CHMP and PRAC, other committees are said to weigh benefits against risks, or efficacy against safety in one form or another. According to a committee member who does not belong to either CHMP or PRAC, . . . risk benefit is always a very important part when we decide whether we are going to give a positive opinion or a waiver to a product if it is of significant benefit, or if it is not of benefit to the patients, or if there are safety concerns . . . [B,B] Though all participants were of the opinion that their committees did a benefit–risk assessment, there were various definitions of what this meant. It is noteworthy that only one of the participants mentioned using a methodology from the EMA Benefit/Risk Methodology project [13], a 3 year project initiated by a working group of the CHMP which is meant to aid the agency in standardizing its benefit/risk methodology and in making the act of balancing as consistent and transparent as possible. For many of the participants, benefit–risk assessment meant following the set procedure:
Ethical considerations
But what is done then is that these two rapporteurs independently from each other provide an assessment of quality, safety and efficacy, and make a recommendation already at the first round of review on the approvability or non-approvability of . . . a therapy. And this is then circulated to the members, they can comment like agree, disagree or we want this question or we want that question to the company, and then there is a formal discussion at the plenary meeting . . . So you could say that this is a very formalized process, well-defined in the legislation and in the rules of procedure . . . [B,B]
The participants’ agreement to participate in our study was asked via email. Those who agreed to participate were then asked if they consented to the recording of the interview as well. In cases when participants declined on the latter, notes were taken. The recorded interviews were all deleted after they had been transcribed. The transcribed interviews were anonymized and were saved in a password-protected computer.
Depending on the committee, the various committee members mentioned different benefit–risk criteria. For example, a member of COMP mentioned ‘significant benefit’ as the benefit–risk criterion, a PRAC member mentioned ‘good pharmacovigilance practice’ and process maps and a CAT member mentioned ‘good clinical practice’.
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The patient perspective and the patient representatives The ‘patient perspective’ is a common theme for the majority of participants. Several participants summarized this perspective through the questions, ‘what would patients think or feel?’ and ‘would patients accept this risk considering these benefits?’ It is the majority assumption that patient representatives either (a) have a personal and direct access to their own experiences as patients or, (b) have a relatively easier access to this perspective. The latter perspective, i.e. that patient representatives have easier access to the patient perspective, referred either to the ability and the practice of patient representatives to ‘collect information from their network (i.e. their patient organizations among others)’ [A,A] or from what this patient representative referred to as an EMA database of patient contacts, the patient representatives’ intimate access to patients (such as the parents of sick children, for example), and/or their access to some consensus opinion from a group of patients. It is noteworthy that for some participants, these two perspectives are not exclusive. One regulator said, The primary way that patients are involved is in the individual level. So it is the individual patient sitting there and giving her view. But you can often see that patients then kind of discuss the items with other patients or even make surveys, you know. They have their ways of getting, or supporting their opinion with other people’s opinion. [B,B] The patient perspective is a major justification for patient participation in these scientific committees. First, patients are the end-users of the drug. As such, the usefulness and the economic possibilities of a drug depend on how these users value it. Second, the patient perspective is important since according to a number of participants who are regulators, patients give something that they (i.e. the regulators) do not have, which is the experience with the disease and some other medications. This allows for the discussion to be heterogenized, which, according to one regulator, provides some sort of focus on the agenda of the discussion. Third, the patient perspective provides some sort of political legitimization to the regulatory process that these committees have. It is interesting and important to note that apart from the majority opinion that patient representatives are needed in scientific committees, most of the participants agree that the participation of patients (who are not patient representatives) is necessary, at least in terms of giving information and advice. As regards the nature of the inputs that patient representatives provide, variability was noticed. One patient representative characterized her/his contribution as ‘objective’, which s/he further defined as being well-informed and going beyond personal experiences. Another patient representative on the other hand
saw her/his contribution as something that comes from her/his personal experience, an experience that other members do not necessarily have.
The participants’ perception of patient representatives’ contributions in the benefit–risk assessment task of scientific committees The risk–benefit tasks It is the opinion of a number of participants that patient representatives bring in something new or original to the discussion. One regulator called this original contribution the ‘non-medical aspect,’ i.e. that aspect that is meta-medical (beyond what is strictly ‘medical’) and meta-scientific (beyond what is strictly ‘scientific’). We shall in the following pages elucidate what this original contribution in the various benefit– risk tasks may mean. Benefit risk analysis In the creation of a benefit–risk picture during analysis, committee members consider various aspects and/or considerations to include in that picture. One regulator participant, for example, mentioned the following aspects that s/he considers during benefit– risk analysis: In respect to benefits we consider the obvious things . . . duration, the generalizability of the evidence of efficacy, alternative treatment, all kinds of things. On the risk side we also consider clinical importance, the nature of the toxicity, predictability, reversibility . . . [B,B] However, for the majority of the participants, this list is incomplete without the meta-medical aspects. Another regulator referred to the contribution of patient participants as providing an experiential picture of the pathology in question: I mean you have the broader view of the pathology when you talk with patient representatives because when you get out of the clinics, you have a different view, you find that it is important talking with patients. [B,A] According to another regulator, the meta-medical contribution of patient representatives in benefit–risk analysis is not only in the provision of aspects that are beyond the list of aspects that regulators regularly look at, but in including aspects that regulators would probably consider as negligible. I suppose the patient perspective is important in that context because some of the side effects that may not seem as risk drivers might be actually important in terms of the impact on the patient and certain impact Br J Clin Pharmacol
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on patient compliance and willingness to use a medicine. [B,B]
understanding of risks and benefits. One patient representative expressed this point as follows:
Thus, these meta-medical aspects, combined with the aspects that regulators generally consider as necessary, form part of the benefit–risk picture that scientific committees look at. It is noteworthy that it is the minority opinion that patient representatives should be limited to benefit–risk analysis, i.e. that they ought not to be included in benefit– risk evaluation and decision making. For one regulator, for example, patients who participate in committees should aid committee members in evaluation and decision making by answering questions, providing data, stating their opinions and narrating their experiences, but not to do anything beyond this.
If you’re a pathologist or a statistician or you know, a regulatory professional, you can calculate, you can look at the numbers, you can work out whether you think this is a sensible scientific rationale. What you can’t do in the same way is say, yeah but how important is it? How significant is it? [A,B]
Benefit risk evaluation It is the majority opinion that patient representatives rightfully ought to go beyond the task of being information providers and consultants. This is an affirmation of the existing system wherein of all the six committees relating to human medicinal products, only two are not mandated to have patient representatives (i.e. the CHMP and the HMPC). This means that for the majority, patient representatives should participate in discussions and be part of the decision making process. According to one patient representative, . . . the message or the assumptions underpinning that framing of the committee (i.e. the CHMP) were that it was a mechanical process, if you feed in the ingredients at one end and turn the handle, you get a judgment at the other end. And the purpose of the committee was simply to make sure that all the evidence, all the ingredients were fed in at the one end, and the handle was turned in a timely manner. But as things evolved, so it was realized that this was essentially an over-simplistic interpretation of the situation and patient perspectives actually were an important part of the process because they’re able to give that insight into the benefits of the proposed intervention. [A,B] For this patient representative, the assessment of benefits and risks cannot be satisfactorily done homogenously and mechanically. In this instance, the mechanical aspect springs from the homogenous. Since the system is assumed to be homogenous, the process becomes monotonous and therefore mechanical. Rather, for this patient representative, committees need the input of another set of stakeholders, i.e. the patients through the patient representatives. The meta-medical contributions of patient representatives allow for more heterogeneity and hopefully, for a less monotonous process. It is the notion of the majority of the participants that patient representatives allow for a specific and concrete 1252
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A regulator gave the example of quality of life scores to illustrate this same point: Another typical question is when there is a quality of life score, which is more of a subjective score, then one could ask the patients if this makes sense in the way that it is assessed and evaluated, and also if this is relevant from the kind of symptoms that are put there. [B,B] Another patient representative cited the necessity of actual patient involvement by giving the example of her/ his experience in one committee’s discussion on the significant difference between being able to walk 20 m as opposed to 40 m: And that is really something you should ask the patients themselves. In those kinds of cases, we brought in these patients and asked, what does it mean, what is the difference for you if you could walk 20 m or 40 m? And then all of a sudden this stupid 20 m which for you and for me would make no difference at all, does make the difference, because it means you can reach your car, and by reaching your car you can drive to wherever you want. You can drive to your work, or maybe also, by walking 40 m you can reach your office and you can do your job. [A,B] In this instance, this difference meant a real impact on this group of patients’ lives (at the very least, the lives of patients who were consulted), and hence the specificity aided in the valuation of the significance of the benefits and the risks. Since patient representatives aid in the appreciation of the significance of the benefits given the condition, and the significance of adverse events and the uncertainties, to a certain extent, patient representatives aid in providing a concrete basis for the values and weights given to specific benefits and risks. This valuation and the weighing of benefits and risks constitute benefit–risk evaluation. Decision making In final decision making, committee members are asked to judge (to grant marketing authorization, for example), or at the very least, are asked to endorse or not to endorse a proposal. For all the committee members, the act of judging or coming up with
Patient representatives and risk benefit
a decision is reached most of the time by consensus, and only in very few instances do committees resort to voting. In the process of reaching a consensus, patient representatives, just like the other committee members, participate in discussions leading towards consensus. However, apart from this generic role that patient participants share with all the other members, there are very specific roles that seemingly only patient participants could fill. First, patient participants, through their contribution to what the patient perspective is, are truly helpful in coming up with a consensus or a decision especially when the benefit–risk margin is narrow, i.e. in moments of uncertainty. One regulator expressed this point this way: Are we clear what the correct action to take, and of course we might want to change behaviour, but if there is uncertainty, if we’re not clear as to what’s the best action for every individual out there, well then I think that’s a situation where we really need to get the input of patients, to explain to us what the patients’ values and judgments might be, how that might impact individuals and decisions . . . [B,B] This regulator, along with a few other participants, cited a specific therapy (which we call therapy A) as an example where the benefit–risk margin is narrow, and hence making the patient perspective explicit through patient representatives was necessary for the final decision making. I can think about an obvious example, the (therapy A) example concerning progressive multifocal leukoencephalopathy life threatening adverse reaction, very rare, and then a very effective drug to treat a very debilitating and very progressive disease. But then it’s the value judgments there, do the patients worry more about being in a wheelchair or do they really worry about their cognitive function and adverse reaction that might affect their brain? So it’s trying to get those value judgments. [B,B] In this situation where risks are high and benefits are high, the concrete expression of the patient perspective through the patient participants seemed to be the focal point in decision making in the sense that after all deliberations and discussions, the final decision making could only be achieved once the patient perspective has been clearly expressed. At this point, regulators want some proof that their decision is, according to another regulator, indeed ‘consistent with the patients’ judgment’ [B,B]. Second, in the act of providing the patient perspective on what level of risk is acceptable given the benefits, patient participants seem more accepting of risks than regulators, especially in life-threatening or severely disabling diseases. Since patient representatives may be more tolerant of risks in certain situations, this latter level of acceptable risk may act as a balance against the level of
acceptable risk for regulators and, in difficult decisions, this patient perspective on acceptable risk may even provide confidence. A patient participant expressed this as follows: I think the patient representative’s role in the committee is to kind of give the regulatory professionals who are there from national competent authorities or other interested groups, you know the commission, the agency whatever, give those people the confidence to be able to make a judgment whether there is probably a significant degree of uncertainty [A,B]. In those moments of regulatory uncertainty, the differing level of acceptable risk for patient participants becomes one of the elements not only to make the decision but to be confident about it.
Discussion In the introduction, we mentioned that according to the Outcome report, the contributions of patient representatives are variable, depending on the questions being addressed and the patients who were selected to attend. Our results provide some clarification on this variability, at least within the area of benefit–risk assessment. Our results agree with the Outcome report that variability may be accounted for by who is invited to attend. In section on ‘the patient perspective and the patient representatives’ we saw that there was variability with how the contributions of patient representatives were characterized, i.e. it could either be primarily an opinion that goes beyond personal experiences, or it could be something very personal. These differences on how contributions are characterized may also account for variability in terms of how patient representatives view what sort of preparation and inputs are required of them. On top of the ‘who’ aspect, the variability that was earlier mentioned in terms of patient representative contribution, specifically within the assessment of benefits and risks, may also be explained by aspects such as the amount of uncertainty in the benefits and the risks, narrowness of the benefit–risk margin and the amount of specificity of actual life situation needed to make the decision, among others. Hence, the more uncertain regulators are (either because of the degree of uncertainty on the medicine in question or because of the narrow benefit–risk margin), the more pressed they would be to get a grip of the ‘patient perspective’, which in turn makes the presence and the task of patient representatives more urgent. The opposite is also true: if the benefit–risk margin is wide and/or if there are not many uncertainties on therapeutic effects and on the necessity of the drug, then the less need there is to validate what the patient perspective is. Patient representative participation is unambiguously necessary during benefit–risk assessment when both benBr J Clin Pharmacol
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Table 1 Summary of the contributions of patient representatives in the benefit– risk assessment task of scientific committees
Benefit–risk tasks
Contributions of patient representatives
Benefit–risk analysis
Additional inputs in the benefit–risk picture, such as experiential information regarding the pathology or some other aspects that regulators might find negligible but may in fact be important from the patient’s perspective Providing a concrete basis for the values and weights given to specific benefits and risks by concretizing and making explicit the significance of these benefits and risks (by providing real-life impact of certain interventions on patients, for example)
Benefit–risk evaluation
Decision making
Especially within areas where the patient perspective is necessary or pressing, validating that the risks of an indication are indeed acceptable for the patients considering the benefits (i.e., provide extra confidence on the decision)
efits and risks are high (such as therapy A above), when benefits are almost equal or are equal to risks (i.e. narrow margin), and when both benefits and risks are low (which may boil down to the question, would patients want and need this drug due to economic or other reasons?). In cases when risks are high and benefits are low, or when risks are low and benefits are high, the necessity for patient representative participation may not necessarily be that pressing. Now we do not in any way say that patient representatives ought to be present in committees only when both benefits and risks are high, when benefits are almost equal or are equal to risks, and when both benefits and risks are low; rather, during these situations, the patient perspective is unambiguously necessary in these sense that reasonable decision making is impossible without it. Not only is the presence of patient representatives pressing during the above-mentioned situations but, in what follows, the patient representatives’ tasks and contributions in the various benefit–risk tasks are also clearly set out, many times irrelevant of whether benefits and risks are high or low (see Table 1). It is interesting that though our study is the first we know that deals with patient representatives’ contributions on the benefit/risk assessment task of scientific committees, our findings accord with recent literature on patients’ contribution in other settings. Notwithstanding the limitations of the comparability, in terms of the conclusion that patient representatives aid in formulating a richer benefit–risk picture, the study by Avery et al. on the patient participation on the UK Yellow Card Scheme [14] concludes the same. In this study, Avery et al. conclude 1254
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that patient reporting could potentially enrich pharmacovigilance since patients report ‘reactions different from those reported by health care professionals, generating new potential signals . . .’. Avery et al.’s conclusion also supports our findings that patient representatives aid benefit–risk evaluation. Earlier, we saw that patient representatives contribute by providing a specific basis for the values and weights given to specific benefits and risks. In Avery et al.’s study, they conclude that patients ‘describe suspected ADRs in enough detail to provide useful information or likely causality and impact on patients’ lives’ [14]. Lastly, that patient representatives’ contributions may be crucial for decision making, especially in a nonstraightforward situation, accords with the findings of Arnardottir [15]. In chapter 7 of her PhD thesis, Arnardottir explored the comparability of the values that regulators, doctors and patients attach to the benefits and risks of an oral anti-diabetes drug and found that regulators, doctors and patients may value major benefits and risks in the same way. She concludes the chapter by stating that the inputs of doctors and patients on individual care can aid regulatory decision making, especially in nonstraightforward situations [15]. We earlier stated that the level of acceptable risk for patient participants may act as a balance against the level of acceptable risk for regulators, and that the patient representatives’ level of acceptable risk may provide confidence in difficult decisions. In this sense, patient participants’ acceptable risk may ease the ‘cautious regulator’ problem, i.e. the ‘progressive lowering of risk tolerance of regulatory agencies’ [16], which incidentally was named as one of the main causes of increased drug development cost and decreased drug development efficiency [16, 17]. Thus, though the intensity and the need for patient participant contribution in benefit–risk assessment may be variable depending on the situation (such as the levels of risks and benefits), the presence of patient participants is obviously an asset in these interdisciplinary scientific committees. They provide an ‘expertise’ that no other member could provide. As such, their inclusion as full members, and hence as co-holders of power, is not only wanted for political reasons. The elaboration of the patient perspective by the patient representatives is an integral part of the existence of such scientific committees and by default, of their procedures such as benefit–risk assessment. Within this study, we touched upon some areas that need further research, such as the characterization of what patient perspective is, the distinction between the inputs of patient representatives who are patients themselves and those who represent patients but are not patients, who the patient is, the inclusion of patient representatives in the CHMP and HMPC, the necessity and the manner of consultation with patients and patient organizations as inputs for scientific committee discussions and the need for more training, support and compensation for patient representatives, among others. We hope that this study
Patient representatives and risk benefit
would aid in providing the initial impetus for future studies within the area of patient participation in scientific committees.
Limitations of the study The number of participants, especially the number of patient representatives (i.e. five), is an obvious limitation of this study. The manner of collecting data also poses its own limitation.
Conclusion The contribution of patient representatives in benefit–risk assessment is a variable of the benefits and the risks involved in the drug. The necessity of the patient representatives’ contribution is strongly felt when both benefits and risks are high, when benefits are almost equal or are equal to risks and when both benefits and risks are low. We also saw that the contribution of patient representatives in benefit/risk assessment can be specifically defined as follows. In benefit–risk analysis, their criteria help define the benefit–risk picture; in benefit/risk evaluation, patient representatives aid in providing a concrete basis for the values and weights given to specific benefits and risks by making specific and explicit the significance of these benefits and risks and in decision making, they provide what may be a crucial patient perspective in terms of the acceptability of risks. Hence, patient representatives provide a specific expertise in scientific committees.
Competing Interests All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare RDLCB and GJMWvT received support from the Dutch Top Institute Pharma for the submitted work and RDLCB received a PhD grant from the Dutch Top Institute Pharma in the previous 3 years. JJMvD has no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years. This study was performed in the context of the Escher project (T6-202), a project of the Dutch Top Institute Pharma, Leiden, The Netherlands.
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