G Model
YPRRV-972; No. of Pages 2 Paediatric Respiratory Reviews xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Personalised medicine in cystic fibrosis must be made affordable Diana Bilton Department of Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP
A R T I C L E I N F O
S U M M A R Y
Keywords: Cystic Fibrosis Personalised Medicine
The recent introduction of mutation specific therapy to a small group of patients with Cystic Fibrosis has created the debate about the affordability of personalised medicine. I would argue strongly that the NHS must find a way to make revolutionary mutation specific therapies available to patients and explore the routes that all parties must explore to facilitate this. A process which engages industry, providers and patients will provide the best long term answers. ß 2014 Elsevier Ltd. All rights reserved.
Therapy for CF entered a new era with the licencing of ivacaftor following successful clinical trials in patients with the G551D mutation [1]. It is critical that we remember when the CF gene was discovered back in 1989 [2] exactly what our predictions and hopes for future treatments were. As a CF research fellow at the time I listened to both patients and consultants talk about the possibility of a gene correcting therapy. There were hopes that this would come in the form of a tablet rather than a nebulised therapy, (which we all new was a significant driver of burden of treatment and poor adherence) [3]. Furthermore we had hoped that such a gene correcting therapy would significantly reduce the need for rescue courses of intravenous antibiotics and in the long run, if introduced early enough in childhood would obviate the need for chronic nebulised therapies. Thus, a tablet therapy that corrects the effect of a mutated CF gene has been on the CF community Christmas list for well over 20 years. I would suggest that we should consider our Christmas wish answered in the delivery of the first mutation specific therapy, Ivacaftor. The trials clearly demonstrate correction of the CFTR defect with significant improvement in sweat chloride coupled with the best improvement in lung function ever seen with any CF therapy and significant reductions in exacerbations requiring intravenous antibiotics [1]. Even in patients with mild disease where lung clearance index was used as an end-point, in case the FEV1 change was not so significant, ivacaftor produced significant benefit in FEV1 [4]. On that basis to even debate now whether mutation specific therapy is affordable feels like the family who had always wanted a dog for Christmas, and planned for that dog, wondering one week after Christmas as to whether they had done the right thing. I propose that ivacaftor and personalised medicine is just like the dog that must be for life and not just for Christmas. In
E-mail address: [email protected].
parallel it is now a responsibility for the CF community to work together with commissioners and the NHS to ensure that personalised medicine can be affordable. We must not be the ungrateful children who want to benefit from a dog’s company but will not ever offer to take it for a walk. It is worth looking at how ivacaftor was made affordable in order for NHS commissioners to agree on its use in England. The ivacaftor story evolved in the new era of specialist commissioning, with clinical expert engagement and involvement in a newly developed Clinical Prioritisation Advisory Group (CPAG). There was intelligent use of UK CF Registry data willingly provided by the CF community to aid commissioners in financial planning. Furthermore there was active dialogue with Vertex the company responsible for development of this exciting new drug. The CF Clinical Reference Group (CRG) was formed to provide expert clinical advice to the NHS specialist commissioners and these reference groups are now part of the new landscape specialist commissioning of NHS England. The CRG membership includes clinicians and allied health professionals in leadership positions within CF services as well as representatives of families and the CF Trust. All of them engaged in CRG work to work on bringing to reality the vision of equitable access to excellence in CF services. In addition to providing service specifications for adults and paediatric CF services to guide commissioning contracts for CF care in England, the CRG was asked to give expert advice to the NHS through the CPAG process. The CRG considered a Health Technology Assessment performed by independent health policy experts and funded by the commissioners. There was no doubt about the efficacy of this ground breaking medication but specific questions were posed as to whether ivacaftor should be recommended for all patients with the G551D mutation or whether on cost-effectiveness grounds the treatment should be limited to certain groups. Having considered the clinical trial evidence there were unanswered questions regarding models of
http://dx.doi.org/10.1016/j.prrv.2014.04.004 1526-0542/ß 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Bilton D. Personalised medicine in cystic fibrosis must be made affordable. Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.04.004
G Model
YPRRV-972; No. of Pages 2 2
D. Bilton / Paediatric Respiratory Reviews xxx (2014) xxx–xxx
cost-effectiveness given that the data available from clinical trials could not demonstrate the long-term effects on the population of introducing ivacaftor early in childhood before evidence of established lung damage or infection. As the trials had appropriately been designed to establish efficacy in addition to standard best care, no modelling had been performed that considered the possibility of a reduction in need for other high cost CF therapies. All the clinical experts were of the view that the principle of specialist commissioning of equitable access to excellence meant that ivacaftor, representing the first true disease modifying agent for CF, should not be limited to certain age groups. Clearly maximum benefit should accrue when used early in disease but as significant benefit was evident across the age groups all patients should have access to the drug. Thus, in the final discussions as to whether the NHS should offer ivacaftor as a therapy to CF patients with the G551D mutation there was no debate about clinical efficacy and access to all. The hurdle which forms the crux of this debate was affordability. The experts on the CRG made clear recommendations to encourage approval of ivacaftor for use in the NHS but that this should not be at the expense of current routine CF care. To return to my parallel of the present of a new dog for Christmas it is clear that the new dog should not cause total disruption of normal household activities and that rules should be laid down to ensure the new dog fits into the household routine. The global price set by Vertex raised severe concerns within the CRG and there was unanimous support for a respectful discussion to ensure a patient access scheme which facilitated an overall cost reduction. Data from the UK CF Registry facilitated financial planning suggesting there were 361 eligible patients in England. Final agreement was reached behind closed doors and covered by confidentiality agreements to allow a patient access scheme which reduced total costs significantly. Negotiations were clearly robust but it is clear that as further new mutation specific drugs are developed the process of negotiating costs to the NHS must be strengthened and formalised. We must acknowledge that the NHS is cash-limited and we cannot allow the companies developing these new therapies to believe that a price accepted by insurance companies in the USA will be acceptable in a government funded healthcare system such as the NHS. It is notable that other countries have looked to the UK to see how negotiations were conducted and at the final cost of the patient access scheme which remains the subject of confidentiality agreements. It is critical that having gained access to ivacaftor that we continue robust negotiations to ensure further mutation specific drugs, that are as clinically effective as ivacaftor, can be introduced to CF care in England. As the responsible family who have introduced the new pet, we the CF community need to ask what it is we want for future CF care and how we can work with commissioners to ensure its delivery. It is clear as a community that we wish the benefits seen in the G551D patient group to be seen across the CF community. We are hopeful that one of the combinations of drugs currently in clinical trials will provide a corrective therapy for the Del508 mutation. This will bring the new era to the majority of the CF patients in the UK. We wish the new era of mutation specific therapy to happen against a background of equity of access to high quality CF specialist care and CF specific medications already in use and of proven benefit. This will be a huge challenge as the budget for CF care sits for England at around £110 million and the introduction of ivacaftor added around £40 million. It is all too easy to declare the new era unaffordable. Do we want our CF patients to be deprived of a new era of care simply because of inertia?
We do need to examine delivery of care and continuously question our cost effectiveness. On the premise that personalised medicine must be made affordable I suggest that whilst our leaders negotiate hard for the lowest price for new therapies, that we in the CF community examine every aspect of our care and question our priorities. A family with a new dog may be unable to travel abroad as a result of their new acquisition. A healthy debate within the CF community should now occur regarding making mutation specific therapies available. We will have to make choices. The packaging of intravenous antibiotics for home use in more costly self-delivery devices was seen as a huge step forward in treating exacerbations at home. Some companies have profited from providing home intravenous antibiotic services and some CF centres have been criticised for taking a more measured approach to costs by providing drugs which the patient or family have to mix themselves. In a world of unlimited resource one would like to add mutation specific therapies to the current practises of readymade home delivered intravenous therapy but in a cash-limited world we may well need to decide where our priorities lie. I propose that we would prefer a new-age of mutation specific therapy for all our patients rather than remain in the world of rescue therapy which has been the case previously. Furthermore if we invest in the new therapies which are effective we will see reduction in the need for intravenous antibiotic therapy and reduction in requirements for hospital beds. Future delivery of care should look different with less hospital based therapies and more individualised care. We need to explore remote monitoring and e based clinics providing specialist team supervision reducing the risks of cross infection. The community should make use of the rich UK CF Registry resource to make evidence based arguments for use of current therapies whilst continuing to support national negotiations on pricing of CF specific medications. We must also be robust in our definitions of efficacy. Ivacaftor has set the bar for an effective CFTR correcting therapy and we must not simply accept a future therapy as effective simply because of evidence of some biochemical correction in ion transport. We must demand clinical benefit in order to persuade our payers that a medicine is worth the negotiations. A community approach between CF teams, commissioners and the industry must yield delivery of best care at an affordable price. In conclusion, personalised medicine must be made affordable by modernising CF care, preserving the excellence that has been created in specialist centres but ensuring that delivery of care does not fossilise .We must move into a new era of care delivery that will be personalised along with the medicines. We have been given a puppy for Christmas and we must adapt to ensure it stays for life.
CONFLICT OF INTEREST The author has no conflict of interest to report. References [1] Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663–72. [2] Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066–73. [3] Sawicki GS, Walter DE, Robinson M. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J Cyst Fibros 2009;8(2):91–6. [4] Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Resp Crit Care Med 2013;187:1219–25.
Please cite this article in press as: Bilton D. Personalised medicine in cystic fibrosis must be made affordable. Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.04.004
YPRRV-972; No. of Pages 2 Paediatric Respiratory Reviews xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Personalised medicine in cystic fibrosis must be made affordable Diana Bilton Department of Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP
A R T I C L E I N F O
S U M M A R Y
Keywords: Cystic Fibrosis Personalised Medicine
The recent introduction of mutation specific therapy to a small group of patients with Cystic Fibrosis has created the debate about the affordability of personalised medicine. I would argue strongly that the NHS must find a way to make revolutionary mutation specific therapies available to patients and explore the routes that all parties must explore to facilitate this. A process which engages industry, providers and patients will provide the best long term answers. ß 2014 Elsevier Ltd. All rights reserved.
Therapy for CF entered a new era with the licencing of ivacaftor following successful clinical trials in patients with the G551D mutation [1]. It is critical that we remember when the CF gene was discovered back in 1989 [2] exactly what our predictions and hopes for future treatments were. As a CF research fellow at the time I listened to both patients and consultants talk about the possibility of a gene correcting therapy. There were hopes that this would come in the form of a tablet rather than a nebulised therapy, (which we all new was a significant driver of burden of treatment and poor adherence) [3]. Furthermore we had hoped that such a gene correcting therapy would significantly reduce the need for rescue courses of intravenous antibiotics and in the long run, if introduced early enough in childhood would obviate the need for chronic nebulised therapies. Thus, a tablet therapy that corrects the effect of a mutated CF gene has been on the CF community Christmas list for well over 20 years. I would suggest that we should consider our Christmas wish answered in the delivery of the first mutation specific therapy, Ivacaftor. The trials clearly demonstrate correction of the CFTR defect with significant improvement in sweat chloride coupled with the best improvement in lung function ever seen with any CF therapy and significant reductions in exacerbations requiring intravenous antibiotics [1]. Even in patients with mild disease where lung clearance index was used as an end-point, in case the FEV1 change was not so significant, ivacaftor produced significant benefit in FEV1 [4]. On that basis to even debate now whether mutation specific therapy is affordable feels like the family who had always wanted a dog for Christmas, and planned for that dog, wondering one week after Christmas as to whether they had done the right thing. I propose that ivacaftor and personalised medicine is just like the dog that must be for life and not just for Christmas. In
E-mail address: [email protected].
parallel it is now a responsibility for the CF community to work together with commissioners and the NHS to ensure that personalised medicine can be affordable. We must not be the ungrateful children who want to benefit from a dog’s company but will not ever offer to take it for a walk. It is worth looking at how ivacaftor was made affordable in order for NHS commissioners to agree on its use in England. The ivacaftor story evolved in the new era of specialist commissioning, with clinical expert engagement and involvement in a newly developed Clinical Prioritisation Advisory Group (CPAG). There was intelligent use of UK CF Registry data willingly provided by the CF community to aid commissioners in financial planning. Furthermore there was active dialogue with Vertex the company responsible for development of this exciting new drug. The CF Clinical Reference Group (CRG) was formed to provide expert clinical advice to the NHS specialist commissioners and these reference groups are now part of the new landscape specialist commissioning of NHS England. The CRG membership includes clinicians and allied health professionals in leadership positions within CF services as well as representatives of families and the CF Trust. All of them engaged in CRG work to work on bringing to reality the vision of equitable access to excellence in CF services. In addition to providing service specifications for adults and paediatric CF services to guide commissioning contracts for CF care in England, the CRG was asked to give expert advice to the NHS through the CPAG process. The CRG considered a Health Technology Assessment performed by independent health policy experts and funded by the commissioners. There was no doubt about the efficacy of this ground breaking medication but specific questions were posed as to whether ivacaftor should be recommended for all patients with the G551D mutation or whether on cost-effectiveness grounds the treatment should be limited to certain groups. Having considered the clinical trial evidence there were unanswered questions regarding models of
http://dx.doi.org/10.1016/j.prrv.2014.04.004 1526-0542/ß 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Bilton D. Personalised medicine in cystic fibrosis must be made affordable. Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.04.004
G Model
YPRRV-972; No. of Pages 2 2
D. Bilton / Paediatric Respiratory Reviews xxx (2014) xxx–xxx
cost-effectiveness given that the data available from clinical trials could not demonstrate the long-term effects on the population of introducing ivacaftor early in childhood before evidence of established lung damage or infection. As the trials had appropriately been designed to establish efficacy in addition to standard best care, no modelling had been performed that considered the possibility of a reduction in need for other high cost CF therapies. All the clinical experts were of the view that the principle of specialist commissioning of equitable access to excellence meant that ivacaftor, representing the first true disease modifying agent for CF, should not be limited to certain age groups. Clearly maximum benefit should accrue when used early in disease but as significant benefit was evident across the age groups all patients should have access to the drug. Thus, in the final discussions as to whether the NHS should offer ivacaftor as a therapy to CF patients with the G551D mutation there was no debate about clinical efficacy and access to all. The hurdle which forms the crux of this debate was affordability. The experts on the CRG made clear recommendations to encourage approval of ivacaftor for use in the NHS but that this should not be at the expense of current routine CF care. To return to my parallel of the present of a new dog for Christmas it is clear that the new dog should not cause total disruption of normal household activities and that rules should be laid down to ensure the new dog fits into the household routine. The global price set by Vertex raised severe concerns within the CRG and there was unanimous support for a respectful discussion to ensure a patient access scheme which facilitated an overall cost reduction. Data from the UK CF Registry facilitated financial planning suggesting there were 361 eligible patients in England. Final agreement was reached behind closed doors and covered by confidentiality agreements to allow a patient access scheme which reduced total costs significantly. Negotiations were clearly robust but it is clear that as further new mutation specific drugs are developed the process of negotiating costs to the NHS must be strengthened and formalised. We must acknowledge that the NHS is cash-limited and we cannot allow the companies developing these new therapies to believe that a price accepted by insurance companies in the USA will be acceptable in a government funded healthcare system such as the NHS. It is notable that other countries have looked to the UK to see how negotiations were conducted and at the final cost of the patient access scheme which remains the subject of confidentiality agreements. It is critical that having gained access to ivacaftor that we continue robust negotiations to ensure further mutation specific drugs, that are as clinically effective as ivacaftor, can be introduced to CF care in England. As the responsible family who have introduced the new pet, we the CF community need to ask what it is we want for future CF care and how we can work with commissioners to ensure its delivery. It is clear as a community that we wish the benefits seen in the G551D patient group to be seen across the CF community. We are hopeful that one of the combinations of drugs currently in clinical trials will provide a corrective therapy for the Del508 mutation. This will bring the new era to the majority of the CF patients in the UK. We wish the new era of mutation specific therapy to happen against a background of equity of access to high quality CF specialist care and CF specific medications already in use and of proven benefit. This will be a huge challenge as the budget for CF care sits for England at around £110 million and the introduction of ivacaftor added around £40 million. It is all too easy to declare the new era unaffordable. Do we want our CF patients to be deprived of a new era of care simply because of inertia?
We do need to examine delivery of care and continuously question our cost effectiveness. On the premise that personalised medicine must be made affordable I suggest that whilst our leaders negotiate hard for the lowest price for new therapies, that we in the CF community examine every aspect of our care and question our priorities. A family with a new dog may be unable to travel abroad as a result of their new acquisition. A healthy debate within the CF community should now occur regarding making mutation specific therapies available. We will have to make choices. The packaging of intravenous antibiotics for home use in more costly self-delivery devices was seen as a huge step forward in treating exacerbations at home. Some companies have profited from providing home intravenous antibiotic services and some CF centres have been criticised for taking a more measured approach to costs by providing drugs which the patient or family have to mix themselves. In a world of unlimited resource one would like to add mutation specific therapies to the current practises of readymade home delivered intravenous therapy but in a cash-limited world we may well need to decide where our priorities lie. I propose that we would prefer a new-age of mutation specific therapy for all our patients rather than remain in the world of rescue therapy which has been the case previously. Furthermore if we invest in the new therapies which are effective we will see reduction in the need for intravenous antibiotic therapy and reduction in requirements for hospital beds. Future delivery of care should look different with less hospital based therapies and more individualised care. We need to explore remote monitoring and e based clinics providing specialist team supervision reducing the risks of cross infection. The community should make use of the rich UK CF Registry resource to make evidence based arguments for use of current therapies whilst continuing to support national negotiations on pricing of CF specific medications. We must also be robust in our definitions of efficacy. Ivacaftor has set the bar for an effective CFTR correcting therapy and we must not simply accept a future therapy as effective simply because of evidence of some biochemical correction in ion transport. We must demand clinical benefit in order to persuade our payers that a medicine is worth the negotiations. A community approach between CF teams, commissioners and the industry must yield delivery of best care at an affordable price. In conclusion, personalised medicine must be made affordable by modernising CF care, preserving the excellence that has been created in specialist centres but ensuring that delivery of care does not fossilise .We must move into a new era of care delivery that will be personalised along with the medicines. We have been given a puppy for Christmas and we must adapt to ensure it stays for life.
CONFLICT OF INTEREST The author has no conflict of interest to report. References [1] Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663–72. [2] Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066–73. [3] Sawicki GS, Walter DE, Robinson M. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J Cyst Fibros 2009;8(2):91–6. [4] Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Resp Crit Care Med 2013;187:1219–25.
Please cite this article in press as: Bilton D. Personalised medicine in cystic fibrosis must be made affordable. Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.04.004
