NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE. Single Technology Appraisal (STA)

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1 Thank you for agreeing to give us a statement on your organisation s view of the technology and the way it should be used in the NHS. Healthcare professionals can provide a unique perspective on the technology within the context of current clinical practice which is not typically available from the published literature. To help you in making your statement, we have provided a template. The questions are there as prompts to guide you. It is not essential that you answer all of them. Please do not exceed the 8-page limit. About you Your name: xxxxxxxxxxxxxxxxxxxxxxxxxxxx Name of your organisation Royal College of Physicians (RCP) Comments coordinated by xxxxxxxxxxxxxx, xxxxxxxxxxxxxx, xxxxxxxxxxxx Are you (tick all that apply): - a specialist in the treatment of people with the condition for which NICE is considering this technology? - a specialist in the clinical evidence base that is to support the technology (e.g. involved in clinical trials for the technology)? - an employee of a healthcare professional organisation that represents clinicians treating the condition for which NICE is considering the technology? If so, what is your position in the organisation where appropriate (e.g. policy officer, trustee, member etc.)? - other? (please specify) 1

2 What is the expected place of the technology in current practice? Patients chronically infected with genotype 1 hepatitis C are currently managed in accordance with previous NICE guidelines and usually receive a total of 48 weeks therapy with pegylated interferon and ribavirin. A subset of patients who show evidence of a rapid, early response (~10%) receive a truncated course of 24 weeks treatment. This regime leads to a sustained virological response rate (SVR), which probably equates to a cure, in around 40% of those treated. Therapy is provided in hospital settings throughout the UK, although data from the Hepatitis C Trust suggest that there is significant regional variation in the provision of care. There are no alternatives to the current treatment and most health care professionals recognise the value of following the NICE recommendations. The aim of hepatitis C treatment is the attainment of a sustained virologic response (SVR) defined as an undetectable serum hepatitis C RNA concentration by sensitive PCR 24 weeks after stopping therapy. This is regarded as tantamount to a cure. The current standard of care (SOC) for hepatitis C in the NHS is currently a combination of pegylated alfa-2a or 2b Interferon (PEG IFN) together with RBV (RBV). Protocols are standardised across the NHS and there are no significant geographical variations in current practice. Current treatments with PEG IFN and RBV are effective in less than 50% of genotype 1 naive patients. The overwhelming majority of patients with genotype 1 require one year of therapy, although some patients can abbreviate therapy after a rapid decline in virus load. Retreatment of prior genotype 1 treatment failures is unsuccessful in more than 80% of patients. A single nucleotide polymorphism predicting response to treatment to interferon has recently been described. The central problem with current therapy is that efficacy is relatively poor over half the patients who are treated do not lose the virus and thus suffer a prolonged course of therapy, with many associated side effects, to little gain. For patients who have failed therapy, NICE approve attempts at re-treatment with a further course of pegylated interferon and ribavirin, although the proportion who respond is very slight (<20%). Recently two new protease inhibitors, Telaprevir and boceprevir have been developed for the treatment of chronic hepatitis C. The advent of the direct acting NS3a protease inhibitors that target replication of hepatitis C has improved therapy for the disease. In controlled clinical trials, boceprevir has improved response rates in patient with genotype 1 and reduced relapse rates. Boceprevir is the first of a new class of direct acting antiviral drugs which dramatically increase the response to treatment for patients with genotype 1 HCV. In clinical trials the proportion of patients who achieved an SVR increased from 38% to 66% for treatment naive patients, whilst in treatment experienced patients response rates increased from 29% to 75% for patients who had suffered a relapse and treatment success increased from 7% to 52% in patients who had responded partially to 2

3 previous therapy. Furthermore a large proportion of treatment naive patients (44%) were successfully treated with only 28 weeks treatment, significantly reducing the burden of therapy. These increases in efficacy are, in our opinion, clinically meaningful and will significantly increase the proportion of patients who are cured and thereby reduce the burden of disease from chronic hepatitis C. The increase in response will, we believe, lead to an increase in the proportion of patients who agree to undergo antiviral therapy. At present many patients with genotype 1 HCV decline treatment as they perceive that the chance of a sustained response is too low to justify the treatment associated side effects. Over the last few months we have seen a marked increase in patients asking for access to these new drugs and we believe that the proportion of patients who come forward for therapy will increase substantially once these highly potent new agents are available. It is our collective view that increasing the proportion of patients who undergo effective antiviral therapy will significantly reduce the long-term burden of disease from chronic hepatitis C and, we believe, will lead to a significant reduction in premature mortality and demand for liver transplantation due to HCV induced cirrhosis and liver cancer. Hence these drugs will be valuable both in increasing the proportion of patients who are cured and in increasing the proportion of patients who are willing to undergo therapy. For genotype 1 patients, SVR with SOC ranges between 38% and 46% but is lower in some groups including patients with advanced fibrosis. Recently Poordad et al have shown in a large phase III trial that the addition to boceprevir to PEG IFN and RBV compared with standard therapy alone significantly increased the rates of SVR in previously untreated adults. Sixty seven percent to 68% of patients (depending upon the arm of the trial) achieved an SVR compared to 40% of Caucasian naïve patients in the control arm. Approximately 44% of patients were able to be treated for a shorter period of treatment for 28 weeks. Anaemia necessitated dose reduction in 13% of the control but 21% of the boceprevir recipients. Boceprevir has also been tested in individuals who have failed PEG IFN and RBV previously i.e. prior partial responders and relapsers. In the non-responder groups under study, the rate of SVR was significantly higher in boceprevir treated patients (59%-66%) than in the control groups retreated with PEG IFN and RBV (21%) (Bacon et al). Similar side effects were reported. Thus, economic considerations permitting, boceprevir PEG IFN and RBV offers improved treatment response rates in genotype naïve and non responder patients compared to the current standard of care. Interferon is contraindicated or poorly tolerated in some patients; these constraints will still apply, particularly in patients with poorly controlled depression or psychotic illness. Interferon and RBV are contraindicated in patients with decompensated cirrhosis. Unfortunately drug-drug interactions with boceprevir and calcineurin inhibitors have not yet been fully established, and thus there are concerns regarding the use of boceprevir with these drugs in liver transplant recipients. The EMEA has suggested that for naive patients without cirrhosis, boceprevir should be given as follows: After a lead in period of PEG IFN and RBV for four weeks, boceprevir PEG IFN and RBV should be given for 28 weeks if hepatitis C RNA is 3

4 undetectable at treatment week 8 and undetectable at treatment week 24. If hepatitis C RNA is detectable at treatment week 8 (but undetectable at treatment week 12 and undetectable at treatment week 24), then boceprevir and PEG IFN RBV should be given for a total of 36 weeks followed by a tail of PegRBV for a further 12 weeks. Stopping rules apply: if hepatitis C RNA concentrations are higher than 100 iu/ml at treatment week 12 or detectable at treatment week 24, the three-medicine regimen should be stopped. For boceprevir relapsers/prior partial responders without cirrhosis, PEG IFN and RBV should be given for a four-week lead in period followed by boceprevir, PEG IFN and RBV for a total of 36 weeks and a further period of 12 weeks of PEG IFN and RBV. For patients with cirrhosis or prior non-responders it is suggested that PEG IFN and RBV should be given as a four-week lead in followed by a further 44 weeks to treatment week 48 of boceprevir, PEG IFN and RBV. The same stopping rules apply, ie hepatitis C RNA is greater than 100 iu at treatment week 12 or detectable at treatment week 24, the three-drug regimen should be discontinued. In the absence of detailed guidelines, it is recommended that the EMEA licencing posology should be followed. It is noteworthy that the protease inhibitors (including boceprevir) were given an expedited review by licensing authorities in Europe and the USA because of the perceived enormous benefits and in France a pre-licensing agreement has ensured that patients have been able to access these drugs prior to licensing. It is therefore clear that health authorities abroad recognise the enormous value of effective therapy for chronic HCV infection and are keen to ensure that patients are rapidly able to access these drugs. We believe that UK patients should also be allowed to benefit from this very significant therapeutic advance. The advantages and disadvantages of the technology The substantial increase in SVR that is achieved with the new technology is a major advance over current treatments and, in our view, justifies the widespread use of these new agents. There is an increase in side effects and complications associated with the new technology and there is a need for increased virological testing to identify early treatment failure and discontinue futile therapy before drug resistance has developed. However, the side effect profile of boceprevir is familiar to experienced practitioners (although the increase in the severity of anaemia may require additional interventions that may increase the costs of the drugs) and we do not envisage difficulties in administering the medication in centres who are well versed in managing patients with chronic hepatitis C. We are therefore confident that experienced practitioners will rapidly familiarise themselves with this new agent. It will be important to ensure that the associated specialised virological services are available and clinicians using this new agent must have access to rapid viral load testing. The clinical trials with boceprevir have, in the main, included the type of patients who are treated in the UK. However the clinical trials excluded patients with advanced cirrhosis, who are likely to be a priority for treatment in many UK centres. It is possible that such patients will develop more profound side effects with boceprevir and such patients may require additional specialised input. 4

5 Taken together it is our view that boceprevir represents a very significant advance in the management of patients with chronic hepatitis C. The drug requires specialised administration by experienced practitioners and to ensure cost effective administration and timely discontinuation of futile therapy boceprevir must be used only in centres who can provide appropriate virological testing. Given the complexity of the treatment and the need for specialised support it is our view that therapy should only be administered by experienced physicians who are familiar with managing patients with hepatitis C. Boceprevir is not active against genotype 3 infection. Patients with genotype 2 with cirrhosis or prior treatment failure should be considered for treatment, as boceprevir is active against genotype 2. However meaningful clinical trials have not been conducted in genotype patients. The number of genotype 2 patients who have failed treatment is relatively small. This treatment should be applied for now in Specialist Clinics. There would be a need for training of Nurses and Health Care Professionals in their use given the potential for adverse events and for the development of resistance. The application of appropriate stopping rules and appropriate treatment duration will be required, ie response-guided therapy. There are no formalised clinical guidelines and therefore boceprevir should only be used within its EMEA licensed indication. The advantage of this technology is that higher sustained virological response rates can be achieved. Treatment however is somewhat complex, requiring a lead in phase together with response-guided therapy rules that have been detailed together with appropriate stopping rules. It also may be necessary to weigh up the necessity and/or disadvantage of treatment for prior poor IFN responders who have advanced liver disease, based on the response to interferon during the lead in. This will necessitate a rapid turn around time for HCV RNA concentrations. Unfortunately patients with cirrhosis respond less well than patients without cirrhosis as patients with cirrhosis are in greatest need of treatment. However, although the response in patients with cirrhosis is somewhat impaired, cirrhotic patients show higher response rates with boceprevir than with PEG IFN and RBV alone. There are some slight differences in response rates between genotype 1b versus 1a, due to the development of resistance mutations. Resistance testing will be required in patients who fail therapy, to assess future treatment options. Although boceprevir trials were not undertaken in the UK, these trial data can be extrapolated to current UK practice. The disadvantage of the treatment is its projected expense: the cost effectiveness of treatment in prior naïve and non responder patients who have either mild and advanced disease will require evaluation. Therefore, depending upon health economic data, an algorithm for deciding which patients are likely to respond to SOC alone and which patients should be treated primarily with boceprevir may unfortunately be required. Such algorithms have not been validated; a complex algorithm will be a disadvantage and the cost savings may not be significant. Factors such as the response to a lead in treatment phase of PEG IFN and RBV, IL28b single nucleotide polymorphism testing (a determinant of host sensitivity to IFN), stage of disease and subtype testing may all require consideration. It is disadvantageous, difficult and expensive to have to treat 5

6 with two or more cycles of treatment with interferon regimens, and it would be optimal to succeed with the first treatment course. Although prior null-responders (defined as patients who had a less than 2 log 10 decline in HCV RNA concentrations at treatment week 12) have not been treated within the phase III trials, such patients could be treated after weighing up the advantages and disadvantages of treatment. Patients with cirrhosis and a prior null response have low response rates. It may become necessary to assess the probability of response after the lead in phase to avoid treatment failure and resistance. Unfortunately this group of patients are generally in most need of treatment, but may require more potent protease inhibitors or different antiviral regimen. The advantageous and disadvantages of postponing treatment in this group will require careful evaluation. Large number of patients in the US study required Erythropoietin to manage anaemia. It is not clear how aneamia will be managed in the UK; in the first instance RBV dose reduction would be attempted, which may impact on SVR rates. Response-guided rules will need to be followed closely. These are published by the EMEA. Virological detection will need to be standardised across the UK; Virological input will be required. Response guided therapy rules should be based on level of detection rather than a level of quantification, with appropriately sensitive assays. The collection of resistance data is highly advised. Any additional sources of evidence Can you provide information about any relevant evidence that might not be found by a technology-focused systematic review of the available trial evidence? This could be information on recent and informal unpublished evidence, or information from registries and other nationally coordinated clinical audits. Any such information must include sufficient detail to allow a judgement to be made as to the quality of the evidence and to allow potential sources of bias to be determined. The relevant evidence is widely available The published papers contain the important evidence of efficacy and safety. We will require cost effective metrics to examine the use of boceprevir in naïve patients, relapsers, partial responders and null responders. Implementation issues 6

7 Centres with experience in managing patients with hepatitis C will be able to deliver this intervention without additional training. However we anticipate that delivering this new medication will require significantly more clinical input than is required with current standard of care. In addition we anticipate that there will be an increase in patients with genotype 1 hepatitis C who come forward to initiate therapy. We therefore believe that additional infrastructure will be required to deliver this new intervention It will be necessary for units with sufficient experience of interferon and RBV in hepatitis C to initiate treatment. Specialist units will need to provide educational forums for using boceprevir in outreach clinics and centres that treat only a small number of patients per year. Resistance testing will be required for patients failing therapy. It is to be hoped that treatment will not be restricted because of cost. The introduction of complex algorthims for segregating patients into those likely to respond to treatment with PEG IFN and RBV alone versus those requiring boceprevir, although reasonable at first glance, may not have a large impact on costs, and may have the undesired effect of restricting treatment access at a time when treatment outcomes are improving. Reliable diagnostic testing for fibrosis and fibrosis stage may require the widespread implementation of non invasive testing for hepatic fibrosis, with the caveats that apply. Alternatively a liver biopsy to stage the disease in all patients may once again become necessary. Equality Chronic hepatitis C is prevalent in deprived minority groups who are poorly represented on health care commissioning groups. These groups include ethnic minorities, injecting drug users and the homeless. Substantial numbers of patients with hepatitis C are derived from disadvantaged patients, ethnic minority groups, immigrant populations, the prison population, the homeless and those attending drug and alcohol services. The use of interferon in combination with boceprevir will require added measures to ensure safety, compliance and efficacy in these groups. 7