Page 66 - 2020_08-Haematologica-web

F. Peyvandi et al.
important. It is also important to provide patients with a positive feedback to underline the value of their contribu- tions.
Recommendation 11
Clinical studies should be performed to provide the best possible evidence needed for regulatory authorities, health technology assessment (HTA) bodies, academia and healthcare providers.
Clinical trials conducted during the drug licensing process provide the most important information for pre- dicting the efficacy and value of new medicines. While clinical trial data are the gold-standard of the evidence- based efficacy needed by regulatory authorities and health care providers, their usefulness often has limitations with respect to HTA and determining their value within the framework of cost-effectiveness studies, primarily carried out in the interest of the decision-making processes of payers. The purpose of most clinical trials is to test hypotheses about the efficacy and side effects of medica- tions compared against placebo or a selected comparator therapy. HTA aims to answer questions about how these findings can be translated into clinical practice and change the standard of care, but also on how to estimate cost- effectiveness, with the goal of informing decisions intend- ed to ensure value for money. Most clinical trials often do not focus on end points such as the relevant patient out- comes requested by HTA bodies and/or payers. These limitations have acquired greater importance since regula- tory authorities introduced new initiatives such as adap- tive licensing in order to accelerate access to innovative treatments, particularly in the context of orphan or rare diseases. Smaller and shorter trials may be able to provide evidence faster, but they will fail to generate enough infor- mation for patient assessment of relevant outcomes and for cost-effectiveness. To minimize these gaps of knowl- edge, and to provide sufficient evidence to promote effec- tive HTA and cost effectiveness analysis, clinical trial designs for innovative therapies should be optimized to reduce uncertainty, eliminate bias, decrease costs, and accelerate patient access.
Recommendation 12
A process to reach better agreement on relevant indicators and methods should be started in order to meet the needs of regula- tory authorities, HTA bodies, academia and healthcare providers, that have different foci, responsibilities and requirements.
There is a strong need for a multidisciplinary consensus on measurable, patient-relevant outcome indicators which reflect the benefits of new and innovative hemophilia therapies. Consensus on the choice of outcome assess- ment instruments should also be reached in order to allow for a more effective combination of data from different sources. These goals will be necessary to obtain harmo- nized and transparent decision-making processes. Another subject for discussion should be whether out- comes should be collected in clinical trials or if data from
other sources such as observational studies including reg- istries should be complementary sources to assess benefit within hemophilia care. Furthermore, a minimum set of methods for outcome determination would help the dif- ferent decision makers to make their assessment. Because hemophilia is a chronic rare disease, and concrete patient- relevant outcomes such as avoidance of joint damage can- not be evaluated at the time of market entry of innovative therapies, it is important to identify appropriate surrogate indicators and agree on statistical methods for prognostic calculations in order to provide estimates also on medium- to long-term consequences.
Recommendation 13
A dialogue with agencies and academia should be started in order to reach understanding of relevant outcomes and to ensure comprehensive and consistent reporting.
Health Technology Assessment bodies and/or payers request information on patient-relevant clinical end points in order to provide the evidence of therapeutic benefit of new or innovative therapies compared to the standard of care. These hard end points are mainly morbidity, mortal- ity and quality of life, but these only partially reflect the benefits associated with innovative hemophilia thera- pies.29 Although mortality in hemophilia was very high before the introduction of replacement therapy, nowadays it is almost comparable to that of the general population, so it cannot be seen as an appropriate outcome to be measured at the time of drug evaluation and market entry.30 Repeated joint bleeds cause morphological changes and in the long run lead to arthropathy; but many years of follow up would be required to assess hemophilic arthropathy and its consequences. Multifactorial influ- ences lead to individual variations in a small patient pop- ulation such as hemophilia pertaining to the bleeding phe- notype, development of arthropathy, and inhibitory anti- bodies. Thus, the measurement of health-related quality of life (HRQoL) might be a reasonable indicator of the long-term outcome and effectiveness of the therapeutic intervention chosen. It can also be converted into utility values to enable the assessment of the quality-adjusted life years gained, and to calculate cost-effectiveness. Both hemophilia disease-specific instruments and generic instruments are available and should be implemented as a standard procedure.
Acknowledgments
Co-sponsoring by Paul Ehrlich Institut, the Ludwig- Maximilian University of Munich and the European Directorate for the Quality of Medicines and Healthcare. Thanks to Isabella Garagiola, Ph.D. from Angelo Bianchi Bonomi Hemophilia and Thrombosis Center for helping us in the preparation of the man- uscript and to all participants and delegates who actively partic- ipated in the discussion with the three working groups, providing their own input and helping to produce this Kreuth V European consensus for treatment of hemophilia.
References
1. SchrammW,vonAuerF,DelaneyF,SeitzR. Blood Safety in the European Community: An Initiative for Optimal Use. Wildbad Kreuth, 20-22 May, 1999. Conference
Proceedings. ISBN 3-00-005705-6.
2. Berger K, Klein HG, Seitz R, Schramm W, Spieser JM. The Wildbad Kreuth initiative: European current practices and recommen- dations for optimal use of blood compo-
nents. Biologicals. 2011;39(3):189-193.
3. Giangrande P, Seitz R, Behr-Gross ME, et al.
Kreuth III: European consensus proposals for treatment of haemophilia with coagulation factor concentrates. Haemophilia. 2014;20 (3):322-325.
4. Giangrande PLF, Peyvandi F, O’Mahony B, et al. Kreuth IV: European consensus proposals for treatment of haemophilia with coagula-
2042
haematologica | 2020; 105(8)