Key note speech held by Prof Bengt Jönsson from Stockholm School of Economics and Chairman of the NDA HTA Advisory Board, at the ZonMw Congres Goed Gebruik Geneesmiddelen, 31st January 2013, on the topic of dealing with decision making under uncertainty for the reimbursement of medicines
Radiation Dosimetry Parameters and Isodose Curves.pptx
Current Approaches in European Drug related Health Care Policy: Relative Effectiveness and Real Life Studies
1. Current Approaches in European
Drug related Health Care Policy
relative effectiveness and real life
studies
Bengt Jönsson
Stockholm School of Economics
Key note lecture ZonMw Congres Goed Gebruik Geneesmiddelen,
31 January 2013
Page 1
3. Regulatory changes
• Drugs have been withdrawn from the
market due to in-appropriate use
– Based on risk benefit assessment
– Data on side effects only one side of the
assessment
• Post-authorisation efficacy studies (PAESs)
a new tool for regulatory decisions
– Conditional market authorization (CMA) or
“adaptive licensing”
– Data on “relative efficacy” also relevant for
HTA
Page 4
5. Regulatory decisions, uncertainty and
opportunity cost
• More stringent criteria for effectiveness and
safety, i.e. net health benefit, may lead to delay
of access to valuable drugs and increasing costs
for drug development
• Relaxed criteria may lead to the introduction of
drugs with a negative net health benefit
• Decisions must be made on incomplete data
– A system for follow-up and re-assessment of ADRs is in
place based on “real life data”
– Increasingly recognized that net health benefit
depends on how the drugs are used in clinical practice
Page 6
6. Health technology Assessment
(HTA)
• Shift in focus from established therapies to new
technologies, particularly drugs
• Limited data for assessment of effectiveness
– Uncertainty about clinical outcome
• Payers are increasingly using HTA, including
relative effectiveness assessment (REA) and cost-
effectiveness analysis (CEA) to inform decisions
• Economic aspects, including price, plays a larger
role for reimbursement decisions
– Specific market access agreements
Page 7
9. Mean cost of taking a NME to the
market
• Di Masi 2003 USD 1 billion
• Paul et al 2010 USD 1.8 billion
• OHE 2011 USD 1.5 billion
(all in 2011 prices)
• Increasing relative costs of new drugs
• New cancer drugs priced at USD 10 000 per
month of treatment
• Equal to monthly salary for an oncologist in
Sweden
Page 10
10. Increasing role for public payment for drugs
• Chronic therapy for RA and MS cost
1000 Euro per month
• New cancer drugs priced at 10 000
USD per month
• Reimbursement is key to market
access
– And for efficiency and equity
• HTA is developing as a major policy
instrument to assess value for money
Page 11
11. The major problem for HTA – Lack of data
• Regulatory decisions based on clinical trials aimed
at investigating if a new drug works as intended
– Balancing benefits and risks
• HTA aims at investigating how a new drug works in
clinical practice compared to relevant
alternatives
– Population (indication)
– Comparator
– Outcome
• Clinical trials do not provide the necessary data
for an assessment of relative effectiveness
Page 12
12. Re-engineering drug development to
meet payer demands
• Early HTA advice on development
strategies
– May help directing R&D towards development
of drugs meeting payer objectives
• Joint regulatory and HTA advice
– May help reducing costs and improving value
of clinical trials
• But there are limits to produce evidence
of relative and cost-effectiveness before
the drug comes to the market
Page 13
13. Payer decisions, uncertainty and
opportunity cost
• More stringent criteria for relative effectiveness
and cost-effectiveness, i.e. value for money, may
lead to delay of access to valuable drugs and
increasing costs for drug development
• Relaxed criteria may lead to the introduction of
drugs with a negative net health benefit
compared to using the resources otherwise
• Decisions must be made on incomplete data
– A system for follow-up and re-assessment based on “real
life data” must be introduced
– Value for money depends on how the drugs are used in
clinical practice
Page 14
14. Methods for the Estimation of the NICE Cost
Effectiveness Threshold
Karl Claxton, Steve Martin, Marta Soares, Nigel Rice,Eldon Spackman, Sebastian
Hinde, Nancy Devlin, Peter C Smith, Mark Sculpher CHE January 2013
• “The central or 'best' threshold is estimated to be
£18,317 per QALY”
• “It is crucial that the cost effectiveness threshold
is seen as representing health forgone as the
additional costs of new technologies are
imposed on the fixed budgets of local
commissioners” (MS)
• “This study also starts to make the other NHS
patients, who ultimately bear the opportunity
cost, less abstract so they can be properly taken
into account when decisions about new health
technologies are being made.” (KC)
Page 15
15. Patients and real life data
• Potential patients are interested in access to new
medicines regard of their costs
• Variations in use of new technologies is seen as
unfair and inefficient
– NICE was introduced to solve the problem with “post-
code” prescribing
• Patients are increasingly involved as a
stakeholder in decisions about use of drugs
– Regulatory decisions about safety
– Development of clinical guidelines
– Reimbursement decisions
Page 16
17. Sir richard
doll
Smoking causes
cancer
Bradford Hill criteria for
causation
Strength of association
Consistency
Specificity
Temporal relationship
Biological gradient
Plausibility
Coherence
Experiment (reversibility)
Analogy
13-02-08 18
18. Collecting real life data
• Data never speaks for themselves
– Data versus evidence
– Evidence depends on the circumstances
• Augmenting clinical trial data
– Inclusion of additional variables (PRO, resource
utilization)
– Parallel data collection outside the clinical trial in an
identical population
• Registries
– prospective, observational cohort studies of patients
who have a particular disease and/or are receiving a
particular treatment or intervention
Page 19
19. Collecting real life data
• Choice of outcome measure
– Mortality
– Age adjusted mortality
– Survival
– Quality of life
– Other relevant outcome
• Work performance
– Working versus not working
– Reduced productivity at work
• Resource utilization
– Inside and outside health care
Page 20
20. Analysing real life data
• The problems with “causation” must
always be considered
• The need for improvement in
statistical methods for analysing
registry data
• The need for modelling
• Opportunities for randomization in
clinical practice should be
investigated
Page 21
21. real life data and policy
• Coverage by evidence development
(CED)
– Requirement to collect data part of the
reimbursement decision
– Data will be used for a revision of the
reimbursement decision
• Pay for performance (P4P)
– Reimbursement is linked to collection of data
on outcome
Page 22
22. Issues related to CED and P4P
• How common is this is different countries?
– Are there provisions for this in legislation
• For which types of drugs is it required?
– Expensive drugs
– Uncertainty about effects
– Uncertainty about their use
• Who is undertaken and paying for the studies?
– What type of studies
• How is the link between study result and decision?
– Open-ended (CED)
– Decided up-front (P4P)
Page 23
23. United Kingdom (NICE)
• Experience: MS risk sharing scheme in 2002
– Price linked to outcome in clinical practice
– Initiated to solve a “political” problem
– Study complicated and inconclusive
– Not used for revision of decision
• Today
– No enthusiasm for CED
– Preference for market access agreements which
mainly consists of price discounts (Tarceva,Sutent)
– Pay for responders only (Velcade, Erbitux)
• Tomorrow
– Depends on the design of the VBP scheme
Page 24
24. France
• Experience
– Long tradition of follow up studies
– Mainly to control that indications are followed
– No transparent link to decision making
• Today
– Studies to assess relative effectiveness and cost
savings (Risperidol, Januvia)
– Secret agreement with the company
• Tomorrow
– CEA will be mandatory at launch and at revision
after five years
– More CED studies but no commitment to specific
decision
Page 25
25. Germany
• Experience
– Possible for hospital drugs but not used
• Today
– Federal Joint Commission and a pharmaceutical
company can agree on performing a (real life) study
to evaluate the effects of a new drug
– The company has to pay for this
– Only one example so far
• Tomorrow
– CED may be more used in the future to follow up
results of price negotiations
Page 26
26. Sweden
• Experience
– CED is used in at least
20 cases by TLV 2002-
12 Evidence on effectiveness
and cost-effectivness.
– Over-representation Evaluating if the use in
clinical praxis follows the
of “life style drugs” specified indication.
Combination
– Follow up data on
restricted indications
– Follow-up data on
cost-effectiveness
• Tomorrow
– To be used more at
the county level
Page 27
27. CED, P4P and CER in the US – Growing importance for
Europe
Page 28
28. Why CED and P4P are going to be the new
standard in health care – Outcome matters
Page 29
29. Conclusions
• Regulators and HTA/reimbursement
agencies/payers have a common objective
– Improvements in public health
• They have different roles and are guided by
different legislation
– But closer collaboration can overcome many of
the present problems
• Real life data is a common interest
– For assessment of risk-benefit
– For assessment of cost-benefit
– For assuring patients that resources are used in an
efficient and equitable manner
Notas do Editor
Thanks for your kind invitation to this important conference. I cannot read the details of the program, but enough to understand that you are looking for ways to make sure that medicines are used safely, effective and efficient; what we call rational pharmacotherapy. Development of new pharmaceuticals is one of the great success stories of innovation for improvement of health and welfare. The historical benefits are enormous. But today there is a crises, of a similar type which we experience in the 1960 when the regulatory criteria was tightened post thalidomide. In the same way as in the 1960 the solution is looked for in terms of improved methods for evaluation of new drugs and new data. The clinical trial which served well for half a decade is not sufficient to provide answers to the new questions about relative effectiveness and value for money. Today we are focus attention on real life data to provide the guidance for rational pharmacotherapy. How did we get there? What are the key issues? What are the policy responses? What is the likely future and how can we shape it? Name, Department
The data for regulatory approval are well established in a continuous development since the 1960s. They are based on randomized clinical trials, designed in co-operation between regulators and the pharmaceutical industry. After market authorization, the data are used for information/marketing to practicing physicians. Limited involvement of other stakeholders such as payers and patients. Real life data has complemented trial data but only for detection of rare side effects. HTA was first developed to assess established non-drug technologies, such as diagnostics and surgery, which have been introduced without proper assessment and evidence of effectiveness. In addition, HTA took a broader view on medical technologies, including economic aspects. But HTA was also applied to drug technologies, such as treatment of hypertension and osteoporosis, mainly to assess the proper indications (over-and underuse).. Since the beginning of 1990s, economic evaluation, or cost-effectiveness analysis was introduced to inform decisions about reimbursement of pharmaceuticals, first in Canada and Australia. In Europe, Holland was one of the first countries to use this instrument. Lately the concept “relative effectiveness” has been introduced as a response to the need for a more coordinated approach to reimbursement in Europe. We can thus see that regulatory approval over time has been complemented with other policy instruments to manage the introduction and use of new drugs. Name, Department
We can see that regulatory authorities have responded in various ways to the challenges involved in making decisions about market authorization. One response is the gradually increasing demands for data for assessment of risk-benefit for drugs in the market. We can also observe that this has resulted in re-calls of market authorization. But the learning is that risk-benefit does not only depend on side effects, it depends also on the benefit, and both are determined by the use of the drug. If used in patients with low risk and/or high benefit the ratio may be acceptable. However, this calculus also requires more transparency in how risks and benefits are assessed and compared. Recently we have seen a call for post-authorisation efficacy studies, which is very much the same as relative effectiveness. Unless evidence is restricted to experimental studies in clinical practice. This is hardly possible, since opportunities for experimental design and randomization is limited in clinical practice. Reletad to this is also a discussion about “adaptive licensing”, which mirrors the use of “coverage by evidence development” for reimbursment decisions. We can note the also regulatory decision making isincreasingly requesting real life data. Name, Department
Name, Department
Partly the demand for more data post-authorisation comes from an understanding that it is not possible to asks for more evidence pre MA. That will delay introduction of new drugs and make development more expensive. It is more efficient to find an optimal trade off between what is required as evidence before and after MA. Some technological advances, such as development of target therapies, with a deeper understanding of the disease, its mechanisms and which patients that benefit from treatment facilitate shorter and smaller trials, in combination with follow-up data to optimize the use of the therapy in clinical practice. Name, Department
After being used to weed out ineffective established therapies, HTA has increasingly been applied where it is most needed, for assessment of new and expensive therapies. Unfortunately this is also where the the method is weakest, since there are no studies available which can be subject of “systematic reviews”, a major tool in HTA. But due to the need for payers to make early decisions, and lack of better alternatives, it has been extensively used to inform reimbursement decisions and therapeutic guidelines, also in situations with limited data. Due to the uncertainties involved, specific agreements about re-assessment and other conditions for reimbursement are common. Name, Department
With some variations, the number of new drug introductions per year have not change very much over more than a half century. Name, Department
But the annual expenditures for R&D in the pharmaceutical industry has continued to increase, resulting in a reduced number of introductions per biliion USD invested. What is depicted in the above graph from BCG as a decline in R&D productivity. Name, Department
Other methods for calculating the cost for bringing a NME to the market confirms the increasing costs over time. This is an explanation for the increasing relative costs of new drugs, and the high prices for drugs used in diseases with low incidence and prevalence. On the other hand, when the drug loses patent, the prices are substantially reduced. But this does not help the relative disadvantage of costs during the patent period when investments should be re-covered.. Name, Department
High prices also means that it is difficult to leave to the patients to make the priorities for use. Without public payment (reimbursement) there is no real access for patients to the new drugs. It also put a lot of pressure on reimbursement agencies to make decisions that are efficient and fair for patients. Name, Department
Clinical trials during the development of a drug focus on evidence that it works as intended. It thus often studied in patients, with comparators and outcome measures that do not necessarily answer questions which HTA agencies and payers are asking: What are the benefits in different subpopulations? What are the extra benefits compared to available used or best alternatives? What is the value for the patient assessed with relevant outcomes? Name, Department
A lot can be done in the development process to make the studies and data collected relevant for HTA and payers. Assessing this need in advance may increase the value of the trials without adding to costs. It is also important to identify development strategies that have a small chance to lead to the desired goals, and redirect efforts to development of potentially more valuable medicines. But there are limits to what is possible and meaningful to do pre market authorization. Particularly taking into account that products may fail. Thus joint advice from regulators and HTA experts is particularly valuable to get at best possible information for a global assessment of the opportunities for a specific potential asset. Name, Department
It may seem trivial that main consequence of wrong reimbursement decisions is a loss of money if potential side effects can be ignored. But with limited health care resoruces there are opportunity costs. Spending money on less valuable products and services means that those money cannot be spent on valuable products and services. Name, Department
As is seen from this recent study from researcher linked to NICE in England, there is a growing demand for finding measures, not only of the outcome of new therapies, but also of those which they replace. The method and estimates presented in the report are debatable, a comparison should always be made to the least important services and products. Calculations of averages is perhaps the most relevant, but the more rational and efficient the health service becomes, the more important will it be to find estimates also of opportunity costs in terms of losses of health. Name, Department
Patients have played a minor role in regulatory decisions. It is assumed that the doctors take patients interests into account in their use of new medicines. HTA and formal reimbursement decisions have made decisions more transparent and given patients as a group a seat at the table when assessment are undertaken and decisions made. Since all citizens are potential patients, everybody using and paying for health services is a stakeholder when it comes to real life data. Name, Department
Everybody wants it, but how should we do it? Name, Department
Sir Richard Doll, one of the most famous epidemiologists can illustrate both the power of real life data and the potential controversies. As his colleague Bradford Hill early noted, it is no straightforward conclusion about what causes disease or what contribute to its cure. The experimental clinical trial has an advantage in terms of internal validity. But we are also interested in external validity. Trials and real life data are thus complements. Name, Department
Data never talk for themselves. They have to be “massaged” to provide information, and to rise to the level of evidence. Data are also, like the human body, better if they are exercised (used). One important point for establishing validity is to make a connection between trial data and observational data. Including similar variables in both trials and observational studies in similar population is one way. Registries in an important source for real life data. Actually, Doll used a “natural registry of NHS doctors for his follow up studies on the impact of smoking on lung cancer. Name, Department
There is no “cock-book” solutions to questions which real world data should be collected. It depends on the circumstances. The choice of outcome measure can illustrate this. Different outcome measures give different answers. From an economic perspective, outcome measures that can be combined to a relevant composite measure, for example quality-adjusted life years (QALY) are to be preferred. Work performance is is also an important economic outcome, which may be ignored if not supported by data. Resource utilization can to a large extent be retrieved from existing administrative and clinical record, but needs to be complemented with resource utilization outside health care for both formal and informal care. Name, Department
The value of real world studies depend on what other supporting information is available to help assessing their validity. See the Bradford Hill criteria as an example. Still most reports from registers and other “real world data collections” are simple descriptions. There are statistical techniques developed which makes it possible to get much more information out of these data bases. One example being instrumental variables techniques frequently used in economics. See for example Heckman, J. (1997) Instrumental variables: A study of implicit behavioral assumptions used in making program evaluations, Journal of Human Resources, 32(3), 441–462. James Heckman is professor of Economics at the University of Chicago and 2000 Nobel Laureate in Economics. Name, Department
A reimbursement decision has to be made based on the information available when the drug first come to market. There are two ways of managing the uncertainty of outcome and costs where real life data are used. The first is CED where real life data are used for a reassessment of the reimbursement decision at a later point in time. The second is P4P where the actual reimbursement is linked to real life data about outcome. Both methods have been proposed and used for a rather long time, both in the US and Europe, and not only for pharmaceuticals. Contracting between purchasers and providers of health care usually includes some conditions where payment is related to outcome. For hospitals, the DRG payment can be complemented with outcome indicators related to quality. Also payment for physicians may include payments related to outcome. However, the use of these methods are still under development, and for example in US, CED has mainly been an extra payment if the provider collected data on the use of the technology. Name, Department
There are many issues related to CED and P4P and there is no time to go deeper into approaches and experiences. I will briefly look at the situation in a selected number of countries which may be of interest as a background for developments in the Netherlands, which I for obvious will not review. My impression is that you have lessons to tell rather than learn from other countries. Name, Department
The MS risk sharing scheme was set up due to the uncertainty about the cost-effectiveness of the new MS drugs, and to make sure that patients got access to the new treatments in an equal fashion. The data collection was organized through a project with multiple stakeholders, and paid for by DH and companies selling the products. It will take to long to review this project in detail, but the conclusion must be that it is seen as a failure, at least in the sense that it did not provide any information that could be used for an informed decision about these drugs in a reasonable time. One of the most important reasons for this was the lack of a relevant control group for comparision to those patients treated with the new drugs. Today the main approach in UK seems to be to achieve market access agreements which include price reductions. In some cases these price reductions have the form of P4P, since payment is linked to measures of response by patients to the treatment (pay for responders only). Velcade (bortozemid) in MM: Refund if no response after four cycles (60 days). Erbitux refund if there is progression in mCRC (scan after 5 weeks). Name, Department
France have a long tradition of follow up studies, but it is difficult to evaluate their impact since they are based on secret agreements between HAS and the manufacturer. Name, Department
Name, Department
CED has been used both to floow-up the restricted indications are followed, and to evaluate outcome and cst-effectiveness. Two examples: Risperdal Consta and Lantus. Consta illustrate the problem to measure the value of improved compliance. Lantusthe individual trade off between risk of hypoglycemic event and reduction in HbA1c. Name, Department
The investments in comparative effectiveness research in the US are important for Europe. Not least for the experiences in development of principles and methodologies for such studies. Name, Department
Over a longer time, we will see a trend towards payment related to outcome. The will make real world data key to management of health care systems. Name, Department