Join ISPOR  | Sign up for mailing List  | Follow Us: LinkedIn Twitter Facebook YouTube
The Official News & Technical Journal Of The International Society For Pharmacoeconomics And Outcomes Research
Policy Analysis

Clare McGrath, Senior Director, Evidence-Based Strategy, Pfizer, Walton on the Hill, Surrey, UK

Patient-Benefit: What Separates Regulatory (Licensing) From HTA Assessments?

The following is taken from the Second Plenary Session, “Patient Reported Outcomes: A European Perspective,” presented at the ISPOR 10th Annual European Congress, 22 October 2007, Dublin, Ireland.

Pharmaceutical companies need to satisfy the requirements of both regulators and reimbursement authorities when developing programmes to assess the patient's experience of disease and the impact of medicines. These requirements differ substantially in terms of the scientific standards for the data to be provided as well as the weight given to them in decision making. This is turn has implications for the design and feasibility of the drug development programme. First, we will present some definitions.

Patient benefit (as distinct from clinical outcomes) has been described as a continuum of parameters ranging from those “proximal to the individual” such as symptoms, to more distal, such as economic impact. Symptoms may be bothersome and impact on daily life, functioning as assessed by specific Quality of Life measures. The symptoms may affect areas of life that are also common to other diseases and can be assessed using “generic” Health Related Quality of life measures (some of which also allow one to assess the relative importance or weight of different health states). More peripherally still is the impact on dependency, use of health and social services which are influenced by external factors, which can make it more difficult to make the link from the symptoms through to the economic impact of disease and interventions. Patient Reported Outcomes (PROs) as defined by the FDA comprise all of these concepts, symptoms, QOL and economic as long as they are assessed by the patient directly. Parameters are shown in Figure 1.

In an ideal world with no constraints, we would be able to study the often complex interrelationships amongst these different levels of patient impact, how each is valued and contributes to service use and other health outcomes. However this is rarely the case with drug development where we are working against the clock and competing for resources across the portfolio of development opportunities. The decision context for patient benefit assessments depends on whether the decision is being made for a label claim or reimbursement. Decisions by a regulator on what should be in the drug label are aimed at informing the individual doctor and patient about the specific benefits and risks of a medicine so that they can decide on its suitability in the specific patient situation. Reimbursement authorities on the other hand are charged with decisions on which drugs should be funded at which price and in which patient populations in a way that makes best use of limited resources. Some reimbursement authorities wish to compare patient benefit across diseases so as to decide on what is cost effective for a population or group of patients (using cost per QALY thresholds).

There are marked differences between regulators and payors in accepted scientific standards and the decision criteria from the patient reports. Regulatory agencies require a rigorous approach that ensures the content and measurement properties of the instrument reflect what patients say is important to them and can measure a minimally important difference due to treatment.

Cost utility analysis uses a cost per QALY threshold that requires consistency in assessment across diseases and may trade off a loss of information or precision in the patient questionnaire in order to be ale to compare across patient groups. Utility measures do not meet the FDA scientific criteria for patient reported outcome often because they are not derived directly from patients and not validated to ensure the abovementioned content and measurement properties are relevant to the disease in question. The required utility measure may also be driven by a jurisdictional preference such as the NICE's stated preference for the EQ5D. There is much debate however about whether consistency in QALY assessment is achievable and indeed whether comparisons across diseases are actually made in deciding on the reimbursement of medicines.

The challenge for drug development then is to develop a robust method of measuring patient benefit that is both sensitive enough to detect small but important effects but is also suitable for comparison with other diseases that my have a significantly different impact on the patient. Of the many measurement systems that exist with varying levels of dimensions, severity, and sensitivity, no single measurement covers all patient groups. The choice of instrument can however have significant impact on the results of the cost per QALY values obtained. Too little relevant content in an instrument can result in a cost per QALY estimate several times higher than that produced by an instrument that contains more relevant information for the research question such as is illustrated in the wet AMD example in Table 1 and Graph 1. These compare the content and measurement properties of 4 different descriptor systems applied to wet AMD, a condition that causes visual impairment. The ability of the instrument to measure visual impairment specifically as in the case of the HUI, and the higher precision of this rating scale contribute to significantly larger improvement in quality of life due to treatment and resulting in a cost per QALY value that would fall within current thresholds. The absence of a vision specific measure (as occurs for the EQ5D and SF8D) results in QALY thresholds well above the threshold for recommending this treatment. By having to adhere to jurisdictional preferences for a descriptor system in order to achieve consistency, the ability to measure the important QOL improvement may be lost and an erroneous decision about treatment made. In considering the different options for measurement systems, we also need to consider the return on the research investment. Clearly, the potential to influence decision making with the patient reported assessment is a key consideration. The FDA label determines what can be used in promotion. This is relevant in the US market that uses a high level of direct to consumer advertising to ensure that information about patient benefits is robust. The FDA guidelines mandate more upfront investment in hypothesis development, instrument selection, and validation. This does present challenges in meeting these requirements during the development programme. Early dialogue with FDA staff is critical to a successful measurement system. Despite the high level of research spending in the field of patient reported outcomes assessment however, there appears to be a shortage of robust instruments to meet the FDA requirements especially for disease areas of high unmet need where the up front research investment in instrument development may not have been made. This is being addressed through both FDA and IMI sponsored initiatives but may not yield instruments for several years to come.

In Europe however, the importance given to patient benefit assessments in regulatory decision-making varies by country Payers have barriers to the use of quality of life (QoL) which is subject to the same scientific standards as the FDA. However, QALYs are systematically used in 3 to 5 countries (such as UK Sweden, The Netherlands). Many uncertainties around the use of QALYs as a single decision criterion exist, so QALYs should be used judiciously in decision making with full knowledge of the limitations of the method for each disease and treatment situation.


Clinical Development needs to meet the very diverse requirements of licensing and multiplepayer requirements in the same programme. This presents challenges in the design of Phase 2 and 3 clinical development programmes within competitive time frames and with available resources. The weight given to patient reported outcomes data is highest in the US given the role in deciding what can be used in DTC promotion. The resulting scientific standards are challenging to meet but helpful in addressing misperceptions about the credibility of patient reported data. This should help in the longer run to improve the acceptance of PRO data amongst European regulators and payers.

Caution should be used in interpreting the QALY assessment. The relevance of the content and measurement precision of the instrument to the disease and treatment in question play a large role in the level of uncertainty in the results obtained. Therefore, rigorous scientific standards should be given priority over jurisdictional preference when deciding on the in the choice of instrument. In addition, by strengthening reporting standards for the authorities requiring QALY assessment to include the descriptive elements of the QALY and the rationale for choice could go a long way to improving their interpretation and the weight given to this types of data in decision making.

  Issues Index | 2008 Issues Index  

Contact ISPOR @  |  View Legal Disclaimer
©2016 International Society for Pharmacoeconomics and Outcomes Research. All rights reserved under International and Pan-American Copyright Conventions. 
Website design by Eagle Systems USA, Inc.