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Supplements New Horizons in the Diagnosis and Treatment of Hereditary Angioedema: Overcoming Barriers to Management and Improving Patient Outcomes
Severity of Hereditary Angioedema, Prevalence, and Diagnostic Considerations
Jonathan A. Bernstein, MD
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William R. Lumry, MD
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Economic Burden Limiting Proper Healthcare Delivery, Management, and Improvement of Patient Outcomes
William J. Cardarelli, PharmD
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Economic Burden Limiting Proper Healthcare Delivery, Management, and Improvement of Patient Outcomes

William J. Cardarelli, PharmD
Another analysis released by a pharmacy benefits management group in April 2018 demonstrated that the cost of some drugs used to treat HAE comprised more than 97% of the total costs of care. In this study, the investigators assessed pharmacy and data claims for 15 million commercially insured members. Data demonstrated that 226 members had at least 1 claim for an HAE during the first 6 months of 2016. These members were then followed for 12 months following their first HAE drug claim to determine their drug use patterns, hospital and ED visits, and total care costs. The average 12-month total cost of care amounted to $409,925. The HAE drug costs totaled $395,507 (97%), with all other medical and pharmacy costs totaling $14,418 (3%) of total healthcare costs. Among the members studied, 49% met criteria for total enrollment, and 43% of these 111 members submitted claims for 2 or more drugs for HAE. Approximately 9% had more than $1.0 million in HAE drug expenditures, with this small group of patients accounting for 20% of the $43.9 million overall HAE drug expenses in the group’s commercial book of business. Fifty percent of HAE drug expenditures were billed through the pharmacy benefit with the other half billed through the medical benefit. One of the investigators noted that with drug costs driving such a high percentage of HAE treatment expenses, medical costs cannot realistically be lowered through use of HAE drugs. Instead, diligent case management following each patient’s first use of HAE treatments must be utilized to ensure appropriate drug use and best realize cost savings regardless of whether the drug is billed to the medical or pharmacy benefit.14,15

However, despite drug costs, appropriate and timely treatment of HAE decreases ED visits, hospitalizations, lost productivity (work/school), and prevents mortality, lowering the overall costs of HAE to the healthcare system.7,8 Innovative treatment paradigms may further lower the cost, especially the encouragement and education of patients to self-manage their disease. As an example, 1 study in the United States demonstrated a $650,000 savings when 249 HAE attacks over 5 months were treated at home by an infusion nurse compared with ED or in-hospital therapy.8

As noted earlier, it must be kept in mind that expenditures to treat orphan diseases, such as HAE, remain proportionately lower than the actual incidence of these diseases.8 As the number of newly approved therapies to treat HAE increases, it is likely that the cost of therapy will decrease.4 It must also be remembered that the costs of not treating HAE appropriately are also quite high. These include not just the direct cost of providing medical care for the patient but the indirect costs on patients, families, and caregivers.8 Orphan drugs, such as those to treat HAE, often represent a sole hope for patients and their families.16 Judicious choices in HAE therapy, usage of evolving treatment pathways, and better availability and access to new treatments will continue to improve QOL for patients with HAE, and coverage for these agents by payers and healthcare systems must continue to end barriers to access and use.4 There is truly an ethical imperative to address and provide better access to orphan drugs for these patients. The development and marketing of safe, effective treatments remains a crucial imperative to optimally address the healthcare needs of patients with rare diseases.16

The Importance of Patient-Reported Outcomes in HAE Management

The goal for best practices in management of HAE is to improve patient outcomes and overall QOL. A patient-reported outcome (PRO) is now the favored terminology for a data element directly reported by either the patient or patient surrogate about their healthcare preferences and experiences. This may include data surrounding their symptoms, functional status, or QOL in general.17,18 Multiple organizations have produced guidance assistance for developing and assessing PROs, including the FDA.18,19 The FDA formally defines a PRO as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else.”19,20

Because rare diseases have a low prevalence in the general population, PROs can be vital in addressing the potential benefits for treatments of these conditions. Surrogate outcomes, such as laboratory or physiologic measures, may not reflect therapy benefits personally valued by patients. While these measures may have demonstrated therapeutic benefit, the patient may not actually feel better or experience improved survival.20 In addition, PROs may be responsive to more discreet therapy effects in smaller studies.20,21 Appropriately chosen PROs could potentially determine smaller improvements in patient physical and emotional function.20

Health-related QOL (HRQOL) is a global goal for all patients throughout life, and HCPs must determine if HRQOL is being optimized among patients with a rare disease to the extent achievable. While generic measures have been previously used to assess both the impact of the disease itself and disease-targeted treatments in orphan diseases, more disease-specific PROs and HRQOL measures are being introduced as efficacy end points for clinical trials of new therapies and long-term surveillance registries for both treated and untreated patient populations.20 As shown in Figure 2, PROs (also referred to as patient-centered outcome measures [PCOMs]) convey value across all stakeholders involved in the healthcare of patients with rare diseases, conferring better ability to translate care and/or observed treatment effect into a more straightforward interpretable measure of patient benefit.22

Currently, optimal and “fit-for-purpose” PROs/PCOMs do not exist for most rare diseases. However, if they are adequately developed, they have a desirable potential to “speak” to patients and better address their principal complaints. PROs offer better ability to obtain a more meaningful and interpretable measure of patient function and the possibility to reduce uncertainty over the effectiveness of treatments for rare diseases. They may be incorporated into both clinical trials and clinical practice, including disease registries, as noted previously, to enhance comprehension of the natural course of disease and to better guide treatment selection. Methods used for PRO/PCOM investigation include but are not limited to22:
  • In-depth pretrial concept elicitation patient interviews to better explore the disease experience (eg, most significant symptoms, disease impact on daily life)
  • Interviews in a clinical trial setting (eg, study exit interviews, subject experience interviews) that may better delineate patient-defined improvement and benefits of therapy
  • Focus groups for patient interaction and comparison of individual experiences
  • Internet and social media platforms
  • Direct patient observation/patient “shadowing” for first-hand experience of what it means for a patient to have a rare disease
  • Audio/written patient diaries for recording of patient experiences
Methods used for PROs in individual instances will also depend on some degree of constraint. However, use of more sources improves the chance to increase the depth and breadth of information available to make qualitative comparisons across groups of patients. This may assist in creation of conceptual models combining patient-based evidence to delineate the relationship between core signs/symptoms, concerns that matter to most patients with the rare disease, and the hypothesized treatment benefit.22

Two validated PROs are available to assess patients with HAE. These include the angioedema activity score (AAS) and the hereditary angioedema activity score (HAE-AS).23-25 The AAS is a symptom-specific PRO measure targeted at the assessment of angioedema activity. This method is validated for all angioedema types, including HAE. AAS is designed as a diary where patients document the presence or absence of angioedema over the past 24-hour period. If angioedema is present, patients answer 5 additional questions based on a 0- to 3-point scoring system.

Minimum and maximum daily score can range from 0 to 15 points total. Cumulative data over 4 weeks (termed AAS28) are then used to present an analysis of disease activity.23,25 The AAS has very good internal consistency, good validity and test-retest reliability, and is sensitive to changes in the activity of angioedema over time. The minimal important difference is 8 points for a 7-day cumulative AAS run (AAS7).25 In contrast, the HAE-AS is a specific method to detect disease activity in C1-INH-HAE.24,25 HAE-AS documents retrospective disease activity over the previous 6-month period. It consists of 12 items that demonstrate a sole dimension/line. A raw score ranges from 0 to 29, which is then adapted to a linear measure with a 0-to-30 score that exhibits good internal consistency. Overall, the AAS and HAE-AS exhibit some similarities and some differences.25

In addition to the AAS and HAE-AS, 2 QOL measures have been developed. The AE-QOL is a symptom-specific questionnaire for adult patients with angioedema that assesses HRQOL. It contains 17 items addressing 4 functions25,26:
  • Functioning
  • Fatigue/mood
  • Fears/shame
  • Food
The AE-QOL covers a recall period of 4 weeks. A higher AE-QOL score indicates a lower HRQOL.26,27 The HAE-QOL is a questionnaire for adult patients with C1-INH-HAE. This survey comprises 25 items grouped into 7 HRQOL domains25,27:
  • Treatment difficulties
  • Physical functioning and health
  • Disease-related stigma
  • Emotional role and social functioning
  • Concern about offspring
  • Perceived control over illness
  • Mental health
This survey covers a 6-month recall period.25,27 This questionnaire has been used in clinical practice, notably in a study that determined that home-based therapy for HAE was associated with better compliance compared with inpatient-based treatment, and that the choice to adopt at-home management was correlated with higher HAE attack frequency.25,28 As shown in the Table, these various questionnaires/methods not only exhibit some differences but also some similarities, and are available in different languages.25

While a validated tool for disease control is not yet available, one is under investigation. It is also important to note that these tools are intended for adult patients and have yet to be validated for the pediatric population with AE/HAE. In addition, while developed in line with FDA and other requirements, such tools have yet to receive formal approval from these governing bodies. That said, they remain promising options in determining important patient values and factors affecting treatment of rare diseases, such as HAE, with more PROs in the pipeline for the future.25

Conclusions

 
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