CADTH Reimbursement Recommendation

Normal Immunoglobulin (Human) 10% and Recombinant Human Hyaluronidase (HyQvia)

Indication: As replacement therapy for primary humoral immunodeficiency and secondary humoral immunodeficiency in adult patients

Sponsor: Takeda Canada Inc.

Final recommendation: Reimburse with conditions

Recommendation

What Is the CADTH Reimbursement Recommendation for HyQvia?

CADTH recommends that HyQvia should be reimbursed for the treatment of primary humoral immunodeficiency and secondary humoral immunodeficiency if certain conditions are met.

Which Patients Are Eligible for Coverage?

HyQvia should only be covered to treat adults with primary or secondary humoral immunodeficiency if it is covered in a similar way as other immunoglobulin replacement therapies (IgRTs) currently reimbursed for the treatment of these conditions.

What Are the Conditions for Reimbursement?

HyQvia should only be reimbursed if prescribed by a specialist with appropriate knowledge and training in primary and secondary humoral immunodeficiency and if treatment with HyQvia does not cost more than the least costly IgRT currently reimbursed for this condition.

Why Did CADTH Make This Recommendation?

• Evidence from 2 clinical trials demonstrated that treatment with HyQvia helped prevent acute serious bacterial infections (e.g., sepsis, meningitis, and pneumonia) in patients with primary immunodeficiency.

• Some types of observational studies suggest that most patients tolerate HyQvia. In addition, patients may be able to self-administer HyQvia at home with appropriate training. The number of monthly infusions could also be fewer compared to conventional subcutaneous immune globulin.

• There is no evidence to show HyQvia is any better than other reimbursed IgRTs used to treat primary and secondary humoral immunodeficiency. Therefore, HyQvia should cost no more than the lowest cost IgRT to ensure cost-effectiveness.

• Based on public list prices, the 3-year budget impact is $185,862,568.

Additional Information

What Is Primary Humoral Immunodeficiency and Secondary Humoral Immunodeficiency?

Primary humoral immunodeficiency and secondary humoral immunodeficiency are disorders of the immune system that make it harder to fight off infections. Primary immunodeficiencies are inherited, whereas secondary immunodeficiencies are acquired.

An estimated 1 in 1,200 people living in Canada have a primary immunodeficiency. Primary humoral immunodeficiency accounts for 50% to 60% of primary immunodeficiencies. The prevalence of secondary humoral immunodeficiencies in Canada was not identified, but is estimated to be much more common than primary humoral immunodeficiencies.

Unmet Needs in Primary Humoral Immunodeficiency and Secondary Humoral Immunodeficiency

Although IgRTs are available and are effective, there is a need for more treatment options to improve adherence, convenience, and tolerability.

How Much Does HyQvia Cost?

Treatment with HyQvia is expected to cost approximately $54,888 per patient per year.

Recommendation

The CADTH Canadian Plasma Protein Product Expert Committee (CPEC) recommends that normal immunoglobulin (human) 10% and recombinant human hyaluronidase (IgHy10) be reimbursed as replacement therapy for primary humoral immunodeficiency and secondary humoral immunodeficiency in adults only if the conditions listed in Table 1 are met.

Rationale for the Recommendation

Two phase III, open-label, non-randomized, single-group prospective studies (Study 160603 [N = 89], and related extension study, Study 160902 [N = 66]) demonstrated that treatment with IgHy10 resulted in clinical benefit for patients with primary immunodeficiency disorder (PID) requiring immunoglobulin replacement therapy (IgRT). The rate of validated acute serious bacterial infections (VASBI) was less than 1.0 infections per patient per year in both studies (P < 0.0001). Direct comparative evidence for IgHy10 versus current IgRTs was not identified, which is a significant limitation of the available evidence, but infectious outcomes observed are consistent with other IgRTs currently used in Canada. Patients and clinical experts both identified the need for a treatment that would reduce bacterial infections and maintain consistent immunoglobulin G (IgG) serum levels, that also minimizes disruptions to the lives of patients through the ability to administer treatment less frequently compared with conventional subcutaneous immunoglobulin (cSCIG) and outside of the hospital setting compared to intravenous immunoglobulin (IVIg). The available evidence, including post-marketing studies, suggests that IgHy10 has the potential to address these needs in some patients. In addition to the clinical benefit demonstrated in Study 160603 and Study 160902, additional evidence and expert opinion suggested that IgHy10 may result in fewer infusions required compared to cSCIG for those patients who can self-administer at home, where improved health-related quality of life (HRQoL) and adherence might be anticipated. Other needs identified by patients included improving HRQoL and tolerability. Evidence to directly support improved HRQoL is not available, and only 21% to 36% of patients in the trials were able to self-administer IgHy10 at home without requiring assistance; however, prospective, post-marketing, and other observational studies suggest most patients tolerate IgHy10.

Using the sponsor-submitted price for IgHy10 and publicly listed prices for all other drug costs, IgHy10 was more costly compared with IVIg and SCIg therapies and was considered similarly effective in the cost-minimization. However, there is no direct or indirect evidence that IgHy10 is clinically superior to other IVIgs and SCIgs currently reimbursed for the treatment of PID or secondary immunodeficiency (SID). As such, IgHy10 should be no more costly than the least costly IVIg or SCIg reimbursed for the treatment of PID or SID.

Table 1: Reimbursement Conditions and Reasons

CPEC = Canadian Plasma Protein Product Expert Committee; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IgRT = immunoglobulin replacement therapy; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin.

Discussion Points

• CPEC acknowledged that the therapeutic component of IgHy10, normal human immunoglobulin (10%) (Gammagard Liquid), is analogous to other IgRTs currently available in Canada to treat PID and SID. In addition, the clinical experts noted to CPEC that the rate of VASBI observed in the pivotal trials of IgHy10 was similar to other IgRTs currently used in Canada.

• CPEC acknowledged that IgHy10 offers potential ancillary clinical benefits for patients with PID or SID in having fewer infusions compared to cSCIG and recognized the similarities to other IgRTs in clinical benefit for reducing infections despite the limitations of Study 160603 and Study 160902, including the lack of randomization and high study discontinuation rates.

• In Study 160603, only 20.5% of all infusions were administered at home without nurse intervention. In Study 160902, 64% of patients and 52% of all infusions required assistance and were unable to continue self-administration of infusions at home. The clinical experts and post-marketing data suggest to CPEC that, in practice, the proportion of patients who might be able to manage their condition with infusions at home is likely higher than what was reported in the studies. Additionally, the clinical experts noted that the ability to successfully self-administer IgHy10 at home depends on the ability to complete training for home infusion, which must be considered along with the use of IgHy10 because patients who are unable to complete this training may be better served by IVIg or cSCIg. CPEC acknowledged that IgHy10 offers an additional treatment option with the potential to be self-administered at home.

• CPEC discussed that determining whether a patient is a good candidate for treatment with IgHy10 should be at the discretion of both the treating clinician and patient. No literature or data inform a particular patient population that would benefit from IgHy10.

• No direct or indirect evidence was available that compared the efficacy or safety of IgHy10 with other IgRTs used for patients with primary humoral immunodeficiency and secondary humoral immunodeficiency. CPEC identified this as a significant evidence gap and was unable to determine the potential clinical benefits of IgHy10 compared with other available IgRTs. As such, the evidence does not support a price premium over currently available IgRTs for adults with primary humoral immunodeficiency and secondary humoral immunodeficiency.

Background

PIDs or inborn errors of immunity encompass a heterogeneous group of disorders that are genetically determined, resulting from inherited defects in the development and/or function of the immune system. An estimated 1 in 1,200 people in Canada live with PID, with more than 70% of patients remaining undiagnosed. The drug under review is indicated for the treatment of humoral immunodeficiencies, which result from B-cell defects that lead to antibody deficiencies and account for 50% to 60% of PIDs. Living with PID predisposes affected people to increased frequency and severity of infections, autoimmunity, and aberrant inflammation and malignancy. The presentation of PIDs can occur at any age, and patients with B-cell (antibody-deficiency) disorders typically present after 6 months of age with recurrent and often severe sinopulmonary infections such as otitis media, sinusitis, pneumonia, and gastrointestinal infections. Diarrhea, fatigue, autoimmune manifestations (such as autoimmune cytopenia), and hearing loss are also common. Secondary immunodeficiencies are acquired and much more common than PIDs. They may result from systemic disorders, immunosuppressive treatments, or prolonged serious illness. Additionally, patients who are critically ill, older, or hospitalized are susceptible to acquired or SID. Secondary humoral immunodeficiency is a type of SID that occurs across a wide spectrum of diseases with a range in the level of susceptibility to infection that can sometimes be reversed. An estimation of the prevalence and incidence of SID or secondary humoral immunodeficiency in Canada was not identified; however, a study by Patel et al. (2019) reported that secondary humoral deficiencies are estimated to be 30-fold more common than primary humoral immunodeficiencies.

Human immunoglobulin preparations for IV or subcutaneous administration, or IgRT, are the cornerstone of treatment in patients with immunodeficiencies affecting the humoral immune system. The clinical experts consulted by CADTH indicated that it is important to note that not only patients with predominantly antibody deficiencies, but also those with other forms of PIDs, such as combined immunodeficiencies or inborn errors of immunity, might require long-term or even lifelong IgRT. Both IVIg and SCIg therapies have limitations, 1 of which is associated adverse events (AEs). AEs associated with SCIg tend to be local reactions, whereas systemic AEs are more commonly reported with IVIg. Other reasons for using SCIg include improved consistency of IgG serum levels (less of a difference between peak and trough levels), administration may be performed at home, and no requirement for venous access. Disadvantages of SCIg compared with IVIg include a higher frequency of infusions, a requirement for multiple injection sites, and compliance from some patients. Treatment with IVIg allows for administration of larger volumes of IgG compared to SCIg, more frequent and direct contact with health care professionals, and less frequent administration. In addition to IgRT, early and aggressive treatment of infections with antimicrobial agents is essential in patients with several forms of inborn errors of immunity, including primary humoral immunodeficiency. Non-drug therapies for the treatment of humoral immunodeficiencies include avoidance of some live vaccines for selected diseases and close monitoring and co-treatment of comorbidities, including autoimmune diseases (cytopenias, enteropathies, celiac disease, thyroid disease, granulomas), respiratory status and function, and malignancies.

Normal immunoglobulin (human) 10% and recombinant human hyaluronidase (IgHy10) has been approved by Health Canada as replacement therapy for primary humoral immunodeficiency and secondary humoral immunodeficiency in adult patients. IgHy10 is an IgRT. Both components of IgHy10 are provided as solutions for subcutaneous infusion and the dosage recommended in the product monograph for IgHy10 varies by previous treatment experience as follows:

• Patients naive to IgG treatment should receive IgHy10 at 300 mg/kg to 800 mg/kg at 3-week to 4-week intervals after initial ramp-up, and adjust as necessary based on IgG levels and clinical outcome.

• Patients previously treated with IVIg or who have a previous IVIg dose that can be referenced should receive IgHy10 at the same dose and frequency as their previous IVIg treatment. When switching from IV treatment, IgHy10 is started 1 week to 2 weeks after the last IV dose. If patients were previously on a 3-week dosing regimen, increasing the interval to 4 weeks can be accomplished by administering the same weekly equivalents.

• Patients previously treated with SCIg should receive an initial dose of IgHy10 at the same dose as their previous SCIg treatment, but administration may be adjusted to a 3-week or 4-week interval. The first infusion of IgHy10 should be given 1 week after the last treatment with the previous immune globulin.

The Health Canada–approved dose of hyaluronidase is a minimum of 75 U/g of IgG.

Sources of Information Used by the Committee

To make their recommendation, the committee considered the following information:

• a review of 2 open-label, non-randomized, single-group, prospective studies in patients with a PID that required antibody replacement therapy

• patients’ perspectives gathered by 1 patient group: Canadian Immunodeficiencies Patient Organization (CIPO)

• input from public drug plans that participate in the CADTH review process

• input from 2 clinical specialists with expertise diagnosing and treating patients with primary humoral immunodeficiency and secondary humoral immunodeficiency

• input from 2 clinician groups: the Clinical Immunology Network-Canada and the Medical and Scientific Advisory Committee of the Canadian Immunodeficiencies Patient Organization (CIPO)

• a review of the pharmacoeconomic model and report submitted by the sponsor.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Information for the patient group submission by CIPO was collected through an online survey of patients and caregivers (N = 246) and semi-structured telephone interviews with patients (N = 8) living with PID. A total of 233 (95%) survey respondents were patients living with PID, and 13 (5%) were caregivers responding on behalf of patients. The telephone interviews were with patients currently receiving IgRT for PID. None of the patients captured in the patient group submission had experience with IgHy10.

The patient group submission described living with PID as being prone to a wide range of infections that are often severe, chronic, and debilitating. According to CIPO, the frequency of infections is dramatically reduced with IgRT. As many patients with PID require lifelong therapy, the method of administration and setting where the treatment is administered are important factors that can significantly affect HRQoL. The patient preference is strongly considered when selecting SCIg or IVIg therapy, along with the efficacy of the specific therapy.

According to CIPO, patients want a treatment that minimizes disruptions to career or personal life. It was noted that administering therapy at a lower frequency and reducing the need to travel to an infusion clinic would help minimize disruption to everyday life as well as reduce the risk of hospital-acquired infections. Telephone interview respondents indicated a curiosity about trying IgHy10, but also described a desire for the same result from treatment, concerns about having a negative experience due to switching therapies, and whether IgHy10 it would be an appropriate treatment option for the individual patient seeking treatment.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of PID and SID in pediatric and adult patients.

The clinical experts stated that treatments for primary humoral immunodeficiency that reverse the course of disease are limited. The experts also noted that treatments for secondary humoral immunodeficiency are limited, but that some etiologies can be reversed. Current options for IgRT are effective, but the clinical experts noted there is a need for treatment options that improve adherence and convenience. The clinical experts indicated that current treatments are time consuming and can negatively affect daily function due to the duration and/or frequency of administration, as well as the need to administer IVIg in a hospital setting. The clinical experts also expressed a need for treatments that are better tolerated, noting IVIg is associated with side effects including headaches, myalgia, arthralgia, and nausea, and requires premedication with antipyretics and antinausea agents. Some patients were also reported as having experienced transient acute kidney injury, aseptic meningitis, thrombotic and hyperviscosity–related side effects, and fever. The experts also reported that not all patients respond to currently available IVIg and conventional SCIg (cSCIg) treatments, and that it is difficult to achieve target levels of immunoglobulin in selected patients with IVIg due to its pharmacokinetics (greater variation in peaks and troughs between infusions), which can translate to suboptimal clinical control of disease.

According to the clinical experts consulted by CADTH for this review, IgHy10 would present an additional treatment option to patients, either as first line for patients who were expected to benefit from SCIg, or as second line for those who do not tolerate IVIg or SCIg. Both experts felt IgHy10 had potential to cause a shift in the current treatment paradigm, particularly in terms of SCIg therapies, because it would expand options for IgRT for patients with primary humoral immunodeficiency and secondary humoral immunodeficiency.

The clinical experts indicated patients who are expected to benefit from SCIg or IVIg are also expected to benefit from treatment with IgHy10. The clinical experts also indicated that patients who are expected to benefit most from switching from IVIg to treatment with IgHy10 include patients with certain comorbidities, those with limited access to health care facilities, those who had severe adverse effects to IVIg, have difficult venous access, or those who prefer not to miss school or work to receive treatment. The clinical experts also noted that patients likely to benefit from switching from cSCIg to IgHy10 include those who require large doses/volumes due to higher body weight or the need for immunomodulation, those who have needle phobia and want to avoid using multiple injection sites, those who want to infuse SCIg less frequently, or those who are unable to adhere to weekly SCIg infusions.

Patients identified by the clinical experts as being least suitable for treatment included those who have little to no subcutaneous tissue (very low body fat) or severe skin conditions preventing the subcutaneous administration. The clinical experts also felt that complex patients that require frequent clinical and Ig monitoring and regular in-person re-assessment (potentially coordinated with other IV treatments) would be less suitable for treatment with IgHy10. The clinical experts also noted patients with a history of poor adherence to treatment, inappropriate compliance, or inappropriate support from a caregiver (particularly for pediatric patients) may also be less suitable for treatment with IgHy10.

The clinical experts indicated that patients with primary or secondary humoral immunodeficiency starting treatment with IgHy10 who also have chronic or active infections are expected to respond to treatment with an improvement in clinical state and normalized blood IgG levels (IgG target levels achieved). The clinical experts described long-term expectations for response to treatment as a reduction in frequency and severity of infections, which should result in fewer visits to outpatient clinics, a reduced rate of emergency visits and/or hospitalizations due to infections, reduced need for antimicrobial treatments or prophylactic use, fewer missed days from school or work, and improved overall health and HRQoL. The experts would also expect the overall burden experienced by caregivers and by the health care system to be reduced.

The experts described a clinically meaningful response to treatment as 1 that would include maintenance of target steady-state serum IgG trough levels (at least 7 g/L), reduced infection rate (no serious infections or significantly less severe infections per year), no ER visits or hospital admissions due to infections, significant reduction in days missed from work or school, improved survival and HRQoL, and remission of autoimmune and inflammatory diseases associated with inborn error of immunity if present. Further, the experts noted that all of these outcomes are clinically meaningful when achieved without serious adverse events (SAEs).

The clinical experts suggested that patients treated with IgHy10 should be assessed for response to treatment every 3 months to 6 months depending on the disease severity, which is consistent with current clinical practice of patients with PID/SID.

Feedback from the clinical experts indicated that discontinuation of treatment with IgRT would be considered if there is a lack of improvement in Ig replacement levels or if response to treatment (as described previously) is not achieved despite increasing doses of IgRT. The experts also noted that issues with adherence (identified by an inability to maintain therapeutic serum IgG levels) may result in discontinuation from IgHy10 because they may be better served by IVIg. Discontinuation from IgHy10 may also be considered based on patient preference or for patients who do not exhibit an improvement in HRQoL as described by the clinical experts.

According to the clinical experts, IgHy10 can be administered at home after appropriate training by a patient support program, similar to current practice for other SCIg preparations. The experts also noted that select cases may warrant infusion of IgHy10 in a health care facility (infusion clinic, outpatient clinic, in-hospital medical day treatment unit), such as when the caregiver or patient is unable to administer the infusion. The experts indicated that a specialist with appropriate knowledge and training in PID and SID should be involved in the diagnosis and initiation of therapy. This may include immunologists, rheumatologists, and hematologists with training in IgRT.

Clinician Group Input

Seven clinicians authored 2 clinician group input submissions on behalf of 2 clinician groups: the Clinical Immunology Network-Canada and the Medical and Scientific Advisory Committee of CIPO. The clinician group input was aligned with the input provided by the clinical experts consulted by CADTH, with the exception of place in therapy and assessment of treatment response, which differed slightly. The clinician groups felt that IgHy10 would likely be used as a second-line treatment (following IVIg or cSCIg) for primary or secondary humoral immunodeficiency in general but could become a first-line treatment option in certain subpopulations of patients with the greatest unmet need. The clinician group input recommended treatment response be assessed at least every 6 months to 12 months, which is longer than the frequency of 3 months to 6 months suggested by the clinical experts consulted by CADTH. The clinician groups also noted that there are considerable benefits associated with the ability to treat patients at home, particularly in terms of rising capacity issues for both inpatient and outpatient beds and the increasing costs of medicines.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.

Table 2: Responses to Questions From the Drug Programs

CPEC = Canadian Plasma Protein Product Expert Committee; cSCIg = conventional subcutaneous immunoglobulin; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IgRT = immunoglobulin replacement therapy; IVIg = IV immunoglobulin; PID = primary immunodeficiency disorder; SCIg = subcutaneous immunoglobulin; SID = secondary immunodeficiency.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

Two sponsor-submitted, phase III, open-label, non-randomized, single-group prospective studies were included in this review. The pivotal study, Study 160603 (N = 89), evaluated the efficacy and tolerability of IgHy10 in patients that were at least 2 years of age with a PID disorder that required antibody replacement therapy. Patients were also required to have a serum trough level of IgG greater than 4.5 g/L and to have been receiving regular IgRT for at least 3 months before enrolment. Study 160902 (N = 66) was an extension of Study 160603 that evaluated the long-term tolerability and safety of IgHy10. The safety extension also followed patients after discontinuation of hyaluronidase for delayed adverse reactions.

Study 160603 consisted of 2 epochs. During epoch 1, patients received IVIg 10% for 12 weeks. Of the 89 patients enrolled in epoch 1, 87 (98%) received IVIg treatment. Subsequently, 83 (93%) of the patients from epoch 1 continued to epoch 2 during which the patients received IgHy10 (75 U/g recombinant hyaluronidase followed by SCIg 10%) administered at 108% of the monthly total IVIg dose every 3 weeks or 4 weeks for 14 months to 18 months. The primary end point in Study 160603 was acute serious bacterial infection rate, defined as the mean number of VASBIs per patient per year. The annual rate of all infections, IgG levels, antibiotic use, health care utilization, productivity, HRQoL, tolerability, and safety were also evaluated.

Patients in Study 160603 that were exposed to treatment had a median age of 35.0 years (range = 4 to 78), were primarily White (91%) and non-Hispanic or -Latino (91%), and 51% were male. The most commonly diagnosed PID among patients was common variable immune deficiency (56%), followed by hypogammaglobulinemia (20%) and X-linked agammaglobulinemia (7%). All patients reported a medical history including disorders of the hematopoietic/lymphatic system, and the majority also reported medical conditions relating to the eyes, ears, nose, and throat (98%) and respiratory system (87%). The median serum IgG trough levels up to 6 months before enrolment were 10.34 g/L (range = 4.05 to 32.00). There were no notable differences in the demographic characteristics of patients who continued into Extension Study 160902.

Efficacy Results

The efficacy results have been summarized with a focus on the results reported during epoch 2 of Study 160603, when patients were treated with IgHy10. Note that in Study 160603, treatment with IgHy10 (epoch 2) cannot be compared with treatment with IVIg (epoch 1) because the study was not designed to assess this.

Infections

The primary end point of Study 160603 was analyzed based on the null hypothesis of 1 or more VASBIs per patient per year tested against the alternate hypothesis of less than 1 VASBI per patient per year, as per FDA regulatory guidance. Comparisons of IgHy10 to other IgRT were not available. A total of 2 VASBI were reported during treatment with IgHy10 in epoch 2; both cases were episodes of bacterial pneumonia that were treated with oral antibiotics without hospitalization. This corresponded to a rate of 0.025 VASBIs per year (upper limit of the 99% confidence interval [CI] = 0.046). The clinical experts on this review agreed that the reported rate of VASBI was aligned with what would be expected from an IgRT treatment. The rate of VASBI was not reported during treatment with IVIg in epoch 1. The rate of VASBI per year before the safety follow-up period was similar among the 66 patients that continued to Extension Study 160902 (0.020; upper limit of the 99% CI = 0.045).

In Study 160603, the rate of all infections reported during treatment with IVIg in epoch 1 was 4.51 infections per year (95% CI, 3.50 to 5.69). During treatment with IgHy10 in epoch 2, the rate of all infections was 2.97 infections per year (95% CI, 2.51 to 3.47). In the Extension Study 160902, the rate of all infections during treatment with IgHy10 was 2.86 infections per year (95% CI, 2.36 to 3.43).

Additionally, Wasserman et al. (2016) did a post hoc analysis of patients from Study 160603 and Study 160902 from the first administration of IgHy10 through the end of treatment. The annual rate of infections and annual rate of VASBIs during IgHy10 treatment were reported by age group (< 18 years and ≥ 18 years). For patients at least 18 years of age (n = 59), the rate of infection was 2.98 per year (95% CI, 2.56 to 3.44) and the rate of VASBI was 0.01 per year (upper limit of 99% CI = 0.02). The rates of infection and VASBI were consistent with the results reported for each of the individual studies.

Immunoglobulin Levels

The pivotal study and extension study evaluated IgG trough levels. The clinical experts consulted by CADTH indicated that IgG trough levels were routinely assessed in clinical practice and used as an indicator for the ability to prevent infection and disease-related comorbidities. Published recommendations for treatment with IgRT suggest IgG trough levels should exceed 5 g/L and ideally be more than 7 g/L. At baseline in Study 160603, the median serum IgG trough levels were approximately 10 g/L. In patients who were at least 12 years old, the median IgG trough level was 10.70 g/L (95% CI, 9.46 to 11.80). The IgG trough levels while receiving IgHy10 during epoch 2 appeared similar to IgG trough levels while receiving IVIg in epoch 1.

In Extension Study 160902, patients were asked to increase the frequency of IgHy10 administration to a 2-week or 3-week interval for a minimum of 4 months to evaluate the effect of varying dose intervals on IgG levels. In summary, the steady-state IgG trough levels were maintained at a median of at least 10 g/L at a dose administration interval of 2 weeks, 3 weeks, or 4 weeks. After 4 months, patients had the option of returning to their initial dose interval or stay on the 2-week or 3-week interval (17 of 66 [25.8%] patients stayed on a 2-week interval for more than 4 months). The ratio of IgG trough levels measured at the end of the safety follow-up period compared with IgG trough levels measured at the end of IgHy10 treatment were also reported, which indicated that IgG levels were maintained or increased following discontinuation of hyaluronidase over a period of approximately 1.5 years (mean duration of treatment was 565.9 days, standard deviation [SD] = 211.8). Although the clinical experts consulted by CADTH indicated that IgG levels are routinely assessed and useful as a reference point, they also noted that treatment decisions are predominantly based on clinical assessments of the patient as opposed to solely relying on laboratory values.

Antibiotic Use

Outcomes related to antibiotic use were identified as an important outcome to clinicians and patients. Antibiotic use was reported as a point estimate of the number of days per month on antibiotics. Based on this, it was estimated that during treatment with IgHy10 in Study 160603, patients were on antibiotics for 1.68 days per month (95% CI, 1.29 to 2.16). In the extension study (Study 160902), the point estimate for days on antibiotics was reported annually. While receiving treatment with IgHy10 before the safety follow-up period, patients were on antibiotics for 64.03 days per year (95% CI, 45.16 to 87.54). The clinical experts consulted by CADTH indicated that the rate of antibiotic use was higher than expected, noting that it is atypical for patients to use antibiotics on a monthly basis. Patients who could not discontinue prophylactic antibiotic use were excluded from the trials, and concomitant prophylactic antibiotic use was not permitted during the trials. This is likely to overestimate the use of antibiotics in the trials; however, the magnitude of overestimation is difficult to determine because the proportion of patients who were using antibiotics prophylactically before enrolment was not reported. Thus, there is significant uncertainty associated with the results for antibiotic use.

Health-Related Quality of Life

HRQoL was evaluated in Study 160603 and extension Study 160902 using the PEDS-QL and SF-36 and reported by age group (2 years to less than 7 years, 7 years to less than 14 years, and at least 14 years). Evidence of validity, reliability, and responsiveness was identified for both the PEDS-QL and SF-36 but not in patients with immunodeficiencies. In Study 160603 using the SF-36 for patients at least 14 years old, the mental and physical summary score was a median of 52.2 (range = 21.5 to 70.8) and 44.8 (range = 13.1 to 61.1), respectively. The HRQoL results were similar in the extension study; the mental and physical summary scores were a median of 51.0 (range = 25.3 to 56.9) and 48.7 (range = 11.6 to 52.9), respectively. Although limited by methods of analysis and sample size, the evidence suggests there was no change in HRQoL following treatment with IgHy10.

Tolerability and Adherence

In Study 160603, 77 of 87 (89%) patients and 350 of 365 (96%) infusions did not require a reduction, interruption, or stoppage of infusion due to tolerability concerns while receiving IVIg in epoch 1. During treatment with IgHy10 in epoch 2, 68 of 81 (84%) patients and 1,103 of 1,129 (98%) infusions did not require a reduction, interruption, or stoppage of infusion due to tolerability concerns. The findings in patients receiving treatment with IgHy10 during the extension Study 160902 were similar to what was observed in Study 160603.

One of the key advantages that was anticipated for IgHy10 was the ability to administer treatment at home, less frequently than cSCIg, thereby improving the convenience and minimizing the impact of treatment on a patient’s life. The clinical experts consulted by CADTH indicated they expected the majority of patients (more than 90%) would be able to self-administer IgHy10 at home, similar to what they had observed with cSCIg in clinical practice. In epoch 2 of Study 160603, 282 of 1,129 (25%) of infusions were administered at home, 231 (82% of infusions at home or 20.5% of all infusions) of which were administered without nurse intervention, and the majority of IgHy10 infusions (847 of 1,129 or 75.0%) were administered at an investigational site. Infusions were required to occur at the investigational site until at least 2 infusions at the maximum infusion interval were tolerated, but the proportion of infusions this applies to is unknown based on the data available. While receiving IgHy10 (before the safety follow-up period) in extension Study 160902, 64% of patients and 52% of all infusions required assistance with self/home-infusion. Reasons for being unable to continue self-administration of infusions at home were due to a medical reason (9 of 63 patients or 14.3%), because of a family member (10 of 63 patients or 15.9%), or for other reasons (37 of 63 patients or 58.7%). Additional information about the reasons for being unable to self-administer infusions at home was not provided. Further, whether the ability to self-administer IgHy10 improves over time is unknown.

Health Care Utilization and Productivity

Outcomes related to health care utilization and productivity were of importance to clinicians and patients. A point estimate of the number of acute physician visits, days in hospital, and days in hospital due to infection were reported per month in Study 160603 and per year in Study 160902.

In Study 160603, patients reported an acute visit to a physician on approximately 0.40 days per month (95% CI, 0.32 to 0.49) while receiving treatment with IgHy10. There was no substantial difference in acute physician visits reported during IgHy10 (after the ramp-up) and during epoch 1 while receiving IVIg (0.33 days per month; 95% CI, 0.23 to 0.45). The monthly rate of days in hospital and days in hospital due to infection were similar in epoch 1 and epoch 2, with overlapping CIs for the reported point estimates. The rate of days spent in hospital per month was 0.06 (95% CI, 0.03 to 0.10) while receiving IVIg and 0.02 (95% CI, 0.01 to 0.03) while receiving IgHy10. Whether the days spent in hospital per month included time spent in hospital due to infusions is unknown. The monthly rate of days spent in hospital due to infection was 0.03 (95% CI, 0.01 to 0.05) while receiving IVIg and zero days/month while receiving treatment with IgHy10. No days spent in hospital is a treatment goal for patients with humoral immunodeficiency; therefore, these results were considered a clinically meaningful result by the clinical experts consulted by CADTH. Overall, these results describing health care utilization and productivity suggest there was minimal disruption to the everyday life of patients because the number of acute physician visits, days in hospital, and days in hospital due to infection occurred at less than 1 day per month per patient. Similar assessments conducted in the extension study yielded comparable results but were reported annually.

In Study 160603, the point estimate for days off school or work during treatment with IgHy10 (epoch 2 after the ramp-up period) and treatment with IVIg (during epoch 1) was less than 1 day per month, or approximately 0.28 days per month (95% CI, 0.20 to 0.37) and 0.23 days per month (95% CI, 0.15 to 0.34), respectively. This suggests that patients experienced minimal disruption during IgRT in the trial based on days of missed work or school.

Harms Results

The overall rate of AEs while receiving IgHy10 was 13.40 per patient during epoch 2 of Study 160603 and 19.75 per patient before the safety follow-up of extension Study 160902. For reference, exposure to IgHy10 in Study 160603 was a mean of 38 days (SD = 10) during the ramp-up period plus 368 days (SD = 104) following the ramp-up period. In Study 160902, patients were exposed to IgHy10 for a mean of 566 days (SD = 212). The rate of AEs was 4.45 per patient during treatment with IVIg in Study 160603, and 7.78 per patient during the safety follow-up with IVIg or SCIg without hyaluronidase during the extension study. The most frequently reported AE while on treatment with IgHy10 was infusion site pain, which occurred at a rate of 1.14 events per patient; the following AEs occurred at a rate of less than 1 event per patient: headache, sinusitis, upper respiratory tract infection, asthma, nausea, fatigue, myalgia, infusion site pruritus, and viral upper respiratory tract infection. During the safety extension study, Study 160902, the overall rate of AEs was 19.75 per patient while receiving IgHy10. The rate of local AEs was 2.62 per patient and the rate of systemic AEs was 17.13 per patient (including infections) or 12.71 per patient (excluding infections).

Additionally, AEs were reported by patients during epoch 2 following the ramp-up period. Overall, 53.1% of patients reported a local AE. The most frequently reported local AEs were infusion site pain, infusion site discomfort, infusion site erythema, and infusion site pruritus. From the available safety evidence, it is unknown whether local AEs were specifically related to hyaluronidase or SCIg. The most frequently reported systemic AEs were headache (30% of patients), asthma (17%) nausea (15%), pyrexia (15%), fatigue (15%); the following AEs were reported in less than 15% of patients: myalgia, vomiting, arthralgia, dizziness, and diarrhea. Additionally, a post hoc integrated analysis of safety outcomes from Study 160603 and Study 160902 reported the overall rate of systemic AEs and local AEs (both excluding infections) by age group (< 18 and ≥ 18 years). Among adult patients (≥ 18 years), 1,200 systemic AEs were reported, corresponding to a rate of 8.63 AEs per patient-year. For local AEs, a total of 429 AEs were reported among adult patients, corresponding to a rate of 3.08 AEs per patient-year.

A total of 2 deaths were reported between the pivotal and extension study, which both occurred during Study 160902. The deaths were caused by toxicity to various agents (n = 1) and cardiac arrest (n = 1); neither were considered related to the study treatments. Serious AEs were infrequently reported; 22 patients reported an SAE in Study 160603 and Study 160902. Two SAEs due to chronic obstructive pulmonary disease were reported, which were the only SAEs reported more than once.

The majority of notable harms identified in the systematic review protocol were captured in the standard reporting of safety results. While receiving IgHy10 in Study 160603, systemic effects included as notable harms occurred at a rate of less than 1 AE per patient as previously described with overall AEs. Infusion site pain was the most frequently occurring infusion-related AE (1.14 AEs per patient) and other infusion-related events occurred at a rate of less than 1 AE per patient. For local reactions, swelling/edema and contact dermatitis were reported at a rate of less than 1 AE per patient, as were infusion site hypersensitivity and thrombotic events. No cases of hypersensitivity, anaphylaxis, thrombocytopenia, acute kidney injury, or aseptic meningitis were reported for patients receiving IgHy10 during epoch 2.

Critical Appraisal

The evidence informing safety and efficacy of IgHy10 is based on 2 single-group, open-label studies. Neither a historical control nor concurrent comparator group were used; consequently, there was no control for potential confounding variables. Additionally, it is not possible to infer causality for reported outcomes assessed in the trials, such as the annual rate of infections, which lacks context or a reference point for evaluation. The single-group study design was also a particular issue in the assessment of safety, in addition to outcomes that were reported as a rate per patient or per infusion. Although this may partly account for varying duration of treatment in each of the reported observation periods, the proportion of patients experiencing a particular AE is unknown, with the exception of commonly reported AEs during treatment with IgHy10 in Study 160603. Most of the outcomes of interest for this review, including the primary end point of the pivotal trial, were not expected to have been impacted by an open-label design; however, patient-reported outcomes such as those related to HRQoL, tolerability and adherence, and safety outcomes, may have been impacted based on patient beliefs about IgHy10. Risk of attrition bias is a concern due to the overall discontinuation rate in Study 160603, in which 21% of patients discontinued from the study primarily due to patient request for withdrawal or AEs. Further, 43% of patients between 2 years and less than 12 years (N = 14) in Study 160603 discontinued from the study either due to a requested withdrawal (29%) or an AE (14%). As a result, the reported study results are likely biased in favour of IgHy10 because the data analyzed are largely based on patients who did not discontinue from the study. Although the selection of outcome measures reported in the studies were considered clinically relevant, the methods of analysis hindered the ability to meaningfully interpret the outcomes. Statistical testing was only used for the primary end point in Study 160603; therefore, multiplicity was not an issue. Within-group changes were generally not reported because results were analyzed as a rate or summarized using descriptive statistics.

The clinical experts consulted by CADTH did not have any concerns regarding the generalizability of the evidence to groups of patients excluded from the trials (such as pregnant females, patients with IgA deficiency, patients required to remain on prophylactic systemic antibacterial antibiotics, or patients with certain pre-existing conditions) or Canadian patient specifically, despite only 1 Canadian study site being included. There were also no concerns regarding the generalizability to patients with secondary humoral immunodeficiency, patients who were IgRT-naive, or patients with lower serum levels of IgG. Concomitant use of prophylactic antibacterial antibiotic use and pre-medications used before administration of IVIg or SCIg were avoided, if possible, during the studies, but their use is common in clinical practice. The clinical experts consulted for this review suggested that an at-home training/support system would be implemented to facilitate administration of IgHy10 at home but the level of supervision in the trials was more intensive that what would be used in clinical practice. IgHy10 also was not studied in patients with secondary humoral immunodeficiency despite a proposed indication and reimbursement request for this patient population. However, the clinical experts consulted by CADTH were comfortable with extrapolating evidence of efficacy from patients with primary humoral immunodeficiency to patients with secondary humoral immunodeficiency.

Indirect Evidence

Indirect evidence matching the inclusion and exclusion criteria of this review was not submitted by the sponsor or identified in the CADTH literature review.

Other Relevant Evidence

Sponsor-Submitted Study in Adult Patients Switching From CSCIg to IgHy10 (NCT02881437)

Description of Study

NCT02881437 was a phase IV, open-label, non-randomized, single-group prospective study, which filled an important gap in the comparison of cSCIg to IgHy10. The primary objective was to examine the difference in IgG trough levels at steady state among adults (18 years or older) with PID requiring IgRT during cSCIg treatment (primarily once weekly) compared with steady-state IgG trough levels after switching to IgHy10 administration every other week at equivalent doses. Among the 22 enrolled patients, the median age was 45.0 years (interquartile range [IQR] = 32.0 to 54.0) and 68.2% were female.

The study began with a 1-week ramp-up period (subcutaneous IgHy10 provided at one-quarter of the usual monthly cSCIg dose) which started 1 week after the last cSCIg infusion before enrolment. Subcutaneous IgHy10 infusions then occurred biweekly at one-half of the initial monthly cSCIg dosage, with follow-up measurements at 3 months and 6 months.

Results

The mean change in steady-state IgG trough level when switching from cSCIg to IgHy10 was −0.30 g/L (SD = 1.54) after 3 months, and −0.29 g/L (SD = 1.35) after 6 months (n = 16). A total of 11 of 19 (57.9%) patients had at least 1 infection in the first 3 months of follow-up, and 8 of 17 (47.1%) between 3 months and 6 months of follow-up. The mean change in the physical component summary of the SF-36 was −0.90 (SD = 4.37) from baseline to 3 months and −2.67 (SD = 5.17) from 3 months to 6 months (n = 12); mean change in the mental component summary was −2.67 (SD = 5.17) from baseline to 3 months and 1.33 (SD = 5.13) from 3 months to 6 months (n = 14).

A total of 21 of 22 (95.5%) patients reported at least 1 local AE and all reported at least 1 systemic AE between baseline and 3 months of follow-up; 12 of 22 (66.7%) reported at least 1 local AE and 16 of 22 (88.9%) reported at least 1 systemic AE between 3 months and 6 months of follow-up. Commonly reported AEs were similar to those in the pivotal studies.

Critical Appraisal

There are several internal validity concerns that limit the certainty of conclusions that can be drawn. The primary concerns are that there was no control group and confounders were unaccounted for, thus causal relationships cannot be established. Although the inclusion and exclusion criteria are clear, some details of the participant disposition are limited (i.e., number of patients screened versus randomized). The open-label design is likely to have biased the subjective end points (direction unclear). There were large losses to follow-up (6 of 22, 37%) which reduces the reliability of the findings for HRQoL. Statistical analyses were not adjusted for multiplicity.

Despite some differences in setting (all of the study sites were in France) and a narrower eligible population than would be seen in clinical practice, the clinical experts consulted by CADTH did not express concern in generalizing the evidence to Canadian adult patients. Applicability of the findings to children is less clear. Exposure to study treatments appeared to match the product monograph, aside from the ramp-up phase (not described in the monograph). Outcomes were clinically relevant, although the clinical experts indicated that they would not rely on IgG trough levels alone for clinical decision-making. The sample size and length of follow-up may have been inadequate to capture rare and/or long-term harms.

Sponsor-Submitted Study on the Safety of IgHy10 in Pregnant Women and Their Infants (Registry Study 161301)

Description of Study

Study 161301 was a registry study providing safety data on women who were ever treated with IgHy10 and their infants — a population excluded from the pivotal studies. All pregnant women who were ever treated with IgHy10 were eligible in 1 of 2 study arms: continued IgHy10 during pregnancy (IgHy10 arm) or switched to another IgRT or alternative treatment (alternative product arm). Nine expectant mothers were enrolled; they had a median age of 34.0 years (IQR = 32.0 to 36.0), were primarily non-Hispanic/Latino (8 of 9, 88.9%), and all were White/Caucasian. A total of 7 infants were enrolled in the study. Patients visited their physicians and were treated according to routine medical practice. Data on IgHy10 treatment was available for 6 (85.7%) mothers in the IgHy10 arm. Among these, the median number of infusions was 4 (IQR = 1.5 to 5.75), received on a 3-week or 4-week interval.

Results

Among the 9 mothers, 4 (44.4%) reported at least 1 AE: 3 (42.9%) in the IgHy10 arm and 1 (50.0%) in the alternative product arm. There were no local or immunologic AEs. One (11.1%) mother in the IgHy10 arm reported an SAE. There were no AEs leading to death or withdrawals due to AEs. Four (44.4%) mothers (2 in each arm) were assessed for anti-rHuPH20 antibodies; all had negative test results (titre less than 160). Eight (88.9%) mothers provided data on pregnancy outcomes; all were live births and 1 birth in the IgHy10 arm was a caesarean delivery.

Infants were born at median 38.0 weeks (IQR = 37.0 to 40.0) of gestation; weight, length, and head circumference were in the normal range for all. Two (40.0%) infants in the IgHy10 arm had congenital malformations. During follow-up, 6 infants (85.7%) experienced at least 1 AE: 5 (100%) in the IgHy10 arm and 1 (50.0%) in the alternative product arm. Two (40.0%) infants in the IgHy10 arm experienced an SAE. There were no AEs leading to death or withdrawals due to AEs.

Critical Appraisal

There are several internal validity concerns that limit the certainty of conclusions that can be drawn. The primary concerns were that there was no control group and confounders were unaccounted for, thus causal relationships cannot be established. There was no statistical hypothesis testing. Selection bias is possible because very few (n = 9) mothers were enrolled, and it is not clear whether women from various centres would differ systematically. Because this was an open-label study, subjective end points may be biased; however, the direction of the bias is unclear. Most data were collected retrospectively, which may have negatively affected quality and completeness. In the IgHy10 arm, 29% of mothers were lost to follow-up, which may have biased AE data in favour of IgHy10.

Despite some differences in setting (all the study sites were in Europe or the US) and a narrower eligible population than would be seen in clinical practice, the clinical experts consulted by CADTH did not express concern in generalizing the evidence to patients living in Canada. The dosage and administration of IgHy10 appear to align with Health Canada–approved dosing; however, pregnant women are not an indicated population in the product monograph. The harm outcomes seem to be clinically important, but no efficacy outcomes were collected. The sample size and length of follow-up were likely inadequate to capture rare and/or long-term AEs.

Post-Authorization Safety Studies and Patient Registry Study

Results from 2 post-authorization safety studies, Global PASS (NCT02593188) and EU PASS (EUPAS5812), and a patient registry study, FIGARO (NCT03054181), were submitted by the sponsor as supportive evidence. Both Global PASS (N = 264) and EU PASS (N = 106) were non-interventional, prospective, uncontrolled, open-label, multi-centre, post-authorization safety studies that evaluated the long-term safety of IgHy10 under clinical routine conditions in US and Europe, respectively. The Global PASS study was conducted between 2015 and 2021 and enrolled patients with PID. The EU PASS Study was conducted between 2014 and 2021 and enrolled patients that were prescribed treatment for PID or SID. The Global PASS reported that 56% of 909 infusions were self-administered at home. The EU PASS reported the proportion of treatments that were administered at a clinical site and at home, by year since the first fSCIg treatment. During first year, second year, third year, and after the third year, 91.2% (n = 83 patients, 909 infusions), 93.2% (n = 556 patients, 600 infusions), 93.2% (n = 28 patients, 237 infusions), and 85.2% (n = 12 patients, 54 infusions) of treatments were administered at home, respectively. FIGARO was a long-term observational study on the utilization and outcomes of IgHy10 under everyday clinical practice conditions. FIGARO was conducted in Europe between 2016 and 2021 and enrolled 156 patients with PID or SID. Data were available for 154 patients, of which 13 were pediatric (younger than 18 years), 120 were adults (18 years to 64 years), and 21 were older adults (at least 65 years); results were analyzed by patient age. FIGARO reported that 81.7% of adults and 57.1% of older adults infused at home.

The results provided by the sponsor for infusions administered at home in Global PASS, EU PASS, and FIGARO suggest that the ability to administer treatment at home was more successful in a real-world setting than the clinical trial setting. However, the generalizability of this evidence to patients treated in Canadian clinical practice is unknown. Additionally, the interpretation of the additional evidence should take into consideration the limitations associated with real-world evidence studies.

Post Hoc Analysis

A post hoc analysis by Wasserman et al. (2021) of 3 studies, including a subset of patients with primary immunodeficiency who participated in 3 consecutive, open-label, uncontrolled clinical studies of IgG therapy, was submitted by the sponsor as supportive evidence. Two of the 3 studies were Study 160603 and Study 160902, which informed the systematic review of HyQvia performed by CADTH. The retrospective post hoc analysis included 30 patients who received at least 1 infusion of each type of therapy (i.e., IVIg, cSCIg, and fSCIg), and was designed to evaluate the efficacy (rates of infection) and tolerability of the 3 routes of IgG administration. The duration of exposure, total number of infusions, and mean IgG dose received during a 4-week period differed between the 3 treatments. As noted in the publication by Wasserman et al. (2021), limitations of the study include a small sample size, selection bias because study participation was voluntary, and year-to-year variations in community infections and other factors that change over time that cannot be accounted for in a sequential study design. The post hoc analysis concluded that across the 3 treatment modalities (IVIg, cSCIg, and fSCIg), annualized rates of VASBIs (0, 0.09, and 0.04, respectively) and all infections (4.17, 3.68, and 2.42, respectively) were similarly low.

Economic Evidence

Table 3: Cost and Cost-Effectiveness

CBS = Canadian Blood Services; CMA = cost-minimization analysis; IgHy10 = normal immunoglobulin (human) 10% and recombinant human hyaluronidase; IVIg = IV immunoglobulin; NOC = Notice of Compliance; PID = primary immunodeficiency disorder; SCIg = subcutaneous immunoglobulin; SID = secondary immunodeficiency disorder; vs. = versus.

Budget Impact

CADTH identified the following key limitations with the sponsor’s analysis: the sponsor’s submitted base case is based on an outdated pre-NOC–indicated population; pricing of IVIg and SCIg comparators used in the BIA are highly uncertain and likely overestimated; there is substantial uncertainty related to the market share in the reference and new drug scenarios; the use of a lower dose for each IVIg and SCIg product for both PID and SID patients did not align with the doses typically used in Canadian clinical practice for both populations; several parameters used to derive the size of the population eligible for treatment with IgHy10 are uncertain, including the prevalence of PID, the proportion of patients treated with IGs, and the annual incidence of PID; and the discontinuation rate was likely overestimated.

CADTH conducted reanalyses that included excluding pediatric patients with PID and SID, changing the individual prices of all IVIg and SCIg comparators to better reflect prices in the Canadian market, revising the market share estimates in the new drug scenario; assuming patients with PID and SID would receive an equal dose and revising the dose for each IVIg and SCIg product for PID and SID patients, and changing the discontinuation rate.

Although the sponsor suggested IgHy10 would be associated with a budget impact of $786,819 over the 3-year time horizon, based on CADTH reanalyses, the budget impact of introducing IgHy10 would result in an estimated budget impact of $43,636,227 in year 1, $62,188,520 in year 2, and $80,037,821 in year 3, for a total budget impact of $185,862,568 over the 3-year time horizon.

CPEC Information

Members of the Committee

Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, Dr. Irene Sadek, Dr. Andrew Shih, and Dr. Peter Zed

Initial meeting date: November 25, 2021

Regrets: Two expert committee members did not attend.

Conflicts of interest: None

Reconsideration meeting date: April 28, 2022

Regrets: None

Conflicts of interest: None