Last month, the Health Economics Authority published a report titled “Evaluation of Medical Gene Therapy Technologies: Are Our Methods Achieving the Purpose?“I summarize some of the key challenges and solutions below.
- Task #1: Initial Evaluation of Clinical Effectiveness. Since gene therapy often targets a rare disease, the sample size of clinical trials is often small and many trials may be based on single arm trials. In addition, if a surgeon is required to perform gene therapy, the actual effectiveness may vary depending on the skill level of the surgeon. In addition, less is known about rare diseases in terms of their current treatments and assessments of patients’ quality of life. I discuss many of the challenges associated with HTA in rare disease assessment in a recent white paper “Challenges of maintaining access to orphan medicines in the framework of HTA“
- Issue #2: Uncertainty about long-term outcomes. Gene therapy promises long-term health improvements, not only by eliminating symptoms, but by correcting the underlying physiology through gene modification. However, clinical trials tend to be short-term and often rely on surrogate results rather than key outcomes of interest to patients. In addition, gene therapy promises a “cure”, but what is not clear is how many patients will need retreatment, and whether gene therapy will make the treatment more or less effective in the future. In addition, if standard discount rates are applied, long-term health benefits may be discounted too much.
- Challenge #3: Connect with value. Gene therapy is currently expensive. The production of gene therapy is much more complex and expensive than the production of small molecules. In addition, many gene therapies target rare diseases. Actually, 72% of rare diseases are genetic. With respect to gene therapy for rare diseases, lowering the price of gene therapy could limit life sciences investment in orphan diseases and consign patients with rare diseases to limited treatment. The persistence of high prices for gene therapy means that payers may not get good value for money as determined by standard cost-benefit analyses. Even if treatment has been associated with value, HTA often does not include broader elements of value, such as caregiver burden, or newer elements of value, such as value of hope, disease severity, real choice value, and scientific spillovers, among others. . New approaches beyond the standard CEA, such as risk-adjusted generalized cost-effectiveness (GRACE) or multi-criteria decision analysis (MCDA), may prove useful for gene therapy.
- Task number 4. Estimating costs. If gene therapy is paid for as a lump sum, this is problematic not only because of the pressure on the budget of the payer, but also because the high costs will be sunk if the treatment is ineffective (compared to conventional treatments, when treatment could be stopped, if the treatment was ineffective). inefficient). Also, for private insurance companies, payers may fund gene therapy only so that individual plans to change health insurance and thus the entity paying for the gene therapy may not be rewarded in the form of cost compensation.
Some other issues include the disability paradox.
Evidence for the paradox of disability has been reported in several therapeutic areas targeted by gene therapy. The paradox of disability, also known as disease adjustment, is that patients with chronic lifelong illnesses rate their quality of life as good or excellent despite being perceived by other non-disabled people as a lower quality of life.Albrecht & Devliger, 1999)
HTA decisions have been made for a number of gene therapies. OHE summarizes some of these solutions across Europe.
Access issues are not a trivial problem.
The price received for processing is an important commercial factor for manufacturers. Price caps in some health care systems can lead to inequalities in access, leading some manufacturers to choose not to seek reimbursement in some countries. a. In practice, this happened when Bluebird recalled Betibeglogene autotemcel (Zynteglo®) from European markets (Pagliarulo, 2021).
OHE recommendations include:
- Take a look at the perspective. The OHE recommends measuring health outcomes throughout life to fully appreciate the long-term value of gene therapy. Sensitivity analysis will be vital as long-term extrapolation of potential benefits is likely to have a significant impact on the assessment of treatment efficacy.
- Think big. OHE recommends considering additional valuable elements in HTA decision making. While there is general agreement that disease severity should influence treatment evaluation, there is no consensus on what other value elements should be included and, if so, how they should be weighted, despite scholars’ calls for their inclusion.
- Develop transparent standards to enable RWE and surrogate endpoints in HTAs.. While RCTs are certainly preferred, OHE wised recommends that “HTA bodies should demonstrate flexibility in accepting alternative forms of evidence where appropriate”. In addition, given the potential long-term impact of treatment, the use of surrogate endpoints may be quite reasonable for many diseases.
- Consider agreement based on results. Due to the high upfront costs of gene therapy and uncertainty about long-term outcomes in drug launches, outcome-based mechanisms or other value-based mechanisms may be useful in addressing uncertainty in long-term outcomes while ensuring patient access. One simple approach would be to amortize payments. The value of information analysis can be used to inform these agreements (see below). Drummond et al 2019). Outcome-based pricing is increasingly being used to facilitate access to gene therapy, especially in Germany, Spain and Italy, but HTA methodologies vary widely across countries (Jorgensen, Hanna and Kefalas, 2020).
- The international cooperation. OHE recommends expanding data collection through registries and international collaboration. Collecting more data and international cooperation is always good in theory, but there are costs involved and the logistics of implementing cross-border cooperation can be complex. However, this is a wise recommendation, and there are some successes. The French National Plans for Rare Diseases (PNMR) have created a national database on rare diseases (BNDMR).
- Ensure early multi-stakeholder dialogue to agree on feasible and appropriate packages of evidence. Establishing an early dialogue between manufacturers and HTAs is of particular interest, as regulatory clearance needs and HTAs may differ; EUnetHTA can facilitate this collaboration. For example, “one of the main barriers to patient access has been the reluctance of most HTAs to accept evidence from single arm trials, despite the fact that traditional RCTs were considered unethical by some in these circumstances.” In addition, it is important to be patient-centered, and it is also important to get the patient’s and caregiver’s perspective on the evidence that should be included in HTA evidence packages. For rare diseases, it is difficult to develop patient-reported outcome (PRO) instruments, so additional weight may be given to patient surveys or patient input during evaluation committee meetings.