The HTA Challenge to Gene Therapy – Healthcare Economist

Last month, the Office of Health Economics published a report entitled “Health Technology Assessment of Gene Therapy: Is Our Approach Fit for Purpose?” I summarize some of the key challenges and solutions below.

• Challenge #1: Initial assessment of clinical effectiveness. Because gene therapies often target rare diseases, clinical trials typically have small sample sizes, and many trials may rely on single-arm trials. Also, if gene therapy requires a surgeon to administer, the actual effect may vary depending on the skill level of the surgeon. Furthermore, very little is known about rare diseases in terms of their current treatment pathways and estimates of patients’ quality of life. I discussed the many challenges of HTA assessment of rare diseases in a recent white paper”Challenges of maintaining access to orphan drugs under the HTA framework“
• Challenge #2: Uncertainty about long-term outcomesGene therapy not only addresses symptoms, but also repairs the underlying physiology through genetic modification, thereby guaranteeing long-term health benefits. However, clinical trials are usually short-term and often rely on surrogate outcomes rather than key outcomes of patient concern. Also, gene therapy promises to be “cured,” but it’s not clear what percentage of patients need to be treated again, but whether gene therapy will make future treatments more or less effective. Furthermore, long-term health benefits may be discounted too much if standard discount rates are applied.
• Challenge #3: Value Linking. Gene therapy is currently expensive. Making gene therapies is much more complex and more expensive than making small molecules. Additionally, many gene therapies target rare diseases. In fact, 72% of rare diseases have genetic origin. For gene therapy for rare diseases, lowering the price of gene therapy may result in limited investment in rare diseases by life sciences companies and limited access to rare disease patients. Keeping gene therapy prices high means payers may not get value for money as defined by standard cost-benefit analyses. Even if treatment is associated with value, HTAs typically do not contain broader value elements such as caregiver burden or more novel value elements such as hope value, disease severity, real option value, and science spillovers. New approaches beyond standard CEA—such as generalized risk-adjusted cost-effectiveness (GRACE) or multi-criteria decision analysis (MCDA)—may prove useful for gene therapy.
• Challenge #4.cost assessment. If a one-time payment for gene therapy is made, not only will this put a strain on the payer’s budget, but the high cost will not be recovered if the treatment is ineffective (compared to traditional treatments, which may be discontinued if they are ineffective) . Also, for private insurers, payers may fund gene therapy just to get individuals to switch health plans, so the entity paying for gene therapy may not get a return in terms of cost reimbursement.

Some other challenges include the disability paradox.

Evidence for the disability paradox has been reported in several therapeutic areas targeted by gene therapy. Also known as disease state adaptation, the disability paradox is when people with chronic lifelong diseases rate their quality of life as good or excellent, even though others perceive their quality of life to be lower.Albrecht and Devlig, 1999)

HTA decisions have been made for many gene therapies. OHE summarizes some of these decisions across Europe.

Access considerations are not a small problem.

The price at which treatment is obtained is an important commercial consideration for manufacturers. Pricing restrictions in some health systems may lead to unfair access, leading some manufacturers to choose not to seek reimbursement in some countries. One. This happened when Bluebird pulled Betibeglogene autotemcel (Zynteglo®) from the European market (Pagliarullo, 2021).

OHE recommendations include:

1. Think long term. OHE recommends measuring health outcomes from a lifetime perspective to capture the full long-term value of gene therapy. Sensitivity analyses will be critical, as long-term extrapolation of potential benefits can have a significant impact on estimates of treatment value.
2. think broadly. OHE recommends that additional elements of value be considered in the HTA decision-making process. While it is generally agreed that disease severity should influence treatment valuations, there is not much consensus on what other elements of value should be included and how they should be weighted, despite academic calls for their inclusion.
3. Develop transparent criteria to incorporate RWE and surrogate endpoints into HTA. While randomised controlled trials are of course preferred, OHE wise advice is that “HTA institutions need to demonstrate flexibility in accepting surrogate forms of evidence where appropriate.” Furthermore, given the potential long-term effects of treatment, for many diseases, the use of surrogate endpoints may be perfectly reasonable.
4. Consider outcome-based arrangementsBecause of the high upfront cost of gene therapy and the uncertainty of long-term outcomes when the drug is brought to market, outcome-based arrangements or other value-based arrangements may help resolve uncertainty about long-term outcomes while enabling patients to access treatment. An easy way to do this is to amortize payments.The value of information analysis can be used to inform the arrangement of these agreements (see 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 approaches vary widely across countries.Jorgensen, Hannah and Kephalas, 2020).
5. global cooperation. OHE recommends expanding data collection through registration and international cooperation. In theory, more data collection and international cooperation are always good, but the costs associated with this and the logistics of implementing cross-border cooperation can be challenging. However, it’s a wise suggestion and has had some success. The French National Rare Diseases Program (PNMR) has created a national database of rare diseases (BNDMR).
6. Enable early multi-stakeholder dialogue to align on actionable and appropriate evidence packagesOf particular interest is establishing an early dialogue between manufacturers and HTA agencies, as regulatory and HTA approval requirements may vary; EUnetHTA can help facilitate this collaboration. For example, “While traditional RCTs are considered unethical by some in this context, the reluctance of most HTA institutions to accept evidence from single-arm trials is one of the major barriers to patient access.” Being central is important, as is giving patients and caregivers a perspective on the evidence to be included in the HTA evidence package. Disease-specific patient-reported outcome (PRO) tools are difficult to develop for rare diseases, so additional emphasis may be placed on patient surveys or patient input during assessment committee meetings.