Addressing Assessment and Access Issues for Rare Diseases

By Christiane Truelove

In August 2022, the US Food and Drug Administration (FDA) approved Bluebird Bio’s Zynteglo (betibeglogene autotemcel), a gene therapy for the rare blood disease beta thalassemia. The drug has a list price of $2.8 million per treatment, but it’s not the first therapy with a multimillion-dollar price tag, and it will not be the last. With the promise of more rare disease treatments on the horizon (particularly genetic treatments for hemophilia and sickle cell disease, which [like Zynteglo] promise to be “one and done” therapies), their much higher per patient cost will create market access and other challenges to payers, providers, and patients.

According to a report by the ISPOR Rare Disease Special Interest Group, the successful development of new treatments for rare diseases and their sustainable patient access requires overcoming a series of challenges related to research and health technology assessment (HTA). Research-related impediments include disease recognition and diagnosis, evaluation of treatment effect, and patient recruitment for clinical research. The primary challenges for HTA for rare disease therapies include a lack of tailored HTA methods, no established standard of care, insufficient knowledge of the natural history of a disease, lack of validated instruments to assess efficacy and effectiveness endpoints, and the application of Institute for Clinical and Economic Review (ICER) thresholds.

In the past, market access issues for rare disease therapies have been mitigated by the size of the population able to be treated, says Darius N. Lakdawalla, PhD, School of Pharmacy at the Leonard D. Schaeffer Center for Health Policy and Economics at the University of Southern California and cofounder and chief scientific officer of Precision Health Economics, a healthcare consulting firm.

With the promise of more rare disease treatments on the horizon, their much higher per patient cost will create market access and other challenges to payers, providers, and patients.

“In that sense, rare disease therapies sometimes faced an easier path than they might otherwise face, but I think that we’re reaching an inflection point where that may no longer be the case—or at least will be the case less often. And in particular, I think the advent of gene therapy, or rare disease and other curative types of therapies for rare disease, is forcing that transition.”

Methodology of HEOR and HTA Assessment
Traditionally, health economics and outcomes research (HEOR) and HTA methods have been “empirically very bad” at capturing the value of treatments for severe illness and rare diseases because, typically, rare diseases feature high unmet need as the populations are smaller and there is less innovation, Lakdawalla says.

“And it’s evident that HTA bodies routinely ignore or make ad hoc exceptions to traditional cost-effectiveness analyses when reimbursing rare disease therapy,” he says. “That’s a signal to all of us that it just didn’t capture the value to payers—let alone patients or beneficiaries—of covering rare disease treatment.”

Traditional health economics methods do not account for the “severity premium” in treating illness, according to Lakdawalla, in that people who are sicker place more value on gains in health than people who are healthier. “It’s a very common and intuitive concept from economics, it’s sometimes called diminishing returns. It’s similar to the notion that someone who lives in a tiny studio apartment values a 500-square-foot addition more than someone who lives in a large mansion in the suburbs. But by the same token, someone who’s very ill places greater value on a given health gain than someone who’s very healthy.”

Translating that to a rare disease, this concept means that the value of health improvement is particularly high for patients with severe illness, and that severity needs to be accounted for. “We now know how to do that in a systematic and mathematically rigorous way, as opposed to just throwing up our hands and trying to guess at what the value should be,” Lakdawalla says. “And now I think it’s up to a large number of stakeholders to conduct the studies the right way, and to make decisions that reflect the additional value of treating highly severe disease, and that will necessarily increase the value that’s ascribed to rare disease treatments.”

According to Jennifer Hinkel, MSc, managing director of the Data Economics Company, the HEOR and HTA methodologies learned in school and metrics such as quality-adjusted life year (QALY) and disability-adjusted life year (DALY) “break down” when they are applied to rare disease populations. While this is a known problem and there is work on alternative approaches to these metrics, there has not been widespread academic acceptance of any of them. “I think this is a very open area for research,” Hinkel says. “People are probably looking to ISPOR to tell us what to do because we don’t know.”

“HTA bodies routinely ignore or make ad hoc exceptions to traditional cost-effectiveness analyses when reimbursing rare disease therapy. That’s a signal to all of us that it just didn’t capture the value to payers-—let alone patients or beneficiaries—-of covering rare disease treatment.”  — Darius N. Lakdawalla, PhD

The fear in the pharma industry is that the experts coming out of the Institute for Clinical and Economic Review (ICER) with backgrounds at QALY-oriented groups such as The National Institute for Health and Care Excellence will be trying to apply QALY, “which is really a very blunt instrument,” Hinkel adds.

Lakdawalla and his colleague, Charles Phelps, have developed an HTA methodology, GRACE (Generalized Risk-Adjusted Cost-Effectiveness), that he says takes methods that have been around for decades, and it fixes an error in those methods. “Rather than starting from scratch, we started with the methods that are commonly used and addressed an error. The error is, typically, economists have assumed that the value of health improvement is the same regardless of context. So, someone who’s a quadriplegic derives the same value from a modest gain and in function than someone who just has knee pain after running. Most human beings find that to be a completely untenable assumption. And the empirical evidence rejects that too. So, we’ve just addressed that issue.”

The GRACE methodology is not only useful for comparative-effectiveness assessment in rare disease but in cancer, end-of-life care, and disability as well. As Lakdawalla and Phelps write, “Our Generalized Risk-Adjusted Cost-Effectiveness (GRACE) approach helps align HTA practice with realistic preferences for health and risk.”

“The HEOR and HTA methodologies learned in school and metrics such as QALY and DALY ‘break down’ when they are applied to rare disease populations. People are probably looking to ISPOR to tell us what to do because we don’t know.”  — Jennifer Hinkel, MSc

Hinkel believes that patient registries also have a role to play in figuring out rare disease therapy values. “It’s these kind of registry models, where patients are proactively opting in to say, ‘Yeah, I’m willing to have my clinical outcome followed over my lifetime because that’s going to facilitate paying for my therapy. If I change insurers or I change hospitals, I’m willing to be followed and will give you my information and follow-up data in return for getting this paid for,” she says. “I think that will be combined with some financial and reinsurance instruments on the back end that the insurers will have to do.”

Role of Patients in Value Assessment
Annie Kennedy, now chief of Policy, Advocacy, and Patient Engagement at EveryLife Foundation for Rare Diseases, has in the past worked with ICER on assessments for Duchenne muscular dystrophy products, as well as helping the organization refine its algorithm for ultrarare frameworks. “We were really concerned that their framework for just the broad assessment of products was not tailored to some of the nuances in clinical trial development for rare disease,” Kennedy says.

She observes that HTA organizations “have come a very long way” in the past 5 to 10 years in acknowledging the expertise offered. Working with “very well-informed patient advocacy organizations that were doing really sophisticated work and patients who had really relevant experience to bring to bear now have much more formalized engagement and processes to bring patients and patient communities into the assessment process.”

“I still think we have a long way to go,” Kennedy says. “But we have made progress.”

One of challenges remaining is that there is no formalized mechanism for including patient experience data within regulatory review at the FDA. This means that when companies are preparing dossiers for payers, that information doesn’t get included.

“What I’ve seen all too often is that we will get into an HTA assessment or we will get to a point where we already have a product that’s approved, and now we’re getting to commercialization. We’re seeing policies be issued that are not reflective of engagement with either the clinical experts that are experts in that specific rare disease or patients who have lived experience with rare disease,” Kennedy says. “And then we’re really forced to be playing what I call ‘whack-a-mole,’ where we’re doing one-off conversations with each of the Medicaid plans and each of the commercial plans to bring forward all that data that we have to bear to inform that decision making.”

According to Kennedy, if patient advocacy groups and pharma knew, in a predictable way, what kind of data should have been included, then that data could be developed and included within the clinical trials so that it’s available for consideration. “And that we’re not in hindsight saying, ‘Gosh, that’s compelling to hear that from a patient or a caregiver that burden has been reduced or productivity has been increased. But wow, we wish we had more data published on that.’ If we knew that would be included, that could be collected in a way that would be considered within that assessment or within that algorithm.”

“What I’ve seen all too often is that we will get into an HTA assessment and we’re seeing policies be issued that are not reflective of engagement with the clinical experts or patients who have lived experience with rare disease.”  — Annie Kennedy

In the United States, some of this last-minute scramble for data can be attributed to payers, biopharmaceutical sponsors, and regulators not engaging earlier with patients. “One of the things we do hear from payers is that they find out really too late that a product is coming or is being approved and that there are patient experience data specifically that are provided to regulators by sponsors that is helping inform their decisions,” Kennedy says. “We would very much like to see that data be made available earlier to payers so that their decisions can be informed also, in the same way that a regulator’s decision is being informed.”

During the 117th Congress, which ended on January 3 this year, EveryLife helped legislators put together the STAT (Speeding Therapy Access Today) Act, a bipartisan, bicameral, community-led bill aimed at improving the development of and access to therapies for the rare disease community. The goal of the legislation is to put together a Rare Disease Center of Excellence at the FDA that would serve as FDA’s coordinating office with rare disease stakeholders, implement cross-center rare disease and condition-focused meetings and policy development, and coordinate regulatory science initiatives for rare diseases. The proposal also seeks to enhance coverage of drugs, biologic, and gene/cell-based therapies to treat rare diseases and disorders so payer coverage policies reflect all of the information used by the FDA to determine a drug’s indicated usage and population.

While rare disease advocates have found allies at the pharma companies developing specific rare disease therapies, it is important that “we can also have direct communication with payers, with clinicians, and with each of the stakeholder groups so that we can make sure that it’s the patients who are also representing their individual experience so that those policies are reflective of patient experience, not necessarily just the priorities of the pharmaceutical company,” Kennedy says.

One example of data left out of access decisions is the impact of a rare disease therapy on caregiver and patient productivity, such as being able to work full time when they could not before or even sleep through the night, or allowing patients to be more independent in their own care, thereby reducing the number of caregiver hours needed. “We conducted a national economic burden of disease study that showed the economic impact of living with a rare disease, which in 2019, was close to a trillion dollars. Nearly 60% of those costs were not direct costs and mark what we consider to be the nonmedical costs,” Kennedy says. “These costs [such as out of pocket and societal] are not the ones that are typically brought into consideration when we think about the traditional health economic models.”

If HTA assessments can go beyond signs, symptoms, functional measures, and biomarkers to include concepts such as pain function, family stress, financial toxicity, and then correlate them to already existing patient-center impacts, “we are going to have decisions that are better reflective of patient values, as well as clinical trial experiences,” she says.

Christiane Truelove is a healthcare and medical freelance writer.