Clinical Researcher—August 2024 (Volume 38, Issue 4)
GOOD MANAGEMENT PRACTICE
Christian K Schneider, MD
Research within the rare diseases space brings its own set of challenges associated with clinical care, regulatory compliance, and commercial activities within the clinical trials environment. Managing each of these realms requires a deep knowledge of the disease state, the development space, and what data and evidence the regulatory authorities and payers will demand.
During a recent panel discussion, experts in innovative trial design, regulatory strategy, market access and reimbursement, and commercialization explored the clinical, regulatory, and commercial pathways to success. The panelists delved into the interdependencies of these areas to unravel some of the challenges and considerations when undertaking a development program for a rare disease treatment.
Panelists included the author of this column, Christian K Schneider, MD, Chief Medical Officer, Strategic Product Development Consulting; Dennis Earle, Senior Director–Development Consulting and Scientific Affairs; Dr. Brad Carlin, Senior Advisor, Data Science and Statistics; and Erika Wissinger, PhD, Senior Director within Market Access and Healthcare Consulting, all of Cencora.
Alternative Evidence Pathways
Increasingly, regulators understand that in rare diseases, randomized controlled trials with a diversity of patients are not feasible.
“A lot of regulators are looking not just at the primary endpoint in isolation, but also other evidence—pharmacodynamics, plausibility of effects, maybe even some exploratory endpoints, and so on,” Schneider said. “There is also growing flexibility to employ novel statistical approaches.”
An area of growing importance with rare diseases is non-interventional or observational studies—both natural history and patient registry studies. One question that arises with these is how to adjust for bias in the data.
As Carlin noted, there are ways to adjust for the possibility of bias in an observational database. “There are statistical tools, such as propensity score matching, that attempt to correct for bias and not having a randomized design,” he said. “There’s reason to believe that carefully applied versions of those methods will be enough to satisfy regulators and other interested parties in rare disease settings.”
There are already clear examples of regulatory flexibility when it comes to natural history and patient registry data.
“Sometimes patients have been enrolled in a patient registry for a long time and a new treatment becomes available,” Carlin said. “If we then give this treatment to a subset of the patients, each can act as their own control just by looking at what happens before and after the intervention. Statisticians call that a crossover study. Normally, we would randomize the order in which the subject receives treatments: some would get treatment and then get placebo, while others would get placebo and then get treatment. In the rare disease space, we don’t have that luxury. Everybody’s starting on ‘placebo’ (their own natural history) and then switching to treatment. That’s an example where regulators have been flexible and have allowed us to get the approvals and information we need on an orphan drug without a randomized design.”
An important consideration with non-interventional studies is whether the data are sufficient to support the statistical objectives.
“In my experience, there’s a wide degree of variability there,” Earle said. “Some disease registries have data approximating clinical trial data in terms of rigor, and others are a lot looser.”
Data rigor is key not only from a regulatory perspective, but also when it comes to reimbursement.
“Any data that can supplement the full value story for the asset in addition to clinical trial data, and that support the messaging around clinical benefit for the patient will be helpful in making a convincing story for the payer,” Wissinger said.
Europe as a Target Market
There has been a lot more discussion of late about whether Europe is still an attractive market for rare disease products, and there are signs of decreased competitiveness in the orphan drug space.{1}
Schneider, however, noted that Europe is a highly developed market, with a lot of experience in handling products such as advanced therapy medicinal products (ATMPs), and with programs for how to work with the agencies. “A key intention of the European Commission is to facilitate innovation and provide incentives by not over-regulating the industry,” he said.
Wissinger added that while Asia is an attractive market from a commercial perspective, Europe also is a large market and one that nearly all manufacturers are still interested in entering. She also noted that, from a health technology assessment perspective, while it is challenging, a lot is changing in Europe with the Joint Clinical Assessment (JCA) coming into effect in January 2025. Under the JCA, European Union members will work collaboratively to evaluate the clinical evidence of new treatments. The JCA will be mandatory for new oncology drugs and ATMPs as of 2025.{2}
“The hope is that it will make the process smoother for the individual pricing negotiations because the clinical efficacy and potentially comparative efficacy [of the new treatment] against standard of care has already been addressed in the JCA,” Wissinger said. “There is cautious optimism at the moment.”
Defining Substantial Improvement for Expedited Approval
Determining acceptable benchmarks for rare disease therapies may not always be about extending survival, but instead might be improving quality of life (QoL). In such a scenario, therapy innovators would need to include an endpoint of patient relevant outcome.{3}
“We all know of examples where an orphan drug does not necessarily produce a better survival outcome for the patient, but does have an advantage,” Schneider said. “An extreme example would be if the current treatment is given intravenously at hospital in the intensive care unit every day, whereas the new treatment is one pill every other month; that’s an obvious improvement in QoL. That’s why it’s important to talk to the regulators so this claim can be considered meaningful for the development program, as it’s something you will need to know early on when you plan the clinical study.”
The payer strategy also should be considered early on because the QoL factor is very important for payer reimbursement in a number of markets, Wissinger said. “It’s the holistic view of the overall benefit to the patient, to the caregiver, and, in some cases, the overall societal benefit—for example, ability to return to the workforce” she explained. “It’s really that specific value message around the benefit for the individual asset.”
Earle highlighted a 2014 recommendation from the American Society of Clinical Oncology that an improvement of overall survival of 20% would be considered generally clinically meaningful. “On occasion, there may be more specific guidance that you can use to guide your clinical development,” he said.
From his experience with clinical studies where there is both a clinical and QoL endpoint, the debate can be whether it’s necessary to show improvement on both of these endpoints, Carlin said. “Sometimes going with the QoL endpoint is worrisome because the QoL concern wasn’t there 10 years ago, so we haven’t really thought hard about this. Moreover, while QoL may be very important to patients, drug developers may worry that doctors won’t prescribe their new therapy if its only significant benefit over the current standard of care is improved QoL. So, while this endpoint is increasingly important, it is on a case-by-case basis.”
Attitudes to Innovative Trial Design
There is often an assumption that regulatory authorities and payers are slow to adapt to alternative methodologies, but in many cases they are open to innovative trial design. For example, the U.S. Food and Drug Administration (FDA) established the Complex Innovative Trial Design (CID) Meeting Program, which offers sponsors using complex adaptive, Bayesian, and other novel designs more meetings with the agency.{4}
“Those meetings are a chance to negotiate the nature of the design, review the existing historical data, and really dig in a little bit more than you would normally within the regulating environment,” Carlin said. “The exchange for this is that FDA is allowed to publish the results on their website, instead of maintaining the developer’s confidentiality until approval. The CID program is just one example of FDA’s recent encouragement to use Bayesian method, causal inference tools, and other novel methods to try to bridge some of the gaps that arise when you can’t do traditional randomized trials.”
The European Medicines Agency (EMA) has published a reflection paper on the use of single armed trials in the rare and other disease spaces,{5} which, again, is where Bayesian methodologies might be leveraged to address gaps in data, Carlin added.
Some of the larger health technology assessments also have clarified their positions on issues such as surrogate endpoints and single-arm studies.
“Germany’s IQWiG (Institute for Quality and Efficiency in Health Care) has specific guidance around what needs to be proven to demonstrate the quality of the relationship between a surrogate endpoint and a hard clinical endpoint,” Wissinger said. “That’s why it’s important that early on, when you’re considering the regulatory strategy, you make sure the evidence also will resonate with payers.”
The benefit of a Bayesian approach is that it encourages a thought process of questioning and making sure everything has been considered before progressing, Carlin added.
Regulatory science is now well established within the health authorities and is considered integral to keeping pace with scientific and technological advances. For example, the EMA’s “Regulatory Science to 2025” strategy seeks to build a more adaptive regulatory system to respond to innovative and more complex therapies.{6} The FDA’s CID program is similarly focused on innovation, and the United Kingdom’s Medicines and Healthcare products Regulatory Agency has its own Innovation Accelerator, which supports developers of innovative products across the regulatory journey.{7}
“What is often clear when dealing with the intersection of clinical medicine and regulatory science is the need to establish that surrogate endpoints are definitively associated with improved clinical outcomes,” Earle said. “And those instruments need to be validated. That is a big clinical regulatory development challenge—and one that remains constant despite the fact that there’s huge unmet medical need in a lot of these rare diseases.”
Getting Innovative Medicines to Patients
From an access perspective, Wissinger pointed to the importance of patient engagement to truly understand what the patient pathway looks like.
“What is the symptom burden and actual impact of burden of the disease?” she asked. “That leads to quantifying the unmet need, which is important for payers, particularly with a new treatment for which there is no real standard of care other than maybe symptomatic treatment. Patient advocacy can also contribute to the generation of real-world evidence, which can be factored into the total package of evidence that’s put in front of payers. There may even be some healthcare provider education necessary; for example, if a treatment will fundamentally change the care pathway for those patients, you want to get some advocacy from the healthcare provider.”
Wissinger added, “Once you’ve passed that health technology assessment hurdle, you also need to think about patient support and patient access schemes. There are logistical aspects to the commercialization, such as managing cold chain supply for patients outside of the main centers. There are a lot of steps that need to be considered as early as possible to make sure that you get the product to the patient.”
Optimizing the Trial with the Patient at the Center
While there is often talk about patient centricity when referring to rare diseases, more needs to be done to bring the trial to the patient, for example, through telemedicine, as much as possible.
“There are a number of clinical evaluations, including limited history, adverse event assessments, and drug administration, that can be done by remote nursing staff to reduce the burden on the patient,” Earle said. “So, keeping it generally focused on patient centricity, supplementing that with specific clinical operations initiatives, and integrating that with some Bayesian methodologies really gives you an optimal chance of having a timely, well-executed, rare disease development program.”
Disclaimer
The information provided in this article does not constitute legal advice. Cencora, Inc., strongly encourage readers to review available information related to the topics discussed herein and to rely on their own experience and expertise in making decisions related thereto.
References
- Despite Previous Gains, Europe is Falling Behind U.S. in Gene Therapy Research. 2024. Rare Disease Advisor. https://www.rarediseaseadvisor.com/features/despite-previous-gains-europe-falling-behind-us-gene-therapy-research/
- Anticipating Issues, Tackling Challenges: Next Steps with the JCA. 2024. https://www.amerisourcebergen.com/insights/manufacturers/next-steps-with-the-jca
- Composite Endpoints, Including Patient-Reported Outcomes, in Rare Diseases. 2023. Orphanet J Rare Dis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474650/
- U.S. Food and Drug Administration. Complex Innovative Trial Design Meeting Program. https://fda.gov/drugs/development-resources/complex-innovative-trial-design-meeting-program
- European Medicines Agency. 2023. Single-Arm Trials as Pivotal Evidence for the Authorisation of Medicines in the EU. https://www.ema.europa.eu/en/news/single-arm-trials-pivotal-evidence-authorisation-medicines-eu
- European Medicines Agency. Regulatory Science Strategy. https://www.ema.europa.eu/en/about-us/how-we-work/regulatory-science-strategy
- Medicines and Healthcare products Regulatory Agency. Innovation Accelerator. https://www.gov.uk/government/publications/innovation-accelerator
Christian K Schneider, MD, is Chief Medical Officer, Strategic Product Development Consulting, and Vice President and Head of Biopharma Excellence at PharmaLex, a Cencora company. In addition, all the panelists contributed to this article.
