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4 Barriers to cell and gene therapy development for rare diseases – and how to overcome them

Cell and Gene

27 September 2018


This article first appeared in Cell and Gene.

Rare diseases, as defined by the Orphan Drug Act, are diseases that affect less than 200,000 people. Given that approximately 80 percent of the 7,000 known rare diseases are caused by a single-gene defect,1 there has been increased research in the development of cell and gene therapies to treat rare diseases.

However, a number of challenges hinder these efforts, including pricing and reimbursement, the high cost of bringing these drugs to market, unique manufacturing and supply chain challenges, and our current limited understanding of disease pathology and progression. While these challenges may seem common across other drug markets, in the case of rare diseases, these challenges are exacerbated by limited patient populations. In this article, we look at the four challenges in greater depth and explore potential responses to help pharma companies be successful in bringing these products to market.

1. Making commercialization viable by tackling high costs together

Given the small patient population, and the high price of drugs aimed at rare diseases, how can we ensure the long-term commercial viability of these drugs? This challenge can be explored from two points of view - how health authorities can promote scientific advancements while also protecting investments in rare disease development and how pharma can collaborate with payers to find better pricing solutions to reduce hurdles for patients to receive treatment.

Over the years, the FDA has taken concrete steps to incentivize the industry to develop drugs for rare diseases. In 2017, the FDA sought to eliminate the backlog for orphan drug requests by responding to future requests within 90 days.2 More recently, the FDA released a Draft Guidance on Human Gene Therapy for Rare Diseases, which pledges that the FDA will be involved with drug companies earlier in the development process. This will not only help streamline development by helping limit the number of preclinical or other preparatory studies but will also lower development costs and increase speed to market.3 But is this enough? There is ongoing debate in the pharma industry that the FDA needs to go even further. For example, while the agency already grants a longer exclusivity period for orphan drugs, this seven-year period is usually outlasted by the 20-year protection offered by patents.4 To sweeten the deal, the FDA may need to consider offering increased protection by expanding this exclusivity period. This would make these drugs more commercially viable, better ensuring capture of initial and ongoing investment in small markets or providing an option for improved pricing scenarios.

On the payer front, as the healthcare industry shifts toward value-based healthcare, orphan drugs and cell and gene therapies that have been prohibitively expensive will be prime candidates for emerging pricing models derived from measuring health outcomes against the cost of treatment. One great example is Novartis’ CAR-T treatment, Kymriah. For this treatment, Novartis only receives payment if the patient shows significant improvement within a month; otherwise, Novartis bears the cost. The use of value-based pricing models for cell and gene therapies would ease the amount of risk that payers take on when reimbursing these treatments, while also increasing the likelihood that patients will have access to these drugs.

With higher rates of approvals, longer periods of exclusivity, and greater utilization of value-based pricing, cell and gene therapies for rare diseases will have a greater chance of both reaching patients and being commercially successful.

2. Improving clinical development: a new age in clinical trial design and recruitment

Companies developing cell and gene therapies for rare diseases are confronted with many of the same challenges faced by more traditional drugs; however, these challenges are amplified. These challenges include small patient populations, high mortality rates, and lack of disease state understanding, making it difficult to set clinical endpoints.

Seeking to address this, the FDA’s Draft Guidance on Human Gene Therapy for Rare Diseases focuses on new clinical trial designs. What will these trials of the future look like? Gone are the days of three-phase randomized, controlled clinical trials. New age trials for rare diseases will be shorter, combining phases to show both safety and efficacy. Later stage trials will be replaced with rollover studies to see longer-term effects of treatment. Control groups will be replaced with natural history studies to illustrate what happens when patient groups go untreated. Natural history studies will also help to identify surrogate endpoints that can serve as early indicators of future outcomes to help expedite trials.

While these trial designs will help improve the process, there is still the inherent issue of recruiting from such small and geographically diverse patient populations. To ease this, there will be increasing demand for accurate patient registries that include relevant information about potential biomarkers for treatment. GSK’s partnership with 23andMe is a good example of how this would work. Genetic data is captured through commercial genetic testing, then used to drive novel drug development and identify patients with specific rare diseases for trial recruitment. Pharma and CROs will also leverage increased use of digital technology to execute remote or highly fragmented multisite trials, making trial participation easier for patients.

Streamlining the clinical trial pathways for gene therapy and rare diseases, as well as reducing the burden on the patient, allows pharma companies to accelerate products to market.

3. Overcoming the challenges of manufacturing and supply chain by partnering with contract manufacturer organizations

There are two major manufacturing challenges. The first is addressing the need for new infrastructure such as advanced supply chains, since the effective handling of these treatments will often require a high degree of customization for the patient (e.g., CAR T cell therapies). The other challenge lies with rare disease and cell and gene therapy products, whose manufacturing requires specialized skills where there is little room for error. As such, organizations will need to decide if they will build the capability or leverage contract organizations.

To address these challenges, in the short term, it is essential that companies have robust chain of custody protocols and supporting technologies to track and monitor these drug products from factory to patient. This ensures the correct patient is getting the therapy that was specifically designed for them, and that the conditions in transit do not damage the drug product. Longer term, the rise of a larger number of small manufacturing sites spread across the country is expected. Smaller manufacturing sites distributed in key geographic regions reduce shipping time, thus reducing the possibility for delays. Taking this one step further, imagine a world where manufacturing sites do not exist, and hospitals or clinics will have the capability and infrastructure to perform specialized manufacturing on-site.

How can pharma get to a commercial scale to support successful complex manufacturing requiring specialized skills? One solution is to outsource manufacturing to contract manufacturing organizations (CMOs) that specialize in gene therapies and rare diseases, similar to the way that clinical research has increasingly relied on contract research organizations (CROs). CMOs manufacture the product as a service and use their expertise to produce high-quality product at a reduced cost.

By using specialists to support the manufacturing process and technology to monitor and localize the supply chain, companies can reduce the risks involved in getting high-quality products to patients.

4. Increasing our understanding of disease states: the rise of natural history studies and companion diagnostics

Currently, there is a lack of understanding of rare diseases, especially around diseases variations and subtypes. This creates the challenge of how to better identify these variations to develop treatments that are then targeted at a specific disease subtype.

Pharma companies will need to spend more time and effort understanding disease states. For rare diseases, natural history studies are critical to provide insight that could help to drive early development, and even serve as a control group in single-arm studies if randomized, concurrent controlled trials are not feasible.5 Natural history studies may also help identify biomarkers that will help tailor these cell and gene therapies to be more personalized to specific subgroups of patients, allowing companies to be more focused in the development process.

Furthermore, to get the best results from treatment, the patient population that would benefit most from treatment needs to be identified. Thus, the industry will likely see an increase in products entering the market that include a companion diagnostic. Both the FDA and payers have an incentive to require drug manufacturers to develop these diagnostics in parallel with drug projects to ensure the best patient outcomes possible. Advancements in next-generation sequencing techniques will make identifying these subgroups easier and more accurate, potentially leading to a “one size fits all” genetic test that could be applied to all rare disease products.

Genetic tests, combined with an increase in understanding of natural history and disease biomarkers, will ensure the correct patients are receiving the therapies being developed.

Cell and gene therapies for the rare disease space are still emerging and will continue to face new challenges around development, the evolving regulation landscape, pricing and reimbursement, and manufacturing. Despite these challenges, the first products have already reached the market. New approaches and solutions, such as some of those outlined in this article, will go a long way to meeting these challenges and reducing the barriers to entry, allowing pharma to bring these products to market more quickly and affordably.

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