The diverse mix of participants in this RARE Revolution roundtable, with representatives from industry, advocacy, consultancy, intellectual property, finance and the media, was no accident. The landscape for the development of rare disease therapies is fraught with challenges, and solving these depends upon close collaboration between all stakeholders. We sincerely hope that the ideas shared here will prompt many more conversations and help to move us towards much-needed solutions.

As the participants explained, the high cost of drug development, restrictive market processes that vary by country and challenges around reimbursement can deter pharmaceutical companies and investors from investing in rare disease therapies in the first place. A perception that the commercial opportunity is too limited, given a low prevalence of the disorder, may be an additional deterrent. 

When companies do invest, the hopes of that community soar, but there are no guarantees that there will be a successful pathway for that product through clinical trials to regulatory approval and then reimbursement, and if the company later withdraws, the emotional impact on the community is enormous. 

A major takeaway from this roundtable is that the chances of a therapy becoming available to patients depends to no small degree on what is done early on. Biotech companies need to be more realistic in their financial planning, taking into account the limitations of available funding mechanisms and the potential benefits of a more diverse investment base, and considering the manufacturing challenges and the requirements of regulators and decision-makers/payers. They also need to plan for setbacks, including the potential that changes may be made to regulatory processes. Regulators, too, need to think about how current frameworks risk making it financially unviable for small biotech companies to develop rare disease therapies.

If a withdrawal is necessary, a company must do whatever it can to soften the blow for the community concerned, prioritising open communication and a commitment to data-sharing. If a sponsor drops a trial, for reasons other than for safety or lack of efficacy, there needs to be a solution to keep it going for patients. As the contributors so insightfully point out, patient groups could work together to hold companies to account for their ethical obligation to facilitate that.

Wide-ranging as it was, the current roundtable could not focus on all the challenges. As a participant commented afterwards, the journey is not “just” about developing a therapy: it is about ensuring equitable access to that therapy. It is heartbreaking for families when a lifesaving or life-altering treatment is not available in their country but is in others. Additionally, while compassionate access to therapies may sometimes be approved by companies, the delays involved place a heavy burden on families. Having appropriate mechanisms in place for compassionate access is essential: delays due to lack of planning by the company and regulatory bodies as well as healthcare professionals can cost lives.

We are deeply grateful to the contributors for their insights, and we hold this roundtable up as an example of the value of multi-stakeholder collaboration. Through working together, we can surely overcome the challenges to reshape the rare disease landscape.

1: Withdrawals

• A pharmaceutical company’s withdrawal from a disease space may happen for several reasons, including safety concerns and lack of regulatory approval, but they may also happen because the therapy is not commercially viable, which is a traumatic outcome for patient communities.

• Companies need to demonstrate innovation and creativity, alongside enthusiasm and commitment, but those qualities are not enough.

• Companies must conduct due diligence as to the viability of completing trials and commercialising the product, and also commit to transparent communication about the risks and potential challenges—from day one.

• Companies should recognise that withdrawing from a disease space may affect the long-term prospect of developing effective therapies because the community may lose enthusiasm and confidence.

• Companies also need to be aware of the risk of study fatigue when enrolment is open for several studies, which is more likely when withdrawals occur.

2: Accountability

• Environment, social and governance (ESG) measures may be a useful precedent for increasing accountability.

• Companies could be required to make a statement to explain how they would respond to worst-case scenarios, such as if its funding model becomes unviable, or if the trial fails.

• A terms of engagement document that sets out the company’s obligations to the patient group could be transformative, but a coordinated approach from stakeholders will be essential.

• At a policy level, thought should be given to the incentives that would encourage companies into the rare disease space, but also to the penalties that may be applied to companies that withdraw from programmes.

3: Data sharing

• The commitment from families must be recognised—there must always be some benefit for the community at the end of the process, even if a company does have to withdraw. Companies should not be fighting legal battles for access to data.

• Companies have an ethical obligation to ensure that data from their trials and studies are shared or published to make the data available for future use.

• Data-sharing agreements need to be put into place.

• Companies could give detailed explanations of the reasons for withdrawal so that other companies could learn from that.

4: Communication

• Companies have been known to communicate poorly when things go wrong during the development of a rare disease therapy.

• Companies need to know that a communication breakdown has a detrimental impact on the reputation of patient advocacy groups because group leaders are left without the information they need to inform or reassure the community.

• Confidentiality agreements may offer a solution to this problem.

• Building a trusting, collaborative relationship between the company developing a treatment and the community should be paramount. 

5: Reimbursement

• Companies need to temper their enthusiasm for scientific innovation with a realistic market access mindset: they must think about reimbursement early on.

• Crucially, companies must understand that cell and gene therapies are assessed in exactly the same way as other products.

• Companies should evaluate health economics earlier.

• Companies must look carefully at the commercial viability of their product, considering the quality of their data, weighing this against the expectations of regulators and payers. 

• Companies must understand how much of the market they can realistically access and not rely on rough estimates.

• Companies should collect real-world evidence on the current standard of care in parallel to their phase 2 and 3 studies to give payers more meaningful data for their value judgements.

• Companies should always collect quality-of-life data that is meaningful to the community impacted and should partner with patient advocacy groups early.

6: Shaping value discussions

• Companies must have an accurate, up-to-date and comprehensive understanding of the burden of a disease and be able to convey this clearly.

• Patient advocacy groups may be an excellent source of information about the true burden of a disease. Existing literature may be deficient.

• Patient groups can help to build the narrative around disease burden so companies can highlight the benefits of therapies.

• Payers and regulatory review boards should be aware that positive messaging that may be included on patient group websites is designed to give hope to the community. It should not be considered as evidence against the need for treatment options.

• Payers tend to concentrate on the direct costs and savings that a rare disease therapy brings. It is vital to draw their attention to the enormous indirect costs too.

7: Manufacturing challenges

• Companies need to be realistic about the costs involved in manufacturing therapies.

• Companies need to be aware of the potential challenges inherent in outsourcing manufacture to a contract development and manufacturing organisation (CDMO).

• Increasing the number of CDMOs will bring alternatives to customers and eventually stop the inflation in costs that has affected cell and gene therapies in recent years.

• Regulators need to be aware that their expectations around research and development are a barrier that may threaten the sustainability of developing therapies for rare diseases: the small disease populations mean that companies may not recoup the costs of overcoming these barriers.

8: Funding mechanisms

• Funding challenges are impeding the development of products for rare diseases.

• The market downturn has had an enduring effect on investor confidence. Erosion of stock price, even when they share positive news or gain regulatory approval, affects companies’ willingness to invest in other disease programmes.

• A more diverse investment base could help companies.

• Non-dilutive funding pathways may help companies who cannot gain venture capital funding.

• Other pathways are needed to offset the reimbursement of therapies.

• An innovative funding model that enables patients in the US to move easily between private payers would make reimbursement decisions easier.

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