Rare diseases are those that are generally defined as affecting less than five in 10, 000 people. The number of rare diseases varies between countries and studies, however it is generally accepted that there are 7,000 different rare diseases in total. While individual diseases may be rare, globally, approximately eight per cent of the population live with a rare disease. This equates to around two million Australians.
Rare diseases, like many other chronic diseases, are often serious and progressive. They typically display a high level of symptom complexity and are a significant cause of ongoing health and psycho-social challenges. There is no cure for many rare diseases, and so improving quality of life and extending life expectancy of people living with a rare disease relies on appropriate treatment and care.
As there are limited treatment options, it is essential that people living with a rare disease can benefit from new and transformative health technologies such as genomics, gene and cell therapies and precision medicine. Timely access to these transformative technologies is critical as many rare diseases progress quickly. Financial support for rare disease is another challenge as research and treatments can be very costly.
Rare disease can be difficult for health professionals to gain specialised knowledge of and experience with when seeing low patient numbers in comparison to more common diseases. Researchers face an uphill battle in securing funding and in coordinating statistically robust studies. In addition, pharmaceutical industry interest in rare disease research and development can be low due to the relatively low demand.
This chapter discusses what the Australian Government is doing to support rare disease and how rare diseases are considered within the current Health Technology Assessments (HTA). The chapter examines the challenges that exist for orphan drugs and antimicrobials in Australia. Other areas discussed include gene and cell therapy, clinical trials, data collections and research for rare disease.
Government initiatives for rare disease
National Strategic Action Plan for Rare Diseases
The National Strategic Action Plan for Rare Diseases (Action Plan), launched in February 2020, is the first nationally coordinated effort to address rare diseases in Australia. The Action Plan outlines principles and actions to bring about the best possible health and wellbeing outcomes for Australians living with a rare disease. It outlines a comprehensive, collaborative and evidence-based approach built on 3 principles: person-centred, equity of access, and sustainable systems and workforce.
The Action Plan has three pillars – Awareness and Education, Care and Support, and Research and Data, and aims to increase awareness of rare disease and improve engagement between sectors, enhance jurisdictional partnerships and collect high quality data of rare disease to facilitate research into the future.
The Action Plan called for the Government to recognise action and policy for rare disease to ensure equity of access to medicines and research/clinical trials for this priority population.
Several other priority groups were recognised including ‘Aboriginal and Torres Strait Islander people; people living in regional, rural and remote areas; people from culturally and linguistically diverse (CALD) backgrounds; and people experiencing socio-economic disadvantage.’
The next step will be to implement the actions agreed to under each pillar. Many of the actions relate to the Committee’s terms of reference and were suggested as recommendations by many submitters.
The Rare Disease Industry Working Group (RDIWG) informed the Committee that it welcomed the Australian Government’s commitment to provide up to $3.3 million for activities to implement the first National Strategic Action Plan for Rare Diseases announced in February 2020. Importantly, the Action Plan’s key priorities include equitable access to the best available health technology.
On 8 May 2018, the Department of Health (the Department) and Medicines Australia entered into a Compact to facilitate and promote cooperation between the parties in respect to ensuring the future sustainability of the Life Saving Drugs Program (LSDP). The agreement is underpinned by the shared principles of:
Stewardship of the Australian health system and a responsibility for its ongoing sustainability
Patient access to clinically effective medicines for chronic progressive rare diseases
Improved value of medicines available on the LSDP that enable ongoing sustainability of the program
Stability and certainty for the investment in medicines for rare diseases, including recognition of the role that transparent and streamlined processes play in encouraging investment
Transparency and efficiency of processes for listing medicines on the LSDP and for subsequent reviews of medicines.
The Department in collaboration with the RDIWG and Rare Voices Australia (RVA) developed guidance to ensure transparency and associated timelines for consideration of medicines seeking funding through the LSDP. This guidance further delivers on the commitment to assist sponsors in preparing an application to make a rare disease medicine available on the LSDP; ensuring access to treatment for people with rare diseases is not unnecessarily delayed.
National Health Reform Agreement
The National Health Reform Agreement (NHRA) is an agreement between the Australian Government and all state and territory governments and was signed in May 2020.
It commits to improving health outcomes for Australians, by providing better coordinated and joined up care in the community, and ensuring the future sustainability of Australia’s health system. It is the key mechanism for the transparency, governance and financing of Australia’s public hospital system.
The 2020‐25 NHRA Addendum provides specific arrangements to ensure Australians with some of the rarest conditions have access to new, life‐saving highly‐specialised therapies in public hospitals. These funding arrangements (50 per cent Australian Government, 50 per cent state and territory governments) apply to high cost therapies recommended by the Medical Services Advisory Committee (MSAC) to be used in Australia and delivered in a public hospital. State and territory governments, as system managers of public hospitals, will determine if, when and where these treatments are delivered. All governments have agreed to greater transparency and improved consultation processes so all jurisdictions can be engaged and informed in technology assessment processes.
In 2020‐21, the Department announced there will be two grant opportunities under the Clinical Trials Activity Initiative including $25 million for ‘Rare Cancers, Rare Diseases and Unmet Need for COVID‐19’ and $25 million for ‘Rare Cancers, Rare Diseases and Unmet Need’.
Health Technology Assessment alternative pathways
Australian HTA processes utilise models that are designed primarily for more common diseases. This presents challenges for reimbursement decisions for rare disease medicines/technologies. Smaller patient numbers impact cost effectiveness, and there is often less clinical evidence available due to the challenges of conducting large-scale clinical trials.
Mrs Nicole Millis, CEO, RVA, highlighted innovation as being critical for advancement of rare disease treatment however the HTA processes need to be fit for purpose to allow the innovative health technologies to be provided to the patients who need them:
For example, fundamental discovery research is of central importance to the development and testing of health technology innovation. Repurposing of medicines also provides an important opportunity to address unmet need in rare disease, but reimbursement of repurposed medicines is inequitable, uncertain and unsustainable. This is a systemic issue for rare disease, where the patient numbers are so small and where current approval processes are inappropriate and inflexible.
Fabry Australia commented:
Incentivising big global pharmaceutical companies to bring international research to Australia is imperative. There is uncertainty about how the Australian regulatory system works and the reimbursement model is unclear, and complex compared to other global models. The pathways need to be clearer and for all stakeholders, particularly those with financial investment in new novel medical technologies to ensure businesses are confident to come to the Australian market.
Specialised Therapeutics Australia (STA) stated that whilst it was understood that the Australian health budget is a finite resource:
… the processes for determining access to life-saving and life-changing technologies need to be faster and more transparent, with fewer administrative and financial barriers.
RDIWG commented that the reimbursement process for rare diseases is unnecessarily lengthy meaning that Australian patients have to wait for treatments for very prolonged periods of time:
Consideration should be given to ongoing negotiation rather than rejection, particularly with regard to price and population, after the first evaluation thus reducing submission churn.
Health Technology Assessment Consumer Evidence and Engagement Unit
In 2019, a designated HTA Consumer Evidence and Engagement Unit was established within the Department’s Technology Assessment and Access Division to allow the development of structured projects of engagement with consumer and patient groups.
The Department provided an example of where further engagement and assistance provided the support required to have a drug listed and reimbursed on the Pharmaceutical Benefits Scheme (PBS) successfully.
The Department has actively supported rare disease organisations to engage in the submission processes, including those put forward by pharmaceutical companies, or in collaboration with clinical specialists. This has been demonstrated through the successful listing of vorinostat (Zolinza®) for relapsed or refractory cutaneous T‐cell Lymphoma (CTCL) on the PBS as a result of submission by Rare Cancers Australia in 2016.
Despite the Department establishing this new engagement unit within the Department, it was clear that the stakeholders were either unaware that the unit existed or they felt that the unit needed to be expanded to provide further assistance.
Patient Voice Initiative commented about the lack of awareness the patient voice has in knowing where they can contribute within the HTA process:
Patients have an opportunity to provide input during reimbursement processes, but most are not aware of this or cannot access sufficient detail about what PBAC or MSAC are considering in order to address the knowledge gaps. Often it is too little, too late because patient knowledge was not part of the R&D [research and development] process informing everything from prioritisation to trial design and aiding recruitment (all identified benefits of patient involvement).
Ms Jane Hill, Chief Executive, Ovarian Cancer Australia, emphasised that there needs to be further reform in patient engagement.
There have been some advances made in the last couple of years, but I still feel that there is a lot to be done in that area. There are some innovative models in Canada and Scotland. There are some good things happening there; some principles, I think, that are worth considering—patient organisations being given prior access to sponsor submissions and having much more engagement throughout the process. I also think all stakeholders should be brought together to discuss reimbursement and approvals.
Ms Jessica Bean, Chair, The Patient Voice, said ‘I think we've seen small but positive steps in terms of consumer engagement with the formation of the consumer evidence and engagement unit. Recognition that there's need for better consumer engagement is really important. I think it has to be embedded across the life cycle.’
Ms Vanessa Xavier, Head, Market Access, Sanofi, expressed the view that the current engagement that patients and clinicians receive during the Pharmaceutical Benefits Advisory Committee (PBAC) process is not meaningful engagement.
Right now, I would say, for the PBS process and the LSDP processes, it's not meaningful engagement. It's not a dialogue. With the call for comments, you can write a very short statement about why you believe the product should be reimbursed, but nobody speaks to you about why it's important to you or what benefits you look for either as a physician or as a patient. So I think we need to do better with regards to engagement.
The RDIWG commented that the patient voice should be incorporated as part of all pathways:
Consumer hearings should be held for all rare disease treatments in order that the patient voice is heard in particular with regard to the effect of the condition on the life of patients and their families and the impact that a new treatment will have to these patients. In accordance with Action 2.1.5 of the National Strategic Action Plan for Rare Diseases, the voice of people living with a rare disease as well as families and carers should be embedded throughout structures and systems that impact rare diseases. Rare disease organisations should work with the HTA Consumer Evidence and Engagement Unit to take a more active role in HTA processes.
Developing rare disease expertise in the Department of Health
Several submitters suggested that rare disease expertise should be developed within the Office of HTA (Action 188.8.131.52 of the Action Plan) and the evaluation template should include content and explanations that focus on the differences as a consequence of rarity.
Associate Professor Michelle Farrah, Clinician representative, Luminesce Alliance was supportive of establishing an Australian Office of Rare Disease.
First of all, I am aware and extremely thankful that the Australian government has endorsed the National Strategic Action Plan for Rare Diseases, and priority 1 and pillar 1 is entirely focused on awareness and education for rare diseases. In terms of extending that vision, an Australian office for rare diseases would be very important. Overseas there's the EURORDIS office, and I think collaborating with them and adopting and translating that to the Australian context would be very important—running summer schools for all stakeholders, educating them on each other's perspective and the framework that's needed to access therapies in Australia. But also the office could have oversight and accountability and coordinate leadership and engagement to promote awareness and health literacy and really focus on access and equity within this office, and develop the infrastructure, the tools and the resources to promote awareness and education and therefore literacy so that we can promote equitable access for all people living with rare diseases, to optimise their therapies.
The establishment of a Rare Disease and Precision Health Office in Government, acknowledging the importance and future promise of precision health in driving person-centred healthcare. A number of similar exemplars already exist, both nationally and overseas. Locally, the Precision Health Council in Western Australia (a ministerial council) was established in 2019. Internationally, in the United States, the Rare Diseases Office within the National Institute of Health has statutory authority and was established through the Rare Diseases Act (2002).
Many pharmaceutical companies raised the issue of the cost of submitting a successful submission to the HTA process. The Committee heard that it cost the pharmaceutical company approximately $240 000 to prepare a reimbursement submission to PBAC. This is often on top of about $120 000 to have the submission put together by a consultant/contractor, therefore making the approximate cost for one submission $360 000. However as many submissions do not get through on first application, the real costs of a successful submission sits between $500 000 to $1 million dollars.
A concern around the high costs of submissions for rare disease was highlighted. Recordati Rare Diseases Australia (RRDA) commented that ‘we struggle to afford any subsequent submissions with the PBAC if our first submission is rejected.’
Rejection of submissions is very common, very few get though in the first round. Our products treat only a very small number of patients, usually children. RRDA sales revenue is only a fraction of other pharmaceutical companies. Second round evaluation of submissions can cost over $300,000.00. This fee does not include the cost of market access consultants preparing submissions which adds another $150 000.00 to the overall cost.
RDIWG echoed this view:
Rare disease submissions are often complex and require additional data analysis and stakeholder engagement. They are rarely recommended following the first submission. The process can take years with multiple resubmissions to PBAC and can be cost-prohibitive even with the Orphan Drug Designation (ODD) fee waiver for the first submission, with subsequent resubmissions costing $166,220 from 1st January 2021. Therefore, the timeframes for claiming exemption of cost recovery fees should be extended for orphan drugs. These changes will provide additional incentives to bring orphan drugs to Australian patients.
Several pharmaceutical companies that supply rare medicines suggested that a waiver of fees should be extended beyond the current 12 month timeframe.
The Committee heard that a waiver of fees would encourage pharmaceuticals to submit more medicines to PBAC in the future.
RRDA commented ‘I believe that we would be able to submit more medicines to the PBAC if the fees for the first 2 - 3 submissions were also waived.
In addition, STA suggested that:
Smaller companies with revenue less than $50 million annually be granted an exemption from paying new fees ‘upfront’ for at least the first two applications, and when, or if, a drug is listed on the PBS, the company then pays those fees in arrears, in instalments when Pharmaceutical Benefits Scheme (PBS) expense on that drug exceeds $3 million per year.
Some submitters commented on the TGA’s fee regime, particularly as it relates to therapies for rare diseases. Dr Falk Pharma commented that an orphan drug designation for a medicine:
… should cover all submissions relating to that medicine with the same active ingredient for the treatment of the same condition.
Similarly, Amicus Therapeutics submitted that the fee waiver that results from an orphan drug designation should be extended to five years (from one year currently) to ‘encourage and support companies to continue investigating and following up with expanded populations such as paediatric indications for a therapy.’
Mr Rod Longmire recommended ‘reducing registration and application fees for small enterprises or organisations with small budgets’ to encourage registration of medicines for small populations.
RESULTS International Australia similarly recommended that fees be waived for ‘essential drugs’ with small markets like drugs for tuberculosis.
Commenting on the prospect of fees being raised to increase the TGA’s budget, Dr Arnold and Dr Bonython said that ‘there are no indications that overseas/domestic vendors will leave the market on the basis of moderate increases in fees.’
Professor Skerritt responded to the discussions of expanding fee waivers by saying:
…with our full cost recovery model, it is always a challenge if, let's say, there's a number of types of drugs that were able to receive a fee waiver. There's not a magic pudding, so that funding would have to come from somewhere, and that would be a decision by government on how to fund it.
In response to the idea of charging different fees based on company size he explained:
The fees are based on effort, and you can imagine, whether it's a new start-up company with a new drug or whether it's a multinational, the amount of effort is the same. There is no differential fee schedule for small companies versus big companies. That would be a question of policy for government.
Managed Access Program
The Managed Access Program (MAP) (formerly the Managed Entry Scheme (MES)) Framework was developed in consultation with representatives of applicants for PBS listing. It came into effect in 2011 as part of the response to the trend for applications for new medicines in rare diseases, which were based on relatively preliminary evidence. The Department is undertaking further consultation with the pharmaceutical industry in the context of the Strategic Agreement with Medicines Australia on this program.
The MAP enables the PBS listing of products, under special circumstances of high unmet clinical need, on terms that allow for the resolution of otherwise unacceptable clinical or economic uncertainty for the PBAC. A submission that would not normally be recommended for listing by the PBAC because of unacceptable clinical and/or economic uncertainty could be recommended under a MAP.
The MAP mechanism means:
earlier access to the medicines by patients;
earlier access to a subsidised market for the sponsor whilst acknowledging that some form of confidential discount may be required in recognition that the initial evidence is less convincing;
clear articulation of the evidence required to resolve the identified area of uncertainty and the consequences of potential outcomes from the additional evidence;
agreement by the PBAC to review a submission once the additional evidence becomes available and to reconsider the listing in light of the new evidence; and
appropriate sharing of risk.
The RDIWG was supportive of expanding the MAP. It commented:
Managed access programs and other outcomes-based arrangements, particularly in the case of small populations and uncertainty of the data, would provide early access to patients while collecting data to reduce uncertainty over time.
Novartis Pharmaceuticals was not supportive of the MAP as they commented that significant risk was borne by the sponsor and the uncertainty around the PBAC process acted as an disincentive for industry:
Managed Access Programs, designed to accelerate access to PBS medicines, (previously known as Managed Entry Schemes) have led to significant risk born by the Sponsor and low uptake across the industry.
Novartis Pharmaceuticals suggested:
Remove disincentives for sponsors from considering applications that may qualify for Managed Access Program. The rigidity and/or uncertainty surrounding the PBAC process can act as disincentive to seeking faster TGA approval through expedited pathways.
The orphan drug program aims to incentivise sponsors to bring medicines for serious and rare conditions to market that would otherwise not be financially viable. The program offers a 100 per cent waiver of TGA fees for application and registration to help offset orphan drug development costs. Similar arrangements operate with respect to reimbursement applications.
In July 2017, changes to the orphan drug program were implemented to create a fairer program that aligns more closely with international criteria without impeding the availability of drugs for rare diseases. In particular the new program provides a more generous orphan disease prevalence threshold (fewer than five in 10,000 individuals in Australia), potentially allowing a larger number of medicines to classify as orphan. However, following approval, the decision to supply the product remains at the discretion of the sponsor.
The eligibility criteria for orphan determination focus on the greatest unmet clinical need and include:
the medicine is for the treatment, prevention or diagnosis of a life‐threatening or seriously debilitating condition
the condition affects fewer than five in 10,000 individuals in Australia
it is not likely to be financially viable for the sponsor to market the medicine in Australia, and
There are no other medicines to treat the condition marketed in Australia; or the medicine provides a significant benefit in relation to efficacy or safety of the treatment, prevention or diagnosis of the condition, or a major contribution to patient care, compared to existing marketed products.
The Australasian Sleep Association noted that under the current orphan drug criteria a medicine is ineligible if the prevalence in Australia of the disease it treats is unknown, as is the case for narcolepsy. It recommended that in such cases the sponsor be allowed to use a ‘reasonable extrapolation of prevalence from comparable countries.’
Viiv Healthcare raised the issue of the TGA needing an alternative pathway for certain drugs that do not neatly fit the orphan drug pathway however there is no alternate pathway for some indications, for example, paediatric medicine for HIV. Viiv Healthcare raised with the Committee the scenario of paediatric medicine for HIV:
ViiV Healthcare previously applied to the TGA seeking orphan designation for a paediatric indication of an HIV medicine. This application was rejected by the Therapeutic Goods Administration (TGA), despite the fact that there are estimated to be only 47 children currently living with HIV in Australia.
Amicus Therapeutics suggested that an orphan drug designation should provide automatic entry to the Priority Review pathway, in order to reduce assessment times for orphan medicines.
Merck Healthcare suggested that ‘the disincentive of the 5 per cent statutory price cut at 5 years of PBS listing, for orphan-designated medicines or medicines which treat small patient populations’.
The GUARD Collaborative informed the Committee that the United States (US) had introduced legislation for orphan drugs back in 1982.This meant that there were a number of orphan drug approvals nearly 40 years ago and had set the industry up well to research and commercialise orphan medicines:
Historically, it is the United States that has taken the first major political steps to accelerate the development of rare diseases therapies, as early as 1982, with the U.S. Orphan Drug Act that led to a sharp increase in the number of approved medicines. The U.S. Orphan Drug Act – unlike more recent EU Orphan Drug Regulation, did not include any provision related to the “significant benefit” of new orphan medicines.
This makes the USA today more attractive to investors and companies than other markets, and as companies and funders are seeking to secure higher returns on their investments, with the concrete outcome of seeing many more generations of orphan medicines come to commercialisation first in the United States and then, only much later, elsewhere.
Life Saving Drugs Program
Most medicines in Australia are subsidised through listing on the Pharmaceutical Benefits Scheme (PBS). Funding for medicines on the Life Saving Drugs Program (LSDP) is separate to the PBS. The LSDP covers medicines if:
they are clinically effective, but not cost effective enough to list on the PBS
they treat life threatening and rare conditions (defined as 1 case per 50,000 people or fewer in the Australian population)
the pharmaceutical company (sponsor) applies for an LSDP listing.
The Life Saving Drug Program (LSDP) provides approximately 430 patients fully subsidised access to expensive and life‐saving medicines for rare and life‐threatening medical conditions. Medicines on the LSDP are available to eligible patients at no cost and for as long as clinically necessary. This program cost $133.6 million in 2018‐19. There are currently sixteen medicines on the LSDP for the treatment of 10 conditions.
The Committee was informed by the Department that ‘Before a medicine is considered for inclusion on the Life Saving Drugs Program (LSDP), a medicine must first be considered by the Pharmaceutical Benefits Advisory Committee (PBAC) and accepted as clinically effective but rejected for Pharmaceutical Benefits Scheme (PBS) listing because it fails to meet the required cost-effectiveness criteria.’
RDIWG said the ‘Australian Government should be commended for providing subsidised access to essential medicines to over 430 eligible patients with rare and life-threatening diseases through the Life-Saving Drugs Program (LSDP).’
Numerous submitters raised concerns about the length of time it takes for medicines to be approved and listed on the LSDP. Some submitters suggested that the two step process should be abandoned. The RDIWG suggested the following:
In a similar way that the Australian Technical Advisory Group on Immunisation (ATAGI) considers vaccines before the PBAC, consideration of products destined for the LSDP by the LSDP expert panel prior to the PBAC would simplify the process. The two-step LSDP process is unnecessarily lengthy particularly with regard to the need to be rejected by the PBAC prior to consideration by the LSDP Expert Panel.
In the case of products to be listed on the LSDP, the inclusion of a LSDP representative as part of the multi- stakeholder review panel would ensure the specific challenges of the disease are well understood and provide clarity on the likely funding pathway prior to PBAC submission.
Alexion Australasia commented that ‘There has been good progress made over the last 10 years, however to achieve world-leading access for rare disease treatment, further streamlining of the assessment process is required as well as greater certainty that products which clearly fit the LSDP criteria will be made accessible to the public.’
Alexion Australasia highlighted the issue of time delays and stated:
Extensive delays to access can occur for these types of products even though they may address a high unmet clinical need.
Fabry Australia highlighted the fact that less than one third of all Fabry patients receive the medical treatment listed on the LSDP.
There are three funded therapies approved on the Life Saving Drugs Program, two of which were listed in 2004. However, the criteria to obtain such medical treatment is very restrictive and not all of the 300+ Fabry patients are on therapy, actually less than a third receive formal Fabry disease medical treatment. The current guidelines do not allow children and young adults to access any treatment until the disease has progressed significantly. In the meantime, there is considerable individual suffering. Current guidelines do not consider the most recent clinical knowledge, such as our improved understanding of the use of cardiac MRI scanning in Fabry disease.
At a public hearing in June 2021, Professor Andrew Wilson, Chair of the PBAC told the Committee the PBAC is aware that the concept of rare disease is changing, with increasing genomic sub-characterisation of more complex diseases. Professor Wilson commented:
This has the potential to further challenge the whole concept of a separate program for life-saving drugs for rare diseases. The PBAC believes there is merit in examining whether the same purposes of the LSDP could be achieved through a PBS section 100 program, with specific criteria, as with other section 100 programs. This removes the need for a second-line assessment and would also provide greater consistency in approval, pricing and ongoing monitoring.
The RDIWG encouraged the Government to consider alternatives for rare disease pathways. It suggested the following:
Other rare disease treatments that do not meet the LSDP eligibility criteria may be able to be funded on the Pharmaceutical Benefits Scheme (PBS). However, special consideration needs to be given to rare diseases being evaluated by the PBAC. Firstly, greater input from expert clinicians and relevant patient organisations would help the PBAC to understand the disease impact, patient relevance and clinical meaningfulness of the (sometimes limited) data presented, and the seriousness of the unmet need.
Secondly, cost-effectiveness needs to be considered in the context of rare disease treatments which often cannot meet the incremental cost effectiveness ratio (ICER) thresholds typically applied to treatments for more common conditions. Alternative measures of value should be considered, including societal perspectives, impact on patients, carers and the community, and indirect economic costs. In the case of orphan drugs, the overall budgetary impact should be given more weight than the ICER.
The RDIWG suggested ‘earlier engagement with the Department of Health would be welcomed by industry in order to be able to identify the appropriate reimbursement pathway, provide the patient voice and establish clinical need so that all parties facilitate the path to access without increasing submission churn.’
In December 2017, the Australian Health Ministers endorsed the Newborn Bloodspot Screening (NBS) National Policy Framework. Healthcare providers offer newborn bloodspot screening to all babies in Australia. This blood test detects certain rare genetic conditions and metabolic disorders. This screening test aims to improve the health of babies by identifying those at risk of developing a serious condition, allowing for early intervention.
The Department supports the national newborn screening framework by conducting initial reviews on new nominations for NBS. Nominations with sufficient evidence proceed to a detailed review with the MSAC. Following receipt of the MSAC advice, state and territory governments deliver the newborn screening programs. Each state and territory decides which conditions to screen for.
Several witnesses discussed the NBS and advocated for a more robust national NBS program that was consistent across Australia.
Ms Louise Healy, Member, Queensland Genomics Community Advisory Group, made the following observation in favour of an aligned national newborn screening program:
Australia should definitely have a national newborn screening program. We do have a national newborn screening framework, and it's a strong framework. But the way it's currently governed and administered does lead to inequities across states, with some states implementing recommendations arising from that policy quicker than other states and therefore babies missing out on that opportunity. I think there's some opportunity for leadership in newborn screening as well. We can look at the horizon and see what's coming and start to think about what a newborn screening program should look like …
Better Access Australia fully supported adding more conditions to the newborn screening program and questioned why Australia was no longer a world leader in newborn screening:
Why do we consider it acceptable for small patient groups to wait three years for access to a process for newborn screening for fatal but treatable diseases only to be told no. Australia once led the world in this testing but hasn’t added a new disease to these tests since 1981.
Many advocates for specific rare diseases were keen to see more conditions added to the newborn screening program. Mr Raymond Saich, President of Australian Pompe Association commented:
Newborn screening is absolutely vital if we're going to stop these tragedies of premature death of Pompe babies. In Taiwan they've had newborn screening since 2005. They're able to diagnose a Pompe baby within five days of birth and get babies into treatment. They can see a difference if a Pompe baby has gone into treatment within five days of birth against 21 days of birth. So it's absolutely vital. Unfortunately here in Australia it takes about three months if you live in the metropolitan areas and six months if you live outside of those areas. First mum and dad have got to realise the baby's not well and get the baby to see a GP—often that's two or three visits. Then you get to see a paediatrician and then eventually a treating specialist. That's how the three months happen so quickly. As I said, if you are outside of metropolitan areas these things get so much harder and it doubles it.
Dr Gaynor Heading, President of Alpha-1 Organisation Australia supports adding more diseases to the newborn screening:
But there are other things that can be done to assist, like newborn screening for alpha-1. We have babies born with so much antitrypsin trapped in their livers that they go to immediate liver transplant. The genetic trials are brilliant not only for lung but for liver, so we can save all those sick babies as well.
Dr Melanie Wong, Co-Chair, ASCIA, discussed the importance of a national newborn screening program for Australia. She illustrated her example using a rare disorder called severe combined immunodeficiency (SCID):
… there are good, reliable newborn screening tests and there are readily available confirmatory tests. SCID newborn screening is currently being piloted in all infants born in New South Wales, funded by a research initiative, so we know that it can feasibly be incorporated into routine practice.
SCID newborn screening is currently under evaluation by the newborn national framework, but this review has, unfortunately, been in progress for almost two years without a formal decision being made. Meanwhile, SCID newborn screening has been successfully introduced in many countries around the world, including the US and New Zealand, so Australia is actually falling behind best practice.
Even if there is a supportive decision following this review process, every individual state will need to accept the decision and allocate funding to add SCID to their current testing regimes. So now we need to progress the newborn framework evaluation. We need to achieve support and funding for incorporation of SCID newborn screening into each state’s program and thus provide a united national screening approach to preventing life-threatening infections and early death in the vulnerable group of children affected by this genetic condition.
Cell and gene therapy
Cell and gene therapies are fundamentally different from more common medicinal products, as they generally have longer than average development times, more stringent manufacturing requirements, and a limited shelf life for products (sometimes as little as 24 hours).
One third of cell and gene therapies are in development for rare diseases. Medicines Australia illustrated the way in which cell and gene therapy will expand in the future:
As of February 2020, there are nine cell or gene therapy products approved in the U.S. treating cancer, eye diseases and rare hereditary diseases. The FDA has indicated that it expects to approve 10 to 20 new cell and gene therapies between now and 2025.
Takeda Pharmaceutical commented that the supply and administration of personalised cell and gene therapies is more complex and different to conventional drug products. It suggested that the Government may need to provide financial assistance to bring these new therapies to patients:
Many institutions may not have the required capabilities to provide these therapies. Instead, it is expected that patients will be referred to a relatively small number of treatment centres where they will be carefully selected for treatment and managed by a multi-disciplinary team with a follow up period that could span over many years. These considerations may require the treatment centre to make additional investments and require financial support by the government.
Roche discussed the future of genetic testing and treatment access in Australia. It suggested:
… the establishment of a national genomics service which, through a range of public and private partnerships, can better link research and clinical care.
The service would support patients and service providers by ensuring genomic testing and subsequent clinical services, including genetic counselling, are provided within a quality framework. It would also help build workforce and research capacity and capability.
The data generated through the research component of the service would be used as evidence to support applications to repurpose existing medicines which can ultimately broaden the number of available treatments listed on the Pharmaceutical Benefits Scheme (PBS) for patients with rare diseases or cancer.
RDIWG encouraged the Committee to consider recommending a fit-for-purpose system for evolving therapies such as gene and cell therapies which have attributes that require special consideration:
Development of such a system will mean that Australians can remain proud of the system which enables sustainable access to interventions irrespective of their health challenge.
In addition RDIWG raised the issue of dealing with limited data at the time of assessment. It suggested:
… there should be a focus on the development of innovative access mechanisms to ensure patients have the advantage of being able to access treatment in parallel to the long-term collection of real-world evidence (RWE).
Novartis Pharmaceuticals commented that the current co-dependent pathways for access to genomic screening for cancer patients leads to delays. It suggested:
A staged introduction of de-coupling of the cost effectiveness of the test and therapy where genomic panel testing is available is likely to improve patient access to targeted therapies for patients with rare diseases, build experience nationally with genomic testing.
The Sydney Children’s Hospital Network supported the streamlining of approval processes for cell and gene technology. It suggested decreasing the time it took to obtain a licence from the Office of the Gene Technology Regulator as this was seen as a barrier to bringing clinical trials to Australia.
Streamlining gene technology licencing processes for investigators and industry. For many advanced therapeutics, clinical trial readiness relies on having adequate facilities (PC2 lab) and navigating complex regulatory processes. Some clinical trials of gene and cell therapies require a licence from the Office of the Gene Technology Regulator under the Gene Technology Act 2000, and most licences require sponsor accreditation. This process can take in excess of 4 months which is currently a deterrent for Sponsors to bring gene therapy clinical trials to Australia.
In addition, the Sydney Children’s Hospital Network proposed more international collaboration:
Enhanced national and international collaborative relationships to more efficiently and effectively identify areas of unmet need, guide the development of policy and regulation, and facilitate timely decision making in collaboration with industry.
GUARD commented that more work is needed to be done by Governments and the integration along the development pipeline.
Federal and State Governments have recognised the promise of genomic medicine and are progressing substantial programs of work to promote the integration of genomic technologies into healthcare. This is not enough. Innovation in approach to discovery, research, development and manufacture of new drugs, treatments and technologies must support this integration.
Clinical trials for rare cancers
Victorian Comprehensive Cancer Centre stated that ‘rare cancers disproportionately affect young patients, are associated with poor survival outcomes, and are under-represented in clinical research.’
Clinical trials are essential to improving outcomes in all patients but rare cancers are frequently excluded from participation in clinical trials because:
Clinical trials are often designed with an ultimate aim of registering a drug for a specific indication. Rare cancers may therefore be seen to be less desirable for inclusion as they represent a smaller number of patients.
Randomised phase 3 trials for rare cancers are not feasible.
For rare cancers, particularly ones that are treatment refractory, there may be no established standard of care.
A number of new tactics to include rare cancers in clinical trials are being pursued. These include:
Tumours can now be defined by specific molecular features (as opposed to the organ of origin), allowing enrolment onto Precision Oncology clinical trials based on the molecular features alone, aka. ‘tumour agnostic’ trial design.
‘Umbrella’ or ‘basket’ trials also facilitate recruitment of rare cancers into clinical trials by allowing a broad inclusion criteria that allows many rare cancer types.
Examples of successful approaches utilising ‘tumour agnostic’ approaches include the identification of NTRK-gene fusions in a wide range of solid tumours types in both adult and paediatric patients, that allows treatment with targeted therapy.
Because pharmaceutical company sponsored clinical trials are driven by market size and the ability to pay for expensive drugs, there is a health policy concern that a lack of clinical trials in some jurisdictions create significant disparities in access to new treatments and to better outcomes.
The Sydney Children’s Hospital Network commented that:
Innovative trials should be encouraged and incentivised, including N of 1, adaptive, organoids and basket trials which are all currently in place in Australia. Regulatory approval pathways for rare diseases should be established to support the translation of these innovative trials into the health system.
Limitations on data, research and clinical trials
In Australia, data for most rare diseases is not captured in either health information systems or registries and there is no coordinated strategy to collect, measure, build and translate data that does exist. For many rare diseases, there are many barriers to effective research and no active research programs. For many people living with a rare disease, participation in a clinical trial may be the only way to access treatment. Yet there are many challenges to running clinical trials. For example, there is no national infrastructure for rare disease clinical trials, nor a streamlined national ethics approval process.
Market rewards for the development of new drugs for unmet medical needs such as new antimicrobials and some drugs for rare diseases can be insufficient to incentivise the needed R&D. This issue has been recognised as problematic and RVA was funded to develop an Action Plan to assist the Australian Government to provide a strategic way forward to support Australians living with rare disease now and into the future.
The Action Plan provides guidance around three priority pillars for Australians living with rare diseases. One of the three pillars is research and data. Action Plan Pillar 3 recommended the following for research and data:
Priority 3.1: Enable coordinated and collaborative data collection to facilitate the monitoring and cumulative knowledge of rare diseases, informing care management, research and health system planning.
Priority 3.2: Develop a national research strategy for rare diseases to foster, support and drive all types of research for rare diseases, contributing to agreed priorities and systematically addressing gaps.
Priority 3.3: Ensure research into rare diseases is collaborative and person-centred.
Priority 3.4: Translate research and innovation into clinical care; clinical care informs research and innovation.
There is an understanding in the Australian rare disease community that, while research may not lead to better outcomes for people currently living with a rare disease, participating in research may drive change for future generations. This is supported by outcomes of the Rare Barometer survey undertaken in February 2018 by EURORDIS, Rare Diseases Europe.
QIMR Berghofer suggested that ‘research funding and grants with a focus on unmet needs and/or neglected health conditions should be developed.’
Alpha-1 Organisation Australia commented that ‘modifying or expanding existing structures could retain rare disease researchers and attract clinical trials to Australia. Other strategies could include:
grant bodies such as the NHMRC could include dedicated rare disease grants and grants for repurposing drugs for rare disease
post-doctoral scholarships in rare disease research could be mandatory in clinical trial design
national awards for rare disease research could be promoted
a standardised rare disease data capture system could be developed / made available and offered to charities / other groups so that patient registries are available in all rare disease and a cohort of patients ready to be enrolled in research (reflecting priorities in the National Strategic Action Plan for Rare Diseases – Actions 184.108.40.206 and 220.127.116.11).
The Pharmaceutical Society of Australia (PSA) represents the 34 000 pharmacists working across Australia. The PSA commented that the ‘expertise of pharmacists can be better utilised to address the health care needs of all Australians.’
Mr Chris Flood, National Manager, Pharmacy Guild of Australia, proposed an opportunity to be considered in the future for pharmacy trials and data collection.
This is where there's a really good opportunity to capitalise on what pharmacists do, particularly if you're looking for patients who are living in regional or remote areas. You could actually have these patients participating and being supported by the local pharmacist who is able to assist with monitoring any of the outcomes. We actually see this already with a lot of the pharmacy trials that happen as part of the agreement. I see lots of opportunities that way.
Rare disease register
RDIWG was supportive of the need to develop a Rare Disease Register and Clinical Trials Network. It commented that ‘this would improve the national co-ordination of data collection and patient identification for trial participation in rare diseases with very small numbers. Additionally, the development of registries and better access to registry data by all stakeholders would facilitate the review of treatments.’
Mrs Sheridan Campbell, Chair, Fabry Australia commented that many rare disease stakeholders and advocates called for a ‘national rare disease registry and coordinated infrastructure to support these clinical trials’.
Professor Farrah from Luminesce called for the establishment of a rare diseases registry:
Another thing that could help with health literacy would be a registry for people who are living with rare diseases. Registries serve multiple purposes in terms of knowing who can potentially access new therapies. I know from my patients that they live with the anxiety that something will be out there with them and I won't know about it and they won't know about it; it's a missed opportunity. While I know that there are privacy concerns with registries, my own experience with my patients is that they're very willing and wanting to be on registries to really make sure that they're not missing out on opportunities. Also they serve important functions in terms of dealing with appropriate clinical trial design, measuring real-world outcomes and informing phase IV studies to promote access, which is very important for the patients we treat.
The Action Plan for rare diseases calls for the Australian Institute of Health and Welfare (AIHW) to re-establish the Australian National Congenital Anomalies Register (NCAR), including rare disease coding.
This will accelerate, extend and nationalise rare disease coding already underway in the Western Australian Register of Developmental Anomalies (WARDA), and contribute to International Classification of Diseases 11th Revision (ICD-11) preparedness.
Equity and funding for rare diseases
Professor Adam Jaffe, Member of Scientific and Medical Advisory Committee, RVA, discussed the future as having better equity for Australians living with rare disease. He stated:
The process needs to involve innovation and new designs to really streamline that. It really comes down to better-value health care. With respect to the previous question on cost, we're really lucky in Australia. It's not the gold standard. We look at France as the gold standard for rare disease. It's written into the law of equity that if you've got a rare disease you have to have equitable treatment and funding.
MOGA was concerned that research priorities, commercial imperatives and advocacy favours access to oncology drugs and treatments for more common cancers in Australia.
For instance, clinical trials for rare cancers are often conducted through collaborative trials groups with less industry support and the data collected may be less suited to registration and reimbursement requirements. The Australian regulatory process and our Government seem reluctant to fund effective treatments for rare cancers even though the overall impact on the health budget would be minimal.
The negative impact of this situation on the quality care of Australian rare cancer patients and the lack of available treatment options is unacceptable. Our national systems for research and development, oncology drugs regulation and reimbursement need to be reviewed and revised to be supportive of drug development and access for rare cancers.
It is expected that novel technologies, such as cell and gene therapies, will provide significant long-term health benefits for patients. The types of interventions in development may have limited data at the time of assessment. Therefore, there should be a focus on the development of innovative access mechanisms to ensure patients have the advantage of being able to access treatment in parallel to the long-term collection of real-world evidence (RWE).
RVA discussed the inequities of Australians living with rare disease:
In the rare disease context, companies often state that it is unfeasible to submit for new indications, due to extremely small patient numbers, lack of conventional clinical trials etc. This means that many people living with a rare disease have to rely on the uncertainty of off-label use or self-fund (often equating to thousands of dollars in costs) to access a medicine that is recommended by their clinician. This is both unsustainable and inequitable.
RVA has sourced de-identified data from one of Australia’s largest public hospitals (that also includes a children’s hospital) around their funding of off-label medicines. This is a sample from 2017 to August 2020.
The data shows 570 instances of off-label hospital use that relate to a total of 30 medications for a total of 144 different indications/ reasons.
GUARD is an alliance of genetic and rare disease networks. It made a comment that acknowledged the challenges the Government has in relation to research funding and incentives and described the reality that often those who get funded is not always the strategic and equitable approach.
… we recognise that incentivising research as a key driver ultimately inevitably leads to inequity. The loudest voices get heard when there is not a strategic and agreed approach.
Myasthenia Alliance Australia suggested government will need to invest in research for rare diseases.
Governments will need to financially support research for rare diseases avoiding dollar driven limitations. Drug companies required by their shareholders to generate a profit are very unlikely to spend money on research when the return on the investment will be low. With a motivation of unrestricted considerations, best treatment outcomes can genuinely be sought.
RDIWG suggested as the Government consider risk-sharing arrangements with manufacturers as it is likely that novel technologies will be associated with high upfront costs, whereas the benefits may occur over a prolonged period of time:
The uncertainty about long-term outcomes will require a sustainable framework for risk-sharing arrangements between manufacturers and the Government.
The Committee heard from stakeholders that were calling for incentives for R&D for drugs and novel medical technologies where the needs exist in paediatrics.
Associate Professor Hansford, Australian and New Zealand Children’s Haematology/Oncology Group, called for changes to our reimbursement system pointing out that often adult cancer drugs were listed on the PBS however the paediatric cancer drugs were not.
Currently, legislation exists around the world—and I would refer back to our submission around some of the specifics—on how you can increase paediatric inclusion. Whether for drug development, for the conduct of clinical trials or the approvals for these new and novel therapies, there are ways about how we can improve our access. Thirdly, paediatric cancer is not adult cancer. On the PBS, most drugs are not accessible for children.
The Association of Australian Medical Research Institutes (AAMRI) commented that in Australia there are few incentives to develop or speed up the availability of drugs to combat rare diseases, or diseases in smaller populations such as in disease sub types or paediatrics. For these populations, the major barrier to approval of new drugs is that clinical trials are incredibly challenging and overly prolonged due to difficulties in recruiting participants as well as being expensive.
The current regulatory pathway seeks trial-based evidence for indicated populations. AAMRI suggested:
There are approaches taken by the FDA in the US that could be considered in Australia by the TGA. One example is incentivising sponsors seeking approval of new drugs to have development plans in place for paediatric populations. Ensuring that there is a streamlined regulatory pathway could safely allow the use of cutting-edge, life-saving therapies in children sooner.
In the US process, sponsors that have responded to this and are seeking drug approval are provided a patent extension of six months and are also provided accelerated approval vouchers that can be on-sold. The provision of such accelerated approval vouchers does not have a direct cost to government but does provide an incentivising mechanism.
Throughout the inquiry, the Committee received evidence from many advocates of rare diseases in Australia. The Committee is grateful to all the impassioned individuals, supportive family members and carers and organisations that put in submissions and took the time to speak with the Committee.
The Committee noted the comprehensive priorities of the National Strategic Action Plan for Rare Diseases (the Action Plan) that were endorsed by many submitters to the inquiry. Several of the priorities related to the inquiry’s terms of reference and it is hoped that the Australian Government will use both the Committee’s recommendations and the Action Plan’s priorities to move forward on rare disease policy reform.
It was evident that the Australian Government needs to consider how best to develop fit-for-purpose Health Technology Assessment (HTA) pathways for rare diseases now and into the future. The biggest challenges are to manage the issue of equity and timely access to new medicines and devices for people living with rare disease. The Committee recommends a new HTA pathway be developed for cell and gene therapy in Australia. The evidence was clear that Australia’s HTA systems will receive an influx of requests for registration and reimbursement in cell and gene therapies and treatments over the next few years. Australia will need to have robust HTA processes in place to enable Australians to access these new treatments in an equitable and timely manner.
The Committee heard that cell and gene therapy and treatment is at the forefront of a new wave of precision medicine that is currently on Australia’s doorstep and these therapies and treatments require new pathways to allow for its seamless regulation.
The Committee believes it is pertinent for the Department of Health to expand its understanding and expertise of rare diseases with a focus on precision medicine and cell and gene therapies. The Committee recommends the establishment of a ‘Centre for Precision Medicine and Rare Diseases’ within the Department of Health. The objective of this Centre is to ensure the capacity of the Department of Health is enhanced to ensure Australians have timely access to new drugs and novel medical technologies, including for rare diseases. This Centre would provide education and training information on precision medicine and rare diseases and would develop a comprehensive horizon scanning unit within the Centre.
A significant advantage of novel health technology development, such as cell and gene therapies compared to that of conventional pharmaceuticals, is their utilisation of modular and platform technologies that can be rapidly reconfigured to treat multiple disease targets such as genetic diseases, cancers and infectious diseases. This may lead to more cost effective treatments in the future.
The Committee agrees with submitters that affordable access to genomic testing is needed not only for patients but for the future of Australia’s health system. Therefore the Australian Government should establish a National Genomics Testing Program to provide equitable access to genomics testing nationwide, including provision for genomics counselling for all patients.
It is the Committee’s view that there is the need for a greater role for patient evidence in HTA decision-making where traditional clinical evidence is inadequate, such as for many rare diseases. It encourages the Department of Health to give the highest possible priority to strengthening the role patient evidence plays in its HTA decisions, particularly in relation to rare diseases.
The Committee believes the Australian Institute of Health and Welfare (AIHW) should be funded to re-establish the Australian National Congenital Anomalies Register (NCAR) and should consider how this register could be adapted to capture appropriate data for rare disease.
Australia’s HTA system needs to take into consideration rare disease and develop robust pathways that provide equity and access to treatments and therapies that don’t fit neatly into the current system such as rare cancers, antimicrobials, orphan drugs, and upcoming precision medicines.
Included in the independent HTA Review should be a pathway that facilitates consideration of new medicines and therapies for paediatric populations for a broad range of conditions. In particular, the Committee believes the Australian Government should streamline a regulatory pathway to safely allow the use of cutting-edge, life-saving therapies in children sooner.
The Committee acknowledges that there are specific problems with how the orphan drug criteria apply to paediatric medicines, as well as to medicines with an unknown prevalence in Australia, which it believes the TGA should remedy. The Committee believes that there is merit in the suggestion that the orphan drug designation should be automatically linked to the priority review pathway, to support faster access to medicines for rare disease patients and to reduce the administrative burden on the TGA.
The Committee is of the view that applicants shouldn’t have to wait for a rejection from the PBAC before they lodge with the LSDP Expert Panel. This current system adds considerable time before patients have access to life saving drugs. A new approach is required that allows earlier and faster consideration. The Committee believes there is merit in either providing sponsors with immediate pathways to the LSPD Expert Panel or considering whether the same purposes of the LSDP could be achieved by providing a new pathway through a PBS section 100 program, with specific criteria, as with other section 100 programs.
One of the main challenges in supporting better rare disease treatment is that research and development of new medicines and devices is time consuming and expensive. The Committee believes that a more sustainable framework is required for rare disease funding and risk-sharing arrangements between manufacturers and the Australian Government.
Lastly, the Committee believes it is imperative that the Australian Government complete the standardisation of the national newborn screening framework so that every baby born in any state or territory of Australia receives the same newborn screening test. Further, the Committee believes that this program should be urgently expanded, based on new understandings of genomic testing for conditions and international best practise, with a review undertaken every two years.