The Pharmafocus debate: Can ultra-orphan drugs be made cheaper?

pharmafile | January 12, 2016 | Feature | Manufacturing and Production, Research and Development, Sales and Marketing |  Drug pricing, Duchenne Muscular Dystrophy, Translarne, access to medicines, ataluren, muscular dystrophy, rare disease, ultra orphan drugs, ultra-orphan drugs 

The recent reimbursement wrangle between PTC Therapeutics and NICE, the UK healthcare watchdog, has once again raised difficult questions about a long-standing pharma industry issue: just why are ultra-orphan drugs so expensive?

Low patient volumes make it unfavourable for commercial investment in orphan drug research, but drug regulators have incentives in place to encourage their development and manufacture by pharmaceutical companies. In the USA, these include exclusive licensing to market such drugs for seven years, faster assessment procedures, and tax incentives. In Europe, it can include exclusive licensing for 10 years, reduction in the registration fees and provision of scientific advice by drug regulatory bodies.

And yet, the costs of orphan drugs are still high. In the UK, NICE is reviewing Translarna (ataluren), a drug manufactured by PTC Therapeutics for the treatment of Duchenne muscular dystrophy. The genetic condition affects just a dozen or so children in the UK every year, and can lead to progressive loss of muscle function and weakness, which can leave children in a wheelchair, before respiratory and heart failure and death before the age of 30.

Translarna is the first licensed treatment for DMD that addresses the loss of dystrophin, the underlying cause of the condition. But NICE estimates that it costs around £220,000 a year for each child – a price that at the moment the NHS cannot afford, even though a NICE appraisal committee agreed the treatment “represents an important development in the treatment of DMD and could potentially prolong the time before children have to use a wheelchair.” Duchenne Muscular Dystrophy affects between eight and 13 boys in the UK every year, and at the moment there are thought to be 65 children in England who are eligible for treatment.

For an insight into the pricing debate over this drug, and to examine whether the high R&D costs do contribute, Pharmafocus gathered opinions from all sides of the debate.

The manufacturer

PTC Therapeutics, which markets Translarna

We are a small biopharmaceutical company. We have spent over $500 million on the discovery, development and commercialisation of Translarna, our first product. Our investment has been a high risk one, with no guarantee of success as DMD was an untreated disease and Translarna a new chemical entity with a new mode of action, which enhanced the challenges of achieving successful development. In addition, we anticipate we will spend $75 to $100 million more in on-going clinical research and registry commitments.

Like other treatments for very rare diseases, the cost of Translarna is driven by the high cost of developing a drug for a very small number of patients. Patients with rare diseases have an equal right to be treated, but without the incentive of an adequate return, it is impossible for a pharmaceutical company to develop, manufacture and commercially supply drugs that will treat only a small number of patients suffering from very rare conditions.

Translarna was granted marketing authorisation by the European Commission on 31st July 2014. Since then, and despite strong support from patients and the clinician community, there has been no access to reimbursed treatment for boys living with this condition in the UK. This is in strong contrast to patients living in other parts of Europe, where Translarna has been available from as early as May 2014. PTC Therapeutics is committed to working with NICE and NHS England to make sure that we provide them with the information needed to release funding for Translarna.

The health economist

Carol Longson is health technology evaluation centre director at NICE, and leads the drug assessment team

[There is an] ethical dilemma, putting it in the context of the patient today versus the patient in the future; we have to give access today but make sure we have an environment that allows patients in the future to have access [in the future]. Actually, what NICE does is not about now and the future, but about making sure there is a fair system for all patients to have equitable access to new drugs, new treatments and to affordable healthcare. So whilst those decisions are incredibly difficult, they are about trying to get the best for all citizens that use our NHS. So it’s difficult, yes, but important, absolutely.

In the UK, and certainly in England, we have a signal about the value of the new cancer drugs as close to their entry to the market as possible, which I think is a really important thing to do. I don’t know if that exists at that point in every country in Europe, but I think it is something that all countries should aspire to: getting those signals about the value of new medicines, and new cancer medicines in particular, as soon as they’re reaching the market. Systems need to gear up to be as timely as possible with these decisions. The one thing that no healthcare system, and definitely no patient has, is time. So that timely decision is key.

The mother of a child in a clinical trial 

Kathy Wedell, mother to Isaac who currently receiving treatment with Translarna as part of a clinical trial

Why should Translarna get funding? Because it works: the Phase III trial for Translarna shows a statistically significant benefit, as do the Phase IIb and Phase III trial results combined. This translates into children walking who would otherwise be in wheelchairs, which in turn translates into longer lives for these children – our children.

Translarna increases stamina, which means kids like my son can do things other 11 year olds take for granted: like managing a week at school as well as going to an after-school club and going swimming. He can get out and enjoy life and have opportunities to learn skills and make friends, as every young person should.

Translarna buys time for our children, while additional DMD drugs are being developed and trialled. Translarna is the first to be approved of a number of promising drugs for DMD. Together these drugs have the potential to turn DMD into a manageable condition, like diabetes (which used to be fatal). 

DMD is expensive to manage. As well as treating medical complications like scoliosis, you need expensive equipment and 24/7 carers. If we in the UK are prepared to invest in new drugs to prevent the progression of DMD, these costs would significantly reduce. It’s a false economy to fund primary care rather than specialist treatments. We need both. In the case of DMD, investing in specialist treatments will reduce primary care costs.

Funding Translarna and future approved genetic treatments brings research investment to the UK economy. In the UK we need to invest in innovative genetic treatments, otherwise pharmaceutical companies will take their research elsewhere. 

The proof of principle of Translarna helps develop treatments for other genetic conditions too. There is a revolution going on in genetic medicine. If the UK government simply refuses to fund new genetic medicines, this country won’t be a leader in genetic innovation, it will be left behind.

Families of children without access to treatment

Sue Barnley’s seven-year-old son, Harry, was diagnosed with Duchenne Muscular Dystrophy June 2013

We know Translarna isn’t a wonder drug, but if Harry could have Translarna, this would keep him mobile for a couple of extra years, by which time there could be another drug on the horizon.

The process we find ourselves in, waiting to get this vital drug for our son, is frustrating, to say the very least. There has to be some progress in getting rare disease drugs through these processes quicker. The related costs of research and development must be looked at, so price does not become a consistent barrier in gaining access to this and other vitally important drugs.

We simply don’t have the time to wait whilst even more consultations take place to discuss costs. If cost is too great a barrier to rare disease drugs making it to the market, then everyone loses out: including the drug companies. Our greatest hope is a treatment that could save our son’s life, and with therapies on the horizon, buying time could make the difference for Harry.

It’s unethical to use children in the UK to research drugs which are proven to work, and then deny them treatment after the trial has finished. Translarna is already available to children in other countries. At the moment, there is no other effective treatment: Translarna is all we’ve got.

Ruth Le Gal has a ten-year-old son with Duchenne muscular dystrophy, Leo

Duchenne Muscular dystrophy is a devastating and horrific illness.  Many families are torn apart when a child is diagnosed. Today, Duchenne parents endure the extra agony of knowing that life-changing medications are on the horizon, but are not yet available for their child outside of clinical trials.

For the vast majority of children with Duchenne who are not able to join a clinical trial, the future is bleak. They will likely die before the age of 30, having lived through years of pain and suffering, all the while knowing that the medicines that could help them are just out of reach. 

Translarna is our miracle drug, and though I can’t really put a price on that, but I do know that there is no need for the medication to be so ridiculously expensive. Nor is there any need for the process of getting a medication to market to be so ludicrously slow and complicated. Regulators insist on years and years of research and clinical trials before they will even consider an application for marketing approval. Common sense would say: ‘These kids are dying, we know the drugs are safe, let’s get the drugs to the kids who need them as quickly and as cheaply as possible.’  

But the system, as it currently exists, makes important medical breakthroughs almost completely impossible. Even when new medications do make it to the marketplace; they are shockingly expensive due to the endless years of R&D that have gone into producing them. 

We do have to question a system that has almost completely stamped out our ability to make medical progress. New and effective treatments are desperately needed for all kinds of devastating diseases. Translarna is one of those treatments, and it is a medication that will make a huge difference to the lives of many people affected by Duchenne muscular dystrophy – if they are allowed to take it.

The drug pricing researcher 

Dr Igho Onakpoya, from the Centre for Evidence-Based Medicine at the University of Oxford

Our concern is that the prices are expensive, and there’s no way to gauge whether their effectiveness provides good value for money. While manufacturers claim that they spend a lot of funds for research and development research indicates that drug companies spend only 1.3% of their revenue on basic research.

The factors reported to influence their prices includes R&D costs, clinical effectiveness, drug quality and disease prevalence. But we do not know if the balance of benefit-to-harm is taken into consideration when setting the prices. There is no evidence for a correlation between the price of an ultra-orphan drug and its clinical effectiveness, and this is why we are advocating for a more transparent process for determining their costs.

You expect higher costs with decreased prevalence, and this is what we found for all orphan diseases. However if you remove the ultra-orphan drugs, you would no longer observe the trend. You would also expect a similar trend for the ultra-orphan drugs if they are analysed separately; however, the reverse was the case. The benefit-to-harm balance should be taken into consideration when setting prices for these drugs

The patient charity 

Dr Diana Ribeiro, director of research at the charity Action Duchenne

The costs of research and development are high for very rare disease, and DMD. These are small patient populations – Duchenne Muscular Dystrophy affects between eight and 13 boys in the UK every year. Some drugs are mutation-specific, or licensed only for use in certain age groups, and as the patient groups are even smaller. From a commercial standpoint these small groups are a very high cost.

One good thing in the UK is the clinical trial set-up; the MHRA has quite a streamlined process, whereas in other countries it’s not so streamlined. But the process for each country is very different – for example in France gaining ethical approval is generally very long and complex, and in the UK there is an overly robust health technology appraisal process I would say, compared to other countries.

It’s important for companies to start thinking about engaging patient groups and stakeholders about the design early. Think about designing a trial in the best possible way to get the best possible outcomes, and ask ‘how can we design this trial to understand the disease’s natural history better?’ That might mean working on biomarkers together with other companies in a non-competitive space; designing arms of trials in different age ranges in order to have a bigger therapeutic range, or thinking laterally about adaptive trial design.

This helps companies, too; if you have really robust pre-clinical data and promising Phase I trials results, then if you have really well-designed trials later on there’s no reason why you can’t apply for accelerated or conditional approval, with robust data to prove a drug has clinically meaningful benefits to patients.

We’re starting to see that happen but there’s still more to do. PTC Therapeutics was the first to really invest in this space; they pioneered a lot of the research and validated the endpoints that we now use routinely for DMD, like the six minute walk test. We have to commend PTC for trying to push this through the reimbursement process in the UK. Translarna was originally submitted for conditional approval in May 2014, and people with DMD are still waiting to access it. All the time they wait, they may lose their ability to walk and so will not be eligible to start treatment, through no fault of their own. We can’t delay this decision any longer.

Where do you stand on the ultra-orphan drug debate? Tweet us your comments @Pharmafocus using the hashtag #PFdebate