Speech to CF Trust Scientific Conference 2013

29 April 2013 at The Wellcome Trust, London.

"Good evening, everyone. It’s an honour to be able to speak to you tonight. It’s a bit overwhelming actually. I feel a bit like a kid speaking to a room full of Father Christmases.

I want you all to imagine – you can close your eyes if you like - I want each of you to imagine you’re in a little wooden boat floating in the middle of the ocean. As you bob up and down, you feel the sun on your back, you can hear the distant sound of birds and you can smell the sea air. Sounds pretty nice. But there’s a problem. The boat is full of holes and water is gushing in. There are sharks. All you have (to bale out the water) is a tea spoon. You spend most of your time baling with your tea spoon trying to stay afloat. You do it all day. You go to sleep, you wake up in a boat full of water and you start baling again. It is exhausting and relentless. You need a bigger spoon. Better yet, you need to find a way to plug the holes. That’s what CF feels like to me.  It’s a fight against drowning in my own mucus.

I was diagnosed in 1978 at the age of 3. When I was 14 my consultant told me I’d probably need a heart and lung transplant in my early twenties and that I’d be lucky to live beyond 25. This [Spoon 1] was standard of care in those days. Well my heart and lungs are still original and I’m still here at 37. During that time, we’ve seen the development of better spoons - nebulised antibiotics like TOBI [Spoon 2], mucus busting therapies like Pulmozyme and Hypertonic Saline; and more effective airway clearance techniques [Spoon 3]. These all resulted from research and I might not be here without them. I want this [Spoon 4] but I have this [Spoon 3]. Kalydeco is a bit different – it’s plugging holes - but I’ll come on to that.

New treatments are exciting and important but, actually, I think it’s just as important to develop better tools to manage symptoms and figure out how to use the tools we already have in a more effective way. 

So I want to talk about three things: the therapeutic portfolio, clinical trials and adherence.

THERAPEUTIC PORTFOLIO

Vertex’s new drug Kalydeco is a small molecule with big implications. This little blue pill is changing the lives of the 4% of CF patients with the G55-1D mutation. Trials to see if Kalydeco works for other similar mutations are underway. Phase 2 data released by Vertex on April 18th, in a press release, has bolstered hopes that Kalydeco might work in combination with various other small molecules to treat a much broader range of CF patients including people like me with the most common delta F508 mutation.

This is incredible – when I read the blogs and hear the stories of people on Kalydeco – it is mind-blowing. It brings a tear to my eye. But there’s a long way to go from Kalydeco to a Kalydeco-like therapy for all 1,800 mutations and it is important to remember that, even for G55-1Ds, Kalydeco is not a cure. These people still have CF.

They still need to do all their other treatments. They still have chronic infections and exacerbations that mean they need IVs - but not as often. They are significantly better, able to do more stuff without getting breathless, put on proper weight, bounce back faster from exacerbations and generally far more resilient. Those on Kalydeco seem able to shake off a cold without it turning into an exacerbation – in other words two weeks in hospital becomes 2 days off work. I hear about patients with G55-1D who’ve come off the transplant list or who no longer need a wheelchair or oxygen therapy. They can go back to work or perhaps go on holiday. Maybe their parents no longer need to act as such full-time carers so they can go back to work or have a more normal life too. These patients are able to think about and plan for the future in an entirely new way. The trajectory of their disease has changed. It is hard to explain because the way CF affects patients and families is so complex - and maybe we need to find better ways of articulating the true value of these medicines - but this is a profound leap forward and it is exciting to think the same approach may help those with other mutations.

For young children whose lungs and other organs are not yet damaged, drugs like Kalydeco could be very close to a cure. For older ones whose organs have been damaged, Kalydeco might freeze the disease but it won’t reverse damage already done. So even if there was a Kalydeco-like treatment for all mutations, symptom-management tools will still be needed. In fact, they may well be needed more than ever because people with CF will be living longer. 

CF is a complex disease and it seems likely that complex combinations of small molecules and other kinds of therapies will be needed. Lots of money is going into small molecule CFTR modulators. As a patient, I worry we are putting all our eggs in one basket. It may not work. It may half work. I think it’s vital for the CF community to nurture some alternative approaches and facilitate some alternative science. I think we need to hedge our bets.

The CF Trust has always been committed to research and I think this commitment is more important now than ever before. Of course, the Trust established and funded the Gene Therapy Consortium and this is pioneering new techniques. While even this is not a “cure” as such it may turn out to be just as important as small molecules or more important. This would not have been possible without the Trust’s funding and the tenacity of those involved. I hope the Trust can continue to support this programme as part of a broader portfolio.

It’s essential that the CF Trust works in conjunction with the CF Foundation and others to achieve a diversified portfolio of therapeutic options. We need to go after better spoons - more effective symptom-management tools (particularly those which can reduce inflammation or neutralise Pseudomonas and other lethal bugs) – as well as looking for new ways to rescue chloride channel function - to plug the holes.

CLINICAL TRIALS

In the UK, about 10% of CF patients have participated in a clinical trial. We need to do more. We make it far too difficult for sponsors to do trials. We need to make it easier because we’re all losing out.

Studies show that simply taking part in a trial can improve a patient’s health and that is irrespective of whether they receive the active drug or placebo; and irrespective of whether the trial has a positive or a negative result. It is not just about being an altruistic guinea pig, it’s about direct benefits (for patients, clinicians and hospitals) and establishing a more positive culture that forces everyone to raise their game and not to settle.

This means making sure that, when there is a new drug, our patients have the opportunity to take part in clinical trials but it also means doing more trials to make sure we are using the tools we already have as effectively as we can.

Trials, funded by the CF Trust, like the TOPIC study on once vs three times a day aminoglycosides, have resulted in significant improvements in care. In some cases they have allowed treatments to be simplified and ineffective ones to be stopped. These kinds of trials are really important and we need to do more.

It also makes sense to get patients and parents involved in clinical research at the design stage. After all, clinicians only see patients and collect data when the patient comes to the clinic - or in hospital. It is the patients and their families who live with CF day-in/day-out. We are the only ones with a 360 degree view. Why can’t we use this experience, and data collected at home, systematically to inform clinical trials, and clinical practice more generally, to make sure we’re asking the right questions and working towards the outcomes that are most relevant to patients in their daily lives? Internet technology has made this easy to do and, if our aim is to improve real world outcomes, I think we have no choice but to embrace it. That’s why I’m really excited by initiatives like CFUnite (backed by The Wellcome Trust), Cochrane and the James Lind Alliance; and the CF Trust’s commitment today to do more to facilitate patient involvement in this more strategic aspect of clinical trials.   

ADHERENCE

This is a big deal and we need to talk about it more. One of the most challenging aspects of having CF, for me, is the heavy burden of daily treatment. Every day I take about 40 pills, 7 nebulisers, a saline nasal rinse, 4 inhalers and do 2 or 3 injections, blood sugar tests and two sessions of self-administered physio. I spend a lot of time washing and sterilising nebuliser equipment. All this takes 3 hours on a good day and up to 4 hours when I am less well. This is my normal. When I get an exacerbation I typically need a 14 day course of hospitalised IV antibiotics. This tends to happen 2 or 3 times a year. I am lucky, for many it is much worse.

So CF adherence is not just popping pills - this is real work, it is difficult and it can be exhausting. You can never take a day off. Some of the treatments are unpleasant - they require a lot of effort and willpower. It becomes much harder to get all your treatments done, and it takes longer, when you’re not feeling so well which is, of course, exactly when you need them most. It is easy to feel overwhelmed with treatments. It’s hard to find a balance. It is hard to create reliable windows for work, family and friends; and for all the other things you have to do to get by in life. 

So we need to find ways to reduce the burden of treatment. Something which saves an hour a day and can be done anywhere is going to have a dramatic impact on quality of life and, I think, adherence. Clearly there is a link between poor adherence and hospitalisation. We do too much fire-fighting and we need to focus more on prevention. We need to recognise the value of prevention.

It may mean simplifying treatments; developing a pill or inhaler to replace a nebuliser (more things like Bronchitol, TOBI Podhaler and Colobreathe); or more creative things, perhaps bringing in some sports psychology techniques; or web-based platforms or smartphone apps that help to manage and motivate or allow people to track their progress or even just talk to someone who’s in the same situation (because don’t forget we can’t meet up due to the risk of cross-infection). This kind of thing could help people live a fuller life, stay healthier, reduce exacerbations and keep them out of hospital. This is worth doing, big time, and I think it’s great that the Trust has highlighted adherence and reducing the overall burden of treatment as key research priorities. It’s a simple relation: reduce the burden, improve adherence; reduce exacerbations.

So here’s what I want you to take away:

The CF Foundation and Vertex have blazed a regulatory trail, given us new tools, shown Pharma that CF is a real market, shown everyone what can be achieved when Pharma works with a patient group. They have delivered a transformative drug for a very small sub-population of CF. I see this as injecting oxygen into the CF research environment. It’s woken people up. It’s like our Big Bang. We need to capitalise. We need to use it to our advantage. That’s why the Trust’s new strategy launch is perfectly timed. It provides a great scientific map but it also sends a clear signal of the Trust’s intent to collaborate with new partners, in new ways and to make resources available to help everyone in the CF community convert their ideas into new therapeutic tools.

And as Yoda said: “do or do not, there is no try".

Thank you." 

EURORDIS: Sounds Like a Plan, Yann!

Last week I was invited by Yann Le Cam, CEO of EURORDIS, to some important rare disease policy events in Brussels. These events brought together a very passionate community of people including EC officials, MEPs, representatives from the European Medicines Agency, national officials, Pharma, researchers, patient groups and others. All these people are working on ways to improve access to orphan medicines and better treatment options for people in the EU with rare diseases.  I was really impressed with the way people from across the spectrum were all working together and making a difference. It felt like there was a great sense of camaraderie and real solidarity with everyone uniting against "the system" which I found surprising and inspiring. I found the experience genuinely moving and it was great to have the chance to meet so many smart people working in such an important and relevant area. 

Based on my recent experience of the issues with getting Vertex’s Kalydeco to patients in need, I was keen to go along and find out what is being done at the EU level to address some of the problems. As I see it, there are problems at almost every point of the drug development cycle from clinical trial design and marketing authorisation through to payers' cost-effectiveness reviews and post-marketing data collection. 

Why does it take so long after EMA Marketing Authorisation for drugs to reach patients? Why aren’t new treatments compared to current standard of care? Why wasn’t Bronchitol tested against hypertonic saline? Why do regulators insist new antibiotics are tested against placebo when hardly anyone with CF is not on at least one antibiotic? Why don’t NICE and other payers take proper account of quality of life, adherence and the effects of a new treatment on patients’ family members? Why don’t people get angry about their governments wasting hundreds of millions on branded drugs when therapeutically-equivalent, lower-cost generics will do the same job? Why do people object to paying high prices for genuine innovation? Why does it cost so much to bring a new medicine to market? These sorts of issues are common to all rare diseases and we stand a better chance of changing things if Pharma, patient groups, clinicians and others work together as everyone’s interest is served by improving access to rare disease medicines and the real problem is often government or State-controlled healthcare providers and health insurance systems.

A rare disease is any disease that affects a small percentage of the population. The European Union considers a disease as rare when it affects fewer than 1 in 2,000 citizens. Rare diseases are frequently chronic, progressive, degenerative and often life-threatening. Over 6,000 different rare diseases have been identified to date and 30 million people in Europe are affected. Rare diseases are also known as orphan diseases because they have traditionally been abandoned by governments and drug companies who cannot justify the investment in researching new treatments for such small groups of people. Despite their vast overall number, rare disease patients frequently lack access to diagnosis, treatment and the benefits of research.

EURORDIS is a non-governmental patient-driven alliance of patient organisations and individuals active in the field of rare diseases, dedicated to improving the quality of life of all people living with rare diseases in Europe. EURORDIS represents 561 rare disease organisations in 51 countries (including 25 EU Member States) covering more than 4,000 rare diseases.

In terms of EU rare disease policy, EURORDIS is clearly the prime mover and they have built a collaborative community of key stakeholders to shape and implement policy at the highest level. Yann Le Cam and his team have built this community and really drive it forward in a way that benefits patients while keeping key stakeholders on board. That is a wonderful thing. Overall I had a fascinating time over the Tuesday and Wednesday in Brussels and I hope to be able to build on my relationship with EURORDIS and the rare disease community as a whole.

The Big Picture 

There seems to be a realisation, in this community at least, that science is progressing in such a way that medicine is increasingly able to address whole new areas of disease and treatments are becoming more personalised. Treatments which only work on a small number of people are very expensive. We are moving into a world of ultra-orphan indications. It is clear that we will not be able to afford to pay for everything. So everyone is thinking very hard about what is funded and how to change the way the system is funded to maximise the benefit. In particular, there is increasing concern about the fact healthcare in the EU is largely “pay-as-you-go”/ unfunded in contrast to pensions which are generally funded, albeit poorly. Economists all agree that healthcare spending is going to become a far more significant proportion of total public expenditure in the future. Social/welfare commitments are seen as fundamental to the EU model so we had better find a way of paying for it! There is an increasing realisation that better healthcare would allow people to work more and for longer so spending in health will take pressure off social/welfare budgets. There should be more “fluidity” between health and welfare budgets. People, in this community at least, are starting to think about this in a more integrated way. 

It turns out that Pharma may be prepared to negotiate caps on general pharmaceutical budgets if it means more spending on orphan products. This is seen as a “re-distribution towards innovation” and something to be welcomed.  Similarly, everyone involved in the rare disease community should help to identify and highlight inefficiencies / waste in healthcare systems so as to force their governments to make savings where possible and create a greater degree of “headroom for innovation”.

There was a lot of talk of the need to mobilise “civil society” to force change. While EURORDIS is seen as a very effective voice for rare diseases in the Brussels village, there is an urgent requirement to mobilise local patient groups and other grass roots activity.

Tuesday 26^th

Seminar on Faster Access to Medicines for Rare Disease Patients: “The Transparency Directive”

Why is it important? 

This measure aims to speed up the process of Health Technology Assessments and Pricing and Reimbursement decisions. It aims to remove duplication of work between the EMA and HTAs in individual countries and to bring greater transparency.

There is already a transparency directive in place but it is “soft” and poorly implemented and it is no longer compatible with the dynamics of the pharmaceutical market, particularly in relation to generics. The “new” Transparency Directive aims to bring greater transparency to the Pricing & Reimbursement (“P&R”) procedures in each Member State (e.g. the HTA reviews carried out by groups equivalent to NICE). According to EU officials, it is widely known that officials in several Member States are currently bribed to delay the entry of generics. A major objective is to stamp out corruption and save money for payers, particularly by accelerating generic substitution.  It is estimated that “late” transition to generics costs the EU more than €1bn per annum. Saving money for healthcare budgets in this way would release funds for the more expensive orphan drugs that will be an increasing feature of the market going forward.

The three elements are:

1. Time Limits: 180 days hard deadline for all P&R decisions but much shorter (30 days) for generics;

2. Statement of Reasons: national authorities must provide verifiable grounds for decisions; and

3. Remedies: legal remedies to be made available to applicants in the event of adverse decision.

The Directive also seeks to bring a clear separation of the Marketing Authorisation (MA) process and P&R processes in Member States and to eliminate duplication of work as far as possible given the fundamental rights of Member States to organise and fund their own healthcare systems (Article 168/7 Treaty on the Functioning of the European Union). The Directive aims to stop competent authorities in Member States from re-assessing aspects that have already been thoroughly assessed by the EMA as part of the MA process; to stop them “re-opening the science” or even re-evaluating the orphan designation.

Richard BergstrÖm, Director General of the European Federation of Pharmaceutical Industries and Associations (EFPIA) talked about how the pharma market had changed. Traditionally, pharma would consider their job done when their products got MA. Now there is a “4^th hurdle” – the Pricing & Reimbursement hurdle. The real issue at the moment is access to medicines and that means who is going to pay, how much and when. The Transparency Directive is a necessary and important technical/procedural measure but it does not address the key issue. He said the current system in the EU is a mess and it doesn’t work for patients, payers or Pharma. It is too fragmented and this makes it very difficult for pharma. Pharma is open to talking about price and doing deals but there is currently nobody to call. For regulatory matters it is easy, you just go to the EMA. For P&R matters, there is no place to go. There needs to be a “front door” where people can go and have a sensible discussion.

It was great to listen to Richard BergstrÖm talk. He has an ability to cut through the procedural language and bureaucratic obstacles to get to the big issues, join all the dots together and say what really matters. It is incredibly refreshing to hear such integrated thinking and, as a patient, I found it extremely encouraging. It is mad that you get  labelled as a shill for the Pharma industry if you criticise government and market inefficiency when in fact your only objective is to get medicines to patients faster and encourage Pharma to take the risk of developing new treatments. The media in the UK is extremely "tabloid" in its approach to these issues and it is very unhelpful. I always feel politicians try to deflect attention from their own failings by seeking to paint Pharma as the bad guys and the media lap this up as it plays so neatly into the anti-capitalist narrative. Why don't people get more angry about their governments wasting hundreds of millions of Euros on branded drugs when generics will do just as well? Yet we balk at paying a decent price for genuine innovation (even though the total amounts represent a fraction of the wastage elsewhere). BergstrÖm  made a strong point when he said society wanted a "tap" of new drugs but they did not want to pay for the pipeline to supply the tap. I got a powerful sense that BergstrÖm  is an agent for positive change and I wish there were more people like him. 

Antonyia Parvanova, the brilliant outspoken MEP who is sponsoring the Transparency Directive and Cristian Busoi MEP who is also instrumental in this legislation, talked about an ambition to build a common market in pharmaceutical products - it is not one of the product categories for which a common market has been established under EU law. They see the Transparency Directive as critical to bringing clarity and transparency to the HTA/reimbursement process, eliminating corruption and saving substantial amounts of money by accelerating the transition to generics and getting new medicines to market faster. 

The emphasis is on showing the value / savings available to all parties rather than sanctions. Payers will save substantial amounts of money, pharma will be better able to invest and patients will get better access to treatments. 

There is a great deal of work going on around the total burden of rare diseases (i.e. health, welfare and social costs) so that we can see the true value of new medicines.

In terms of broader EC policy, Jaroslaw Waligora (Policy Officer, DG Health and Consumers) talked about the importance of patient registries in rare diseases. These are seen as crucial to effective research going forward. Currently there are hundreds of separate rare disease registries around the EU, not compatible with each other and hard to access. They need to be easier to aggregate and analyse. There are some initiatives that are helping (e.g. EPIRAR, EJA Joint Action, RD Connect) and there is a new EC initiative to establish a common platform (IT tools, software). This aims to bring greater compatibility, enable better data analysis and facilitate clinical trials. The disease-specific “European Reference Networks” made up of “Centres of Expertise” are an important part of this too.

Several audience members raised concerns about the Data Protection Directive and made the point that it raises barriers to patient registries which are so crucial to rare disease research. EURORDIS has released a clear statement on this issue (in defence of patient registries) and others with an interest in rare disease research should voice their concerns too. This issue is particularly important to CF and if patient registries are made impossible to operate as a result of the Data Protection Directive, as proposed, it will be a serious barrier to the development of new treatments.

There were about 100 people in the room including EC officials, MEPs, other officials from Member States, people from EMA, Eurordis, Pharma, Researchers and Patient Groups. The meeting was broadcast live over the web.

EURORDIS “Black Pearl” Gala Dinner 2013

This was a fundraising event with around 300 people in attendance. The aim was to explain the achievements to date of EURORDIS and the rare disease community but also to highlight the massive challenges ahead and the need for greater cross-border co-operation. They played some incredibly moving videos showing real life stories of people with rare diseases. Awards were presented to certain individuals and companies who had made a significant difference to the lives of those with rare diseases.

EURORDIS Awards 2013

Policy Maker Award: FranÇoise Grossetête, MEP

European Rare Disease Leadership Award: Dr Ruxandra Draghia-Akli

Volunteer Award: Lesley Greene

Scientific Award: Dr Ségolène Ayme

Patient Organisation Award: AlstrÖm UK

Company Awards: Celgene, Prosensa, Genzyme

Media Award: Andrew Jack

Lifetime Achievement Award: Former First Lady of Germany, Mrs Eva Luise KÖhler

I sat next to the wonderful Avril Daly who is a Board Member of EURORDIS, Head of Public Affairs for the Irish Charity Fighting Blindness and a leading figure in the Irish rare disease community. We talked about CF in Ireland and the work of EURORDIS. Avril’s energy and commitment is incredible and she is a true inspiration. Others on my table were Ken O’Reilly and others from Biogen Idec and Axel Van Der Mersch who is a major funder of EURORDIS. 

Wednesday 27^th 

EURORDIS “Round Table of Companies”:  Improving Access to Orphan Medicinal Products

Yann Le Cam gave a presentation summarising the latest policy initiatives and emerging thinking around rare diseases in Europe. Key themes included:

Evidence of EMA flexibility: when it comes to new orphan drugs

Adaptive/Progressive Licensing: the idea that you could start off with a licence in respect of a small population after a small trial but then gather more data and do progressively larger studies to build the evidence base and get a progressively broader licence over time. This would mean a constant cycle of data and a need for regulators and payers to become more comfortable making decisions on less evidence (at least initially)

Progressive Pricing: as the indication expands, pricing comes down.

Clinical Trials: trials need to anticipate the need for much better therapeutic value demonstration (HTA).

Payers: will always have their own views but they should not re-open the science as assessed by EMA.

Marketing Authorisation: EMA and others should share more information, more quickly with HTAs and Payers.

Value: what is value in orphan drugs? Greater focus on value-added for patients, physicians, payers, pharma, society as a whole.

FDA/EMA collaboration: move towards stronger collaboration in terms of scientific advice, protocol assistance, trial design, regulatory processes.

The two key initiatives being sponsored by the European Commission, namely CAVOMP and MOCA, are designed to improve access to orphan medicines and treatments for rare diseases. The emphasis is on creating a more efficient market and creating real value for all parties rather than thinking about the issues in terms of Corporate Social Responsibility which has been shown to be ineffective.

“CAVOMP”: Improving Informed Decisions Based on the Clinical Added Value of Orphan Medicinal Products

This is essentially a proposed methodology for removing duplication of work and sharing information more effectively (among regulators, national competent authorities, HTAs, payers, patient groups, clinicians, et al.) through the whole lifecycle of a new drug (Orphan Designation – Protocol Assistance – CHMP Opinion – Marketing Authorisation – HTA – Reimbursement). A key part of this is a permanent co-operation mechanism for HTAs building on the EUnetHTA. EUnetHTA is a network of government appointed organisations (from EU Member States, EEA and Accession countries) and a large number of relevant regional agencies and non-for-profit organisations that produce or contribute to HTA in Europe. See: http://www.eunethta.eu/.

EUCERD made a formal recommendation to the EC in September 2012 and the EC is considering how to implement it and incorporate it into future policy.

“MOCA”: Mechanism of Coordinated Access to Orphan Medicinal Products

The objective of this work is to find common, non-regulatory approaches to ensure better, timely and equitable access to orphan medicines after their marketing authorisation.

A key aspect is better identifying the true value of new orphan drugs and moving to a pricing system based on value rather than cost. While it is acknowledged that payers will want visibility on cost construction as a quid pro quo for market exclusivity, there is a need to move towards a more rational value-based approach. This is called the Transparent Value Framework (“TVF”).

The main criteria under discussion as part of the TVF are:

a) Availability of alternative treatments / unmet medical need;

b) Relative effectiveness (clinical improvement, QoL, etc. vs side-effects) and societal impact;

c) Response rate; and

d) Certainty of evidence.

I took part in a "breakout” session to talk about this and I raised some points about the burden of treatment in diseases like CF: a) that new treatments which reduce the burden of treatment and which are likely to have a positive impact on adherence (with potential associated savings for payers) should be valued more highly; and (b) that it is important for clinical trials to be designed in a way that provides HTA’s (and clinicians/patients) with the information they need to assess the benefits of new treatments in comparison to current standard of care as it exists in reality rather than as perceived by the FDA / EMA. These points were well received, people felt they were relevant to rare diseases generally and a number of people came up to me afterwards to say what a useful discussion it was and that they were keen to talk more.  

The final report is due in March 2013 and the EC will consider how best to implement the proposals and how to factor them into future policy.

Research also shows a great inequality of access to medicines amongst Member States (particularly in the countries suffering financial hardship) and major inequalities in pricing. For example, the Czech Republic pays more for medicines than the UK.  As a result of “reference pricing” where certain countries in the EU insist on paying the same as certain other countries in the EU system (even if they are in financial distress and benefiting from special deals with Pharma), there is now a tendency for Pharma to refuse to supply certain markets so as to protect pricing power in other more important markets. There are discussions going on as part of the MOCA process around mechanisms to improve equality in these areas. “Differential Pricing” is seen by all (including Pharma) as a viable option. This would involve countries in the EU with lower GDP/capita being charged lower prices.

The other topic of the day was “National Measures”. Each Member State has been told to develop a national plan for the treatment of rare diseases and this includes improving access to new orphan medicines. A few countries have implemented their plans, notably France, some have developed but not yet implemented (e.g. UK) and others are still developing.

Another topic discussed at various points was the concept of the “right to reimbursement” and free movement within the EU. In other words, rare disease patients resident in one country should be free to travel to other countries in the EU and be entitled to the same level of treatment. This is seen as an important long term objective. There are increasingly cases of people travelling or even moving to places where they can get treatment which is not available in their home markets and even cases where parents of children with rare diseases cannot afford to move to a new country so they put the child up for adoption to go to families living in countries where treatment is available. France absorbs a lot of patients in this way and it is seen as a major issue in terms of equality and sustainability.

Eurordis will be making all the presentations and other materials available on their website in due course. A huge amount of ground was covered in much more detail than I go into here but I hope this gives a flavour of everything.

This is a great community of people. I had expected it to be a lot of hot air and grand talk of unrealistic ambitions but I was surprised at the level of camaraderie and the way people were cutting through to practical issues. It was also very striking how everyone from the EC, MEPs, Pharma and Patient Groups were genuinely collaborating with a shared goal of getting medicines to patients faster. It was quite inspiring and definitely something to build on. 

In addition to the brilliant team at EURORDIS, I met people from the European Commission, European Medicines Agency’s Committee for Orphan Medicinal Products, Fighting Blindness, Alliances Maladies Rare, the European Network for Ichthyosis, the Belgian National Health Insurance System and the following Pharma companies: PTC Therapeutics, Pfizer, Genzyme, BioMarin Europe, Bioden Idec and Celgene.

I attended these events as a representative of the CF Trust and I would like to thank them for part-funding my trip.

Bronchitol™ - FDA Webcast

January 30, 2013 Meeting of FDA Pulmonary-Allergy Drugs Advisory Committee (PADAC)

Review of New Drug Application for Bronchitol (dry powder mannitol)
Sponsor: Pharmaxis
Decision: Negative Recommendation

This meeting was live webcast and the recording has recently been made available by the FDA.

Click on the links below to access the recordings or additional materials.

Recording of the Open Public Hearing
Highly recommended for anyone with a personal or professional interest in CF. This section is not part of the formal evidence but includes short speeches by people with CF, specialist CF physicians and senior representatives from the CF Foundation and CFRI designed to give the committee additional context and a patient perspective.

Meeting Agenda

Briefing Materials

Presentation Materials

Full webcast information

Additional Information

Meeting Minutes

I wrote a commentary on this meeting and posted it here on February 10, 2013:
Bronchitol: Power to the Patient

And this follow-up post on the same day:
Bronchitol: Future Prospects in the US

Bronchitol™: Future Prospects in the US

This is a follow-up to the detailed commentary on the decision - Bronchitol: Power to the Patient

Several of the FDA committee members seemed to want to recommend Bronchitol™ because they could see it would be a valuable treatment option for some patients. However, they felt the Company had not provided them with sufficient evidence to safely predict which patients would benefit from the drug in a way that justified the risks. Some of the committee members said they might be more comfortable if it was restricted to CF adults with FEV1 of 40-70% rather than anyone aged 6 or over.

As for the drug's future prospects in the US, Pharmaxis announced the FDA decision a couple of hours after it was made on 30 January 2013 and then immediately followed by announcing a $40m capital raise to support the continued development and commercialisation of Bronchitol™ for CF in the EU and US. Clearly this implies the Company intend to try again with the FDA and, perhaps, that they were expecting a negative initial decision. 

Given Bronchitol™ is approved and marketed in other jurisdictions, it looks like Pharmaxis have a revenue stream for the drug that will allow them to sit on it for a while and look for patterns in usage of the drug in the EU and Australia and perhaps set up another trial to give them a better idea of the type of patients that benefit. With or without another study, based on the existing body of data and clinical experience outside the US, it seems likely that Pharmaxis will re-approach the FDA in the future with a restricted indication (e.g. excluding patients under the age of 18 and perhaps with a 40% threshold FEV1) and an enhanced monitoring/risk minimisation plan in line with the EU approval. 

You can access the meeting materials and recorded webcast here: PADAC Materials and Webcast

Bronchitol™: Power to the Patient

I recently watched the live webcast of the FDA’s meeting where they decided not to approve Bronchitol for Cystic Fibrosis in the US. It was a real eye-opener and I thought it would be worth summarising the decision and providing some commentary from the patient perspective. It made me think about who should be weighing the risks and benefits of new medicines in cases where patients are experts with specialist doctors and treatment options can have major implications on their lives. There were some fantastic presentations and speeches by doctors and other prominent people in the CF community and I hope everyone with a personal or professional interest in CF has the chance to watch them when the footage is eventually put on the FDA’s website.

The FDA’s Pulmonary-Allergy Drugs Advisory Committee (“PADAC”) met on 30 January 2013 to discuss the new drug application for dry powder mannitol (trade name Bronchitol™) for oral inhalation, developed by Pharmaxis, for CF patients aged 6 years and older. Bronchitol™ is inhaled with a hand-held, breath activated device. It acts by inducing an influx of water into the airway, improving hydration of airway secretions, and increasing mucus clearance by making it less thick and sticky and stimulating a cough.

In February 2011, Bronchitol™ achieved regulatory approval in Australia for patients with CF aged over six years. When the EMA’s CHMP initially reviewed the Bronchitol™ application in June 2011, it issued a negative recommendation on the basis the benefits had not been shown to outweigh the risks. The original indication claimed was for patients aged 6 and over but during the evaluation procedure, Pharmaxis modified this to exclude patients under the age of 18. While the aggregated clinical trial data showed a small improvement in FEV1, it was not clear if this would really be sufficient to improve patients’ condition and, on balance, it was not deemed to justify the risk of bronchospasm and haemoptysis. Pharmaxis submitted a request for re-examination on the basis of an enhanced post-marketing monitoring programme (using, among other things, the UK CF Patient Registry) and a detailed risk minimisation plan; and, in February 2012, CHMP gave a positive recommendation resulting in EU marketing authorisation for CF patients aged 18 and over from 13 April 2012.    

The PADAC were being asked to recommend Bronchitol™ for patients with CF aged 6 and over in the US. They voted unanimously that the efficacy/safety data failed to provide evidence to approve the drug.

Summary of PADAC’s Decision

Here is a summary of the reasoning behind the committee’s decision:

In one of the Phase III clinical trials, a relatively large number of people dropped out for various reasons. This meant there were some “gaps” in the data and the Company sought to resolve this by excluding the drop-outs or by using statistical techniques to impute randomised values to fill the gaps. As a result, PADAC felt some of the conclusions may have been statistically unreliable.

They felt the aggregate data from the clinical trials provided underwhelming evidence for efficacy in terms of the key FEV1 endpoint. There was some debate on whether the standard of statistical significance should be lowered in this case on the basis statistically insignificant improvements in FEV1 could still yield important benefits from a clinical perspective in addition to standard of care.  

There were concerns about safety, particularly a slightly elevated risk of bronchospasm and haemoptysis which seemed more prevalent in younger patients.

They did, however, accept that Bronchitol™ was very effective in some patients with significant improvements in terms of airway clearance, FEV1 and reduced exacerbations; and that it made a significant impact in terms of reducing the heavy burden of treatment associated with CF and materially enhancing quality of life. They saw that clinical benefits and quality of life gains are linked in real life i.e. a treatment which yields quality of life gains is more likely to get done and therefore clinical benefits are more likely to be achieved.

In addition to the data presented by the Company, there was some powerful supporting evidence from experts such as Dr Diana Bilton[1] speaking on behalf of the Company and, in the Open Public Hearing, several people from the CF community spoke about how effectively Bronchitol™ could help clear the airways, dramatically reduce the burden of treatment and improve quality of life primarily by saving approximately 40 minutes per day when substituted for comparable products such as nebulised hypertonic saline. Patients and specialist physicians also explained how important it is to make new treatment options available as CF affects people in such different ways. Different patients respond differently to standard treatments and end up with a bespoke blend of treatments that must be reviewed and adapted over time. The more treatment options that are available, the more likely it is that patients and their physicians will be able to construct a blend of treatments that will work for a given individual.

Pharmaxis acknowledged that Bronchitol™ is not suitable for all patients and that some will experience adverse reactions. However, it may not be possible to pre-define the population for whom it will be effective. They argued that specialist clinicians would, in fact, be able to manage the risks effectively and the specialist physicians in attendance firmly agreed.

The FDA was obviously uncomfortable with this approach and they closed the door. They felt it would give physicians an unsafe level of discretion. Some of the FDA committee members said something that really struck me. They said, in effect, that if the FDA approves Bronchitol™ on the basis proposed, doctors and parents will blindly force patients to take it in addition to standard of care just because is approved and that the FDA needed to protect the American people. 

This did not seem to take into account the level of expertise of those who would be prescribing the drug nor that of the patients themselves, nor did it take into account real life risk management tools (i.e. the ability to do mini-trials for individual patients, do effective monitoring and to stop the treatment at any time).

Patient Perspective

Treatments for CF require a great deal of time and effort and pose real challenges for patients trying to balance family, work, education, and other responsibilities with management of chronic disease. The typical adult patient probably spends between 2 and 3 hours per day doing all their “maintenance” treatments including oral medication, inhalers, nebulisers, airway clearance and exercise. This is work that has to be done to stay at a given level.

Typically the airways of a person with CF become colonised with at least one serious bacterial infection (e.g. Pseudomonas aeruginosa or Burkholderia cepacia complex) and this brings a vicious cycle of infection flare up (exacerbation), inflammation and scarring that results in severe lung damage and, in 90% of cases, early death in the absence of a successful transplant. The challenge is to delay the point where the lungs become colonised and, when they do, manage the infections through a maintenance treatment regime to stretch out the exacerbation cycle.

Each exacerbation requires an enhanced level of treatment, typically a 14 day course of 2 different intravenous antibiotics, additional physiotherapy and often this requires hospitalisation. An adult with CF who experiences 2 or 3 exacerbations per year would be doing well. Overall, this means a very significant amount of time is spent doing maintenance treatments and dealing with exacerbations.

As part of a maintenance treatment regime, commonly used mucolytic agents such as Pulmozyme® and hypertonic saline are similar in effect to Bronchitol™ but they are administered by nebuliser. Nebulisers like these take about 20 minutes each (including preparation and time taken to clean the nebuliser mouthpieces after each session) and they are generally done at least twice per day. A lot of people also find hypertonic saline nebulisers very unpleasant to do and there is some evidence to say that average adherence is poor. Pulmozyme® and some forms of hypertonic saline require refrigeration and they both require specialist nebuliser equipment that needs a power source. Clearly an inhaler is more convenient and portable.

In addition to being time-consuming, treatments for CF can be difficult to do and unpleasant so effective disease management requires a lot of motivation and will power. Recent research presented at the 2012 North American Cystic Fibrosis Conference[2] shows that depression is a relatively common symptom in people with CF, that there is a link between depression and non-adherence and that a lower level of adherence leads to lower FEV1 and a higher level of exacerbations.

This adherence issue is an important one and it is certainly worth drug companies developing more convenient delivery modes for treatments (i.e. inhaler versions of nebulised drugs) in order to boost adherence and bring about all the patient and payor benefits that would result from less frequent exacerbations. Leaving aside the adherence issue, the opportunity to substitute a drug like Bronchitol™ for a nebulised alternative represents an opportunity to liberate 40 minutes every day even before taking into account any additional relief that may result from a reduction in the frequency of exacerbations. For people with a relatively short life expectancy who spend significant amounts of their waking hours doing treatments, liberating 40 minutes of every day while also gaining some lung function and slowing the cycle of exacerbation (or, at least, not sacrificing anything in this respect) is a very big deal.

When Bronchitol™ was recommended for use within the NHS by NICE in October 2012, Dr Bilton stated:

“The clinical studies of Bronchitol™ showed very promising results in what is a complex therapeutic area. This new treatment has the potential to delay lung function decline in CF patients, thereby reducing the associated risks of exacerbation and mortality. Bronchitol™ brings a clear step change in efficacy and ease of use to a patient population that currently spend large amounts of time on laborious nebulised therapies. These patients will be delighted to have a new inhaled treatment option.”

At the same time, Jo Osmond, Director of Clinical Care at the Cystic Fibrosis Trust, said:

“We are very pleased with this decision from NICE, as we firmly believe that Bronchitol™ is an important addition to CF care, which will help to relieve the burden of treatment for adults with this debilitating condition”.

In terms of real life risk management, patients who fit the basic criteria may just need to try Bronchitol™ to figure out whether any benefits outweigh any side-effects in their particular case. As is common with other existing CF drugs and in line with product guidelines, the first dose of Bronchitol™ must be administered under clinical supervision to make sure the patient tolerates the drug and does not experience acute adverse symptoms. For patients who pass that test, the principal on-going risks associated with Bronchitol™ are bronchospasm and haemoptysis. These are symptoms which are relatively common for CF patients anyway so they could easily and immediately detect and report any changes and the simply stop the treatment. A sensible monitoring regime which may, in effect, resemble a mini-trial for each patient could easily be implemented. This is essentially what happens in the UK and, in reality, this is the way CF care works every day - lots of experiments, lots of feedback and continuous vigilance.

Many of the standard CF medications have what most people would see as serious side-effects and it is understood that these may need to be off-set with additional medications. In my own case, I started taking steroids with a view to recovering lung function knowing it would necessitate extra calcium supplements to fortify my bones (to counteract the additional risk of osteoporosis) and, having been in a borderline state of CF-related diabetes for a couple of years, that it would very likely move me into full diabetic territory requiring daily blood glucose monitoring and multiple daily injections of two different insulin products. In the event, it did prove to be a tipping point in terms of diabetes without delivering any observable benefit in terms of lung function. As steroid dosing varies (e.g. going up during an exacerbation and coming back down, in graduated steps, to maintenance levels afterwards) we need constantly to judge how much insulin to take in order to balance the steroid effects and control glucose levels. We also take antibiotics that carry a risk of tinnitus and loss of hearing. I have tinnitus as a result of an antibiotic I previously took. I took these decisions willingly and on a fully informed basis because anything that brings a reasonable chance of preserving the functionality and condition of my lungs outweighs a risk of damage to parts of me which are not vital. We have to be pragmatic, manage risks and make trade-offs all the time.

CF patients are generally experts on their own condition and they are treated by specialist physicians at specialist CF centers. We have to monitor ourselves, make observations and provide feedback to our specialist medical team (including respiratory doctors, physiotherapists, dieticians and others). In this way, we settle upon and regularly review the optimum blend of treatments in partnership with our medical team. In my opinion, it would be impossible to treat CF in any meaningful way without high quality feedback and an effective partnership between patient and doctor.  

Individuals attach different weights to risks and benefits and even their own risk tolerances may change over time according to their disease state and life circumstances. Perhaps there is a need for a new regulatory approach which allows individuals to have a bigger role in determining whether the benefits of a new treatment outweigh the risks in their personal context. 

These are not arguments for regulators to make specific decisions on behalf of each individual after somehow divining their unique risk tolerance. In fact, they are arguments in favour of a reduced scope of regulation which sees more decision-making authority delegated to the individual or, more accurately, the doctor-patient partnership. I believe these issues are particularly relevant to decisions about new drugs for rare diseases where the perception of benefits and the tolerance for risks are perhaps more subjective. Treatment options can have a material impact on the trajectory of the disease and quality of life.

The FDA makes its decisions based on a hypothetical average risk tolerance but there is really no such person as the average patient. It is unfortunate that patients in the US will, for now, be deprived of this important treatment option partly because the FDA committee members felt it would be a bad risk/benefit trade for a hypothetical patient that exists only in their minds.   

Fortunately, in CF and other rare disease cases, the patients themselves are often expert and working in partnership with specialist medical teams so a greater level of regulatory delegation may well be safe, appropriate and workable. As things unfold, I would urge the FDA to think of itself more as an enabler than a paternalistic gatekeeper when it comes to new drugs for rare diseases. Delegating more of the risk/benefit assessment down to the level of the individual doctor-patient partnership would leave less therapeutic opportunity on the table. 

A Broader Personal Perspective

The session was streamed live over the FDA’s website and freely accessible. I followed the presentation of the data and subsequent discussion. For me, as a patient, it was fascinating and thought-provoking. It was great to have a window into this world and directly experience how the process works. Subsequently, PADAC confirmed to me that they intend to make the recorded footage available on their website. You can read the briefing materials issued prior to the meeting on the FDA website by clicking on the link below and, when the recording is available, it will be posted on this page too:

FDA Meeting Materials and Recorded Webcast

There were some really powerful and eloquent submissions during the Open Public Hearing by people in the CF community. As a CF patient, I found these speeches extremely moving, validating and encouraging. These people chose to attend the meeting to give the FDA panel their own unique, super-informed perspectives. As a patient, it is difficult to describe how good it made me feel to hear what was said during this session. It provided very direct confirmation that there are some incredibly bright, talented and committed people, with a true understanding of the problems people with CF face every day, working so hard to help people with CF. We get to know our doctors and other specialists very well in a clinical setting but we are not really aware of all the additional work they do in terms of research and development. Even with brilliant support, CF can be a lonely struggle at times. The risk of cross-infection means we are advised not to meet others with CF. Social media is helping in this respect but that can be a two-edged sword. It is not often that I feel directly understood but, listening to these people speak, I felt not at all like a lone struggler.

The people who attended the FDA meeting and spoke so eloquently and powerfully during the Open Public Hearing included Ronnie Sharpe, Jerry Cahill, Emily Schaller and Emily Gumbine, all of whom have CF. Specialist physicians included Moira Aitken (Professor, Division of Pulmonary and Critical Care Medicine, University of Washington Medical Center), Ahmet Uluer (Director, Adult Cystic Fibrosis Program, Boston Children’s Hospital) and Michael Boyle (Director, Adult Cystic Fibrosis Program, Johns Hopkins University). Additional speakers were Carroll Jenkins (Executive Director, Cystic Fibrosis Research, Inc.) and Bruce Marshall (Vice President, Clinical Affairs, CF Foundation).

This experience made me feel energised, inspired and excited about the future of CF care. More specifically, the FDA session confirmed:

• deep FDA/medical profession understanding of CF and the real life problems that go with it;
• high-level understanding of the heavy treatment burden and the fact that this makes it difficult to build and maintain a life;
• common intent to develop additional treatment options recognising that people with CF respond differently to particular medications; and
• common intent to develop alternative modes of drug delivery in order to reduce the treatment burden on people with CF.

When the recorded version of the webcast becomes available, I encourage anyone with a personal or professional interest in CF to watch the Open Public Hearing which lasted for about an hour or, even better, watch the entire session. I am not sure when it will be made available on the FDA’s website but I urge them to get on with it. I also urge the CF Foundation, or someone else with some clout, to obtain the footage of the Open Public Hearing and put it on a website with some commentary and background information for the benefit of patients, families and others in the CF community.

Here is a link to my follow-up post: Bronchitol: Future Prospects in the US

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[1] Dr Diana Bilton is Consultant Physician and Honorary Lecturer, Department of Respiratory Medicine, Royal Brompton Hospital, London and lead investigator for the first of the Bronchitol Phase III trials.

[2]  Riekert, K.A. (October 2012), Adherence…Where’s the App for That?, Plenary Session III, NACFC 2012. Available for download here: https://www.nacfconference.org/plen.archive.html