Sunday, 10 February 2013

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:

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

[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:


  1. Oli,

    You raise some important points. And you know from my comments to David Shaywitz and Michelle Mayer that I strongly support the argument that regulators must approve things that are safe and work in at least some people, and they leave the decision as to whether to prescribe to the physician treating the individual patient in front of them, depending on the particular profile of that patient, and their individual risk tolerance.

    All that would argue that the FDA should have approved Bronchitol™.

    But some of the arguments you marshall are not not valid, and would set a dangerous precedent. The idea that "benefit which is not statistically significant (on average) may still be of clinical benefit" really cannot be tolerated. If a trial does not reach statistical significance, it has not proven that THERE IS ANY BENEFIT AT ALL, IN ANY SINGLE PATIENT. In other words, it is an absolute requirement to see enough benefit in enough people for that to reach significance before we can conclude there is ANY benefit. This is an absolute premise of the clinical trial model, and of evidence-based medicine altogether.

    Just because you and I both believe that regulators should be more willing to approve, where products are pretty safe and effective in at least some people, we cannot allow approval of medicines where the statistical basis for believing there is any benefit is in doubt. That lead us back to quackery.

    The FDA panel, rightly, pointed out weaknesses in the Bronchitol™ dataset. It could easily be argued that the company didnt do a great job of its late stage clinical development. That the company, and not the FDA, let down CF patients.

    In the end, the primacy of a statistically significant Phase 3 trial of acceptable design and quality is a gold standard for approval that we should not lightly dispense with.

    So for all the moving accounts from patients, I, at least, was not convinced that Brochitol™ should have been approved on the dataset that was presented to the FDA.

  2. This comment has been removed by a blog administrator.

  3. I also think this was a fantastically written and researched article. Regarding Sciencescanners comment about the data-set Pharmaxis presented to the FDA, I agree there are some funnies in the clinical data, but when you stand back and analyse the data peculiarities on balance its explainable. I believe the FDA statisticians and FDA Committee have adopted an extremely conservative and harsh approach to analysing the effiacacy and overstating the risk. There was a big placebo response particularly evident in the small lungs of adolocent and children, with control a 40 mg of mannitol twice daily (lower dose of the active drug). The combined studies demonstrated a 7.3% improvement in FEV1 (from patient baseline readings) which is a pretty robust improvement. This drops to 3.7% once you back out the placebo response, with one of the two studies having a p value of 5.9% and the other highly significant. Your can read more here on my blog.

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