To be or not to be (Musings on IPF and Esbriet)

Updated: 25 March 2016
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Another blog on my spouse having idiopathic pulmonary fibrosis (IPF) and its treatment with pirfenidone (Esbriet^®). See Further Reading for additional resources.

The theme is how do patients with an incurable disease make decisions when the treatment has adverse side effects that make life miserable. Who helps them?

IPF - BACKGROUND
In brief, idiopathic pulmonary fibrosis (IPF) is an incurable, chronic progressive disease typically affecting people over 65, in which the lung's normal connective tissue is replaced by scar tissue. Scar tissue forms when the body has an injury anywhere, but in IPF, for unknown reasons, the scarring (fibrosis) does not stop as it normally does. 

IPF's cause is unknown but the disease causes the lungs to become stiff and impairs their ability to function, i.e., move oxygen into the bloodstream and body tissues.

IPF has a median survival of 2-4 years from diagnosis. Most patients die within 3-5 years but some patients live much longer. See a simplified diagram of ways IPF typically progresses.

IPF - TREATMENT
Until pirfenidone (Esbriet^®)) no effective treatment existed for IPF. In clinical trials Esbriet^® was shown to decrease scarring (fibrosis formation) and the incidence of death from all causes and from IPF alone. See below for more details.

Cost: Esbriet^® was funded in the UK and elsewhere before in Canada but it now is, In Canada Esbriet^® costs provincial governments ~$43,000 CDN per patient per year.

DILEMMA
Esbriet^® gives IPF patients hope for a longer life but, to some, that comes at an incredible cost to quality of life due to side effects.

The good stuff 
Although not a cure, Esbriet^® offers the hope of maintaining lung function as measured by FVC (forced vital capacity - how much air a person can exhale during a forced breath). In IPF, FVC is a key measure of disease progression. Esbriet^® doesn't improve FCV but does slow its decline.

Esbriet^® has also has been shown to offer patients better life expectancy. For example, after one year:

• 3.5% of patients on Esbriet^® (n=22 of 278) died from all causes, versus 6.7% on placebo (n=42 of 277), a reduction of ~48%. 
• 1.1% (7 of 278) died from IPF related causes versus 3.5% (22 of 277), a reduction of ~68%.

Of course, given the type of IPF disease a patient has makes such statistics iffy at best. No one knows how an individual's IPF will progress.

The bad stuff 
Unfortunately, Esbriet^® has many side effects, also known as adverse events/reactions. It's important to recall that all drugs have side effects, ranging from harmless to severe reactions that require drug cessation.  

Also, with any drug's side effects, an individual may experience none, some, or all. A given side effect may show up immediately or only after being on the drug for awhile. Plus some side effects occur more commonly, others are rare. 

A complicating factor with side effects is that identifying them as directly related to the implicated drug can be difficult. The side effect may be due to drug interactions, a symptom of a co-existing disease, etc. 

Identification is easier if a side effect is well documented as commonly occurring and stops when the drug is stopped, even temporarily. This applies to sun sensitivity and Esbriet^® (see below).
Adverse events related to Esbriet^® include:

abdominal pain bloating gas nausea constipation diarrhea vomiting decreased appetite taste changes difficulty sleeping hot flushes headache indigestion, heartburn, or acid reflux

itchy, dry, or red skin sun sensitivity (e.g., sunburn, skin rash, blistering or peeling skin) sweating tiredness weight loss muscle or joint aches or pains Cough or hoarseness sore throat sneezing ear congestion dizziness

From my spouse's experience: 

• Suppose you cannot get proper sleep, night after night (insomnia), so you always wake up tired.

• Even when sleeping reasonably well, you're exhausted during the day.

• You have no appetite and what you eat tastes different (awful).

• You lose ~5 lbs every 10-14 days because you must force yourself to eat.

• After eating anything, you're always bloated, have a stomach pain, suffer indigestion, and feel nauseous, often gagging during meals. 

• After eating (and taking Esbriet^®), you feel dizzy for a short time.

• You alternate between diarrhea and constipation, the latter sometimes requiring extreme measures.

• Your throat is always sore and you think you're coming down with a cold but it doesn't happen. 

• You spend 1 hour in the sun and develop a sunburn and measles-like rash on exposed skin which lasts for weeks and requires stopping Esbriet^® for a month, then going back on in increasing doses until the optimum dosage is reached.
• The rash also means in future wearing long sleeves and a wide-brimmed hat (even in summer with temperature 30^oC+) and lathering exposed skin with 50+ SPF lotion to walk outside and enjoy a sunny day.

• You regularly suffer severe headaches. 

With these side effects eventually life becomes miserable. Do you 

• Stay on Esbriet^® because it extends your life?
• Stop taking Esbriet^® and opt for a better of quality of life though it may be shorter than if on the drug?

DOCTOR INPUT
In general, respirologists/pulmonologists review lung function tests, and, if they see lab measures like FCV haven't decreased, assume you will stay on the drug because it's helping. Indeed, they want you to stay on the drug, because opting for life is paramount in their world.

Severe side effects seem to mean almost nil to physicians, presumably because they've never experienced such hell. Also, as physicians, naturally they want to believe they can do some good, even if a disease is devastating and incurable. 

What doesn't happen is discussing the options and consequences (albeit uncertain), i.e., the reality of an incurable disease and what patients can expect, albeit based on population studies, which may or may nor apply to individual patients.

Often well meaning physicians assumes patients and their families want only hope and cannot deal with grim realities. Best to ignore them? 

To be fair, I'm unsure what physicians could say, given the uncertainties. As well, they know that some patients may grab onto something they say and it could come back to bite them. And some doctors may not want to unduly influence patients one way or the other. Mind you, in other circumstances, I've found that's often not true. And so it goes....

But physician reluctance to discuss realities gives patients precious little upon which to base life and death decisions, even if definitive outcomes  are unknown. Fortunately, I'm okay with reading the medical literature and research findings, but suspect many are not. 

Perhaps that's how it must be. As in life, after all is said and done, individuals are responsible for their own choices. But it would be nice to make informed choices based on a physician's knowledge and experience of your circumstances combined with what population studies show. 

BOTTOM LINE
How can patients with incurable diseases choose the best treatment option, even when one doesn't exist?  In our case, my spouse went off Esbriet^®  for a month due to sun sensitivity adverse event (mandated by physician), then again later, due to other side effects that led to an unbearable quality of life. While off the drug, the symptoms lessened and many disappeared altogether.

He's back on Esbriet^® now, opting for extending life and coping with drug's side effects. We'll see how it goes. Sadly, we have no real support nor wise advice when making decisions. We could join a support group and may do that in time. 

In closing, let me emphasize that there are far worse fates than developing IPF later in life. Overall, both I and my spouse feel pretty darn lucky, even with the latest side effects being a 'bummer', as we'd say in the 60s. Life is good, all things considered.

As always, comments are most welcome. Be aware that comments are moderated, but only to prevent spam.

FURTHER READING
Idiopathic pulmonary fibrosis: now a treatable disease and other highlights from the 2014 American Thoracic Society Annual Conference. CMAJ, May 27, 2014. 

Brett Ley B, Harold R. Collard HR, and Talmadge E. King, Jr TE. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;183( 4): 431-40.

King TE Jr, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2083-92. Epub 2014 May 18.

My earlier blogs on IPF

Sweet Dreams (Musings on funding of Esbriet for IPF)

Updated: 18 Feb. 2015

This blog is a follow-up to Good vibrations (Musings on new research on idiopathic pulmonary fibrosis) - initially posted 1 Sept. 2014  and updated 27 Dec. 2014 - in which I discussed how physicians vary in their approaches to patients with idiopathic pulmonary fibrosis (IPF) and the drug pirfenidone (Esbriet^TM).

• To access the 4 earlier blogs on IPF: 'While my guitar gently weeps' (Musings on idiopathic pulmonary fibrosis)

The blog's title derives from one of the Eurythmics' biggest hits, often sung by Annie Lennox on her solo tours.

To our surprise in early Dec. 2014 we were notified by a representative of the company that makes Esbriet (Intermune/Roche) that Peter had been funded by Alberta's Short Term Exceptional Drug Therapy (STEDT) program to receive Esbriet.

NOTE: We were not notified by a physician but by the manufacturer's rep, an RN. She told us the drug would be available at 3 locations, one of which was the UAH Rexall pharmacy, about 2 blocks from us. She gave us their phone number so that we could confirm when the  Esbriet could be picked up. Maybe it was because the physician that got the funding is no longer Peter's respirologist, since he moved to a nearby city and we got a new doc.

BACKGROUND
Much earlier our first respirologist had applied to STEDT on Peter's behalf. But Alberta's then Minister of Health, Fred Horne, indicated to forget STEDT unless CDEC OR Canada's provinces negotiated what they deemed a reasonable cost for Esbriet. That made us cynical of ever getting Esbriet. But it turns out there was hope.

QUANDARY
So now we are delighted to have STEDT funding for Esbriet for about 8 months with these provisos:

1. DOC #1: The physician with Esbriet experience is no longer Peter's respirologist. 
2. DOC #2: The new respirologist has no experience with it  - few physicians do, given its cost - and will be on leave beginning in the next few months. 
3. SIDE EFFECTS: So far, there are none that warrant stopping the drug. Nausea, dizziness, and extreme fatigue occur but Peter's okay with them so far. 
4. LAB TESTS: The Esbriet RN also told us to get baseline laboratory results for ALT, AST, and bilirubin monthly for 6 months, then quarterly, since Esbriet may affect the liver. Our family doctor kindly wrote a standing lab request. 

DOCTOR vs MANUFACTURER'S REP

About Esbriet's significant side effects, in the absence of physician involvement, the manufacturer's representative helped. Suspect this is because the manufacturer doesn't want patients to discontinue the drug because of adverse side effects. She gave advice on how to minimize a key side effect, gastrointestinal issues. For example:

• Take pills ~5 hrs apart since Esbriet's half-life is 2 1/2 hrs. 
• Increase dosage slowly and cut back if side effects are onerous.
• She said she'd check with us later about adverse effects. And we can always call the toll free number for help at any time.

BOTTOM LINES

I admit we're an outlier, having changed physicians. But even if we still had the initial respirologist who applied for Esbriet funding under STEDT, would the situation be similar? Who knows?

It makes sense that manufacturer's representatives want to ensure Esbriet helps patients and is not discontinued due to side effects.

Alberta's healthcare system is wonderful in many ways and staffed with dedicated health professionals. But I also know from helping many seniors that to claim AHS is patient-centred is not a reality. 

Care is more cost-centred because it has to be, given the Alberta government's choice of priorities and taxation policies, e.g., tax breaks to oil companies, a flat tax that favours the wealthy, and no sales tax like other Canadian provinces. All more acute now that oil prices have tanked.

Sometimes doctor visits are similar to a factory assembly line. After 'x' minutes, you're given a clue to exit. Some docs specify you can discuss only 'x" issues. While I understand where they're coming from, and dig they need to earn a living and pay for their office's overhead, it's hardly patient-centred care. 

I look forward to learning how Peter's new respirologist manages his care using Esbriet on what will be his final journey. To be continued...

FOR FUN
Love this song and in some ways it resonates with this blog's theme.

• Sweet Dreams (Are Made of This) by Annie Lennox, Live 8, Hyde Park, London, 2005 

As always, comments are most welcome. 

Good vibrations (Musings on new research on idiopathic pulmonary fibrosis)

Updated: 27 Dec. 2014 

AND THE BEAT GOES ON
This new blog is to relate what I discovered

1. When generous friends wrote Alberta's then Health Minister, Fred Horne asking for Esbriet to be funded for idiopathic pulmonary fibrosis (IPF), including Minister Horne's response when I contacted him directly. 
2. Interesting tidbits from additional medical research on IPF.
3. How physicians vary in their approach to patients with IPF.

*** Plus - and it's a huge plus - a surprising update in early December (see blog's new ending). 

BACKGROUND
In 2013 my spouse was diagnosed with IPF, a deadly disease with no known cure and a median life expectancy after diagnosis of ~3 years.

Besides the diagnosis, it was a shock to learn that the one known treatment at the time (pirfenidone / Esbriet) was approved for use by Health Canada, but not funded by provincial governments.

I subsequently read many scientific papers on the issue and wrote 4 blogs that examined what it's like to get an IPF diagnosis and why Esbriet is covered by public funding in the UK but not Canada. In brief, reasons include

• The Canadian Drug Expert Committee (CDEC), under the auspices of CADTH, decided that Canada should not fund Esbriet (18 April, 2013). 
• The clinical trial results at the time were equivocal and CDEC opted for seeing the glass half empty, no doubt partly because Esbriet is expensive ($40,000 - $50,000/yr). Provinces would prefer not to pay for a drug that slows, but does not cure IPF, a disease affecting mainly the elderly.
• To access the 4 earlier blogs on IPF: 'While my guitar gently weeps' (Musings on idiopathic pulmonary fibrosis).

Although we are fortunate to have great health insurance, it did not cover a drug as expensive as Esbriet. We understand why our drug maximum is $2000/yr, otherwise the plan would be unsustainable.

HOW GOVERNMENT RESPONDS 
Many friends kindly wrote the Alberta government, usually the Health Minister, Premier, or their MLA, using a variation of the Canadian Pulmonary Fibrosis Foundations' provincial advocacy packages. Regardless of how personalized they made their appeals - including that they knew the UK but not Canada funded Esbriet - in return all, including me, received what amounted to a government form letter, which totally ignored the content of our letters.

In return I wrote Minister Horne and asked him to cut the crap and reply to 3 simple questions.

To his credit, Fred Horne replied to my direct questions. If I interpret Minister Horne's reply correctly:

1. Unless CDEC recommends Esbriet funding, Alberta won't fund it.
2. Alberta's expert committee (ECDET) accepts (rubber stamps) CDEC's decisions.
3. Forget about Alberta's Short Term Exceptional Drug Therapy (STEDT), unless a drug is approved for public funding by CDEC OR Canada's provinces negotiate what they deem a reasonable cost for Esbriet.

Alberta Health's replies were as expected. I just wish the government would be more transparent and upfront, instead of giving citizens the hope that maybe you can get your expensive drug, with unknown or iffy efficacy, under special funding. 

Maybe you can, but only if you are a cute child with a rare disease or if your disease is more common (e,g., cancer), thereby involving more voters. Cynicism or reality? You judge. 

WHAT RESEARCH SAYS

Since I wrote the prior blogs, new research has emerged on Esbriet's value in treating IPF, notably,

• IPF now a treatable disease (CMAJ) 
• Two drugs reduce the progression of IPF
• In 2014 The Journal of the American Medical Association (JAMA) reported that pirfenidone (Esbriet) reduced the relative risk of death or disease progression by 43% compared with placebo.

Accordingly, CADTH is looking at another submission on pirfenidone (Esbriet) and seeks input. 

In the meantime, Esbriet's maker, Intermune was bought by Big Pharma's Roche for $8.3 billion, likely in the hope that the U.S. FDA will approve Esbriet for use in the USA. Effects of the takeover on Esbriet's public funding in Canada remain to be seen.

A TALE OF TWO PHYSICIANS 

My spouse's initial lung specialist (pulmonologist / respirologist) is a physician with much experience, who gave Peter hope that he could get funding for Esbriet, which might significantly help, although not cure, his IPF. The doc patiently spent much time explaining IPF and its possible clinical courses.

He put us in touch with Esbriet's maker to investigate if our insurance would pay. He submitted Peter's name to Alberta's Short Term Exceptional Drug Therapy program (STEDT).

But he soon moved his practice outside our city to what is often called a 'bedroom community'. Although relatively close, driving is a challenge and I could not see travelling there for continuing care. 

Unfortunately, we quickly learned that Esbriet funding was a no-go (as explained above in correspondence with Fred Horne). The original respirologist was hopeful that it would eventually be funded, especially if enough people drew the Minister's attention to the issue of IPF and Esbriet / pirfenidone. Thus, we asked friends to write the Health Minister.

In a pulmonary care exercise program with an Edmonton primary care network, we were told that IPF could deteriorate quickly at any time (acute exacerbation), and we needed a physician to manage it. We opted for a respirologist who was younger and therefore the wait time to see her was less and was affiliated with the University of Alberta Hospital, the facility closest to us.

Her approach was caring but more or less 'all business' and straight forward.

• She reassured Peter not to worry about no Esbriet funding. The drug is not a cure for IPF and has significant side effects. 
• Her approach was, Let's take a few key tests (lung function, echocardiogram, CT scan, 6 minute walking test, review earlier sleep apnea test results) so that she could assess his current medical condition. 
• Then she would discuss where he was at and treatment options.

We appreciated this approach: Let's assess the current state of the disease. What can we do, if anything?

LEARNING POINTS
Some of the key things we've learned:

1. Public advocacy programs for government funding of expensive drugs to treat incurable diseases are worthwhile but work better under certain circumstances.

• Many voters are mobilized to advocate the cause. 
• Helps, but does not guarantee success, if
• Celebrities participate
• Disease is common
• Victims pull at heart strings 

2. Government funding of drugs is shrouded in smoke and mirrors. 

• Health Canada approval does not equal provincial funding.
• Governments seem content to let advocates 'piss in the wind' and only fess up to reality when pressed.
• Provincial exceptional drug therapy programs to fund high cost drugs for rare conditions do not apply to drugs unapproved for funding by CADTH's CDEC. [Except perhaps for children with heart-wrenching diseases like this little girl.]

3. Lung specialists vary in their approaches to dealing with patients with life-threatening, incurable diseases.

• One approach does not fit all because communication involves a communicator (Dr.) and a recipient (patient), and recipients vary greatly in their ability to accept harsh facts. 
• In our case a reality-based approach is okay. 

4. Evidence-based medicine is highly touted and used to denigrate or justify many treatments. But often the evidence is not there or is conflicting or flawed or tainted by private interest and politics. 

• Canada's CDEC clearly puts cost-effectiveness first. No doubt cash-strapped provinces prefer this. 
• Otherwise, why would the UK's NICE committee recommend funding Esbriet to treat IPF, and Canada's CDEC recommend the opposite, based on the same evidence? 
• For the record, NICE's 64-page report is transparent and discusses all issues in detail. CDEC's report is 5 pages. 
• UK experts noted that it was unlikely that clinical trials for IPF treatments can ever have enough statistical power to detect a difference in mortality. They recognized this limitation.
• Yet new studies show Esbriet reduced the relative risk of death or disease progression by 43% compared with placebo.
• Canada's experts chose to ignore statistical power.
• Statistical power: Ability of a study to detect a real difference, if one exists. Power is affected by how big the difference is and sample size. If a difference is big, it's easier to detect. And large sample sizes make a real difference easier to detect. 

5. Autopsies show that IPF coexists with many serious conditions, making diagnosis and treatment options difficult. As an example, 

• In discussing why spouse's lung biopsy showed evidence of pulmonary hemorrhage, not one specialist could explain it. 
• Seems medicine remains both a science and an art. 

UPDATE
Miracle of miracles, early in Dec. 2014 we learned that the Alberta government would fund Esbriet under the STEDT program. For this we thank Peter's initial respirologist, Dr. Lyle Melenka. See

• Expensive drug for deadly, rare lung disease funded by Alberta government (24 Dec. 2014)

FOR FUN
As Peter and I deal with a diagnosis of an incurable disease, idiopathic pulmonary fibrosis, we focus on the glass half full. Every day, every month, every year is a blessing.

Which brings me to an old but fabulous Beach Boys ditty.

• Good vibrations (Love this song)

Further Reading

• Autopsies in acute exacerbation of idiopathic pulmonary fibrosis (Interesting findings. Perhaps they can be of use in treating IPF.) 
• Acute exacerbation in idiopathic pulmonary fibrosis. 
• Clear diagram of the 3 types of disease progression in IPF.
• Drugs for rare diseases. Evolving trends in regulatory and health technology assessment perspectives (CADTH, Aug. 2013)
• Quote in Summary on Alberta: 'A Short Term Exceptional Drug Therapy program for funding high-cost non-formulary drugs for rare conditions is available for both in-patients and outpatients.' [In theory, not in practice.]

As always, comment are welcome.

While my guitar gently weeps (Musings on idiopathic pulmonary fibrosis)

Updated: 3 Dec. 2013

This is the fourth of an ongoing series about idiopathic pulmonary fibrosis (IPF) and the refusal of Canadian provinces to fund the only known effective drug to treat it, pirfenidone (Esbriet).

This blogs title comes from a song that George Harrison wrote for the Beatles in 1968.

As noted in the prior blog, I'll try to explain why Canada and the UK made diametrically opposed decisions based on the same data.

To recap, the Canadian Drug Expert Committee (CDEC), under the auspices of CADTH, decided that Canada should not fund Esbriet (18 April, 2013). 

But in a report also published in April, 2013 the UK's National Institute for Health and Care Excellence (NICE) recommended public funding of Esbriet. 

NICE assessed that Esbriet provided a modest but significant improvement in IPF and "recommended pirfenidone because the benefit to patients justifies the cost."

NICE also recommended pirfenidone be discontinued if there is evidence of disease progression (a decline in per cent predicted FVC of 10% or more within any 12 months). So if Esbriet was shown not to work for an individual, it would not be funded for that person. 

The NICE Report is 64 pages and discusses the evidence for and against Esbriet in detail using the principles of evidence-based medicine. NICE also gives supplementary information. See Further Reading below.

In contrast, CDEC presents a 5-page summary of why they said no.

Judge for yourselves which review is more credible. Perhaps unfair, but NICE is more transparent. With CDEC are we just supposed to accept that they know best, accept the evidence and conclusions in the summary, and not worry about explicit details of their in-depth thinking?

This blog will focus on two key issues: 
1. Efficacy - contradictory studies 
2. Cost - contradictory interpretations 

Like each one of us, I interpret findings through the filter of my education, background, and biases. See original reports to assess for yourself. 

I've chosen selective data to minimize info overload and eyes glazing over. Although findings are simplified, I’ve tried to retain their essence. 'Panel' refers to either CDEC or NICE's expert committees.  

EXECUTIVE VERSION
For those who prefer the bottom line as the first line, my thesis is that Canada’s experts put cost first and chose to see the cup as half empty, whereas UK’s experts put patients first and saw the cup as half full. 

Who decided and how?
The UK NICE process is provided with specific details of who, what, how, and when. 

NICE assessed multiple sources of information and opinion, including clinical specialists, systematic review of scientific studies on pirfenidone, governments, professional medical and nursing associations, representatives designated by patient groups, and the manufacturer of pirfenidone. 

Canada's CDEC used its Common Drug Review process. Information sources included a systematic review of the clinical trials on pirfenidone, a critique of the manufacturers pharmacoeconomic evaluation, information submitted by patient groups on issues important to them, and the opinions of CDEC members. 

Criteria used to decide
Both groups based decisions on three main criteria:

1. Efficacy (inc. FVC, quality of life and mortality rates)
2. Cost and cost effectiveness
3. Safety and tolerability

Readers are directed to the original reports for Esbriet's safety and tolerability. Adverse side effects exist but are not serious enough to contraindicate using the drug to treat IPF, although long term effects will need to be monitored.

1. EFFICACY (Does Esbriet work?)
In medicine, efficacy means clinical effectiveness. Does a drug produce a measurable effect that is meaningful and beneficial to patients? 

To measure the effectiveness of Esbriet, the panels looked at the same two RCTs* of adults with mild-to-moderate IPF in 72-week, double-blind, multicentre trials with similar protocols: 

CAPACITY-2  (PIPF-004 in UK)
CAPACITY-1 (PIPF-006 in UK) 

*RCT The randomized clinical trial (RCT) is the gold standard of medical research. Similar individuals are randomly assigned to a treatment group (who take the drug) and a control group (who take a placebo). Double blind means that patients and researchers do not know who is in which group. Then, if there is a difference (patients on the drug improve more than those on placebo), it is more likely to be real. 

The primary outcome in both studies was the change in the percentage of predicted FVC* from baseline to week 72. 

*FVC. Forced vital capacity (FVC) is the volume of air that can forcibly be blown out after a deep breath in and is universally acknowledged as a reliable measure of lung function. A decline in FVC indicates disease progression. A10% decline within 6-12 months is associated with a significant increase in mortality.

In one study (CAPACITY-2) there was a statistically significant* improvement in the rate of decline in per cent predicted FVC with pirfenidone compared with the placebo (4.4% difference), but not the other study (0.6% difference).  

* Statistically significant. A 'statistically significant difference' means the results are unlikely to be due to chance and are more likely to be real. 

Neither Canadian nor UK assessors could explain why the results of the trials were contradictory.

A pooled analysis (possible because the protocols and methodology in both studies were similar), showed a statistically significant improvement in the rate of decline in lung function (per cent predicted FVC) with pirfenidone compared with placebo of 2.5%.

In other words, if data from both studies were analysed as if in one large study, the results are statistically significant (unlikely to be due to chance) and favour Esbriet, as does the one clinical trial. 

Canada v UK #1 (Efficacy and FVC)
Canada's experts noted that, if the 2 studies were contradictory, pooled results must be regarded as ‘exploratory’, i.e., not as valid.  

In contrast, UK experts noted the near-identical design of both studies and agreed that analysing pooled data, although exploratory, was reasonable. 

They concluded that the trials provided evidence that was adequate for assessing the clinical effectiveness of Esbriet. In one study and using pooled data, the drug showed a modest but significant improvement over a short duration (72 weeks).

Canada v UK #2 (Efficacy and Mortality)
Both studies showed no statistically significant difference in IPF-related deaths. 

However, a pooled analysis of IPF-related mortality suggested that pirfenidone was associated with a statistically significantly higher probability of survival compared with placebo.

Canada's experts noted that, in both studies, Esbriet showed no difference in prolonging life. Results of pooled data were invalid. Hence, there was insufficient evidence to determine if Esbriet prolonged life. 

In contrast, UK experts noted that it was unlikely that clinical trials for IPF treatments can ever have enough statistical power* to detect a difference in mortality. Because of the relatively small number of IPF patients in the studies, there aren't enough patients dying over the short duration of the two clinical trials (only 72 weeks) to detect a difference.

UK experts recognized this limitation as one that would probably always exist in clinical trials of drugs to treat IPF. Although a possible survival benefit was uncertain, the UK decided this was the only evidence available for decision-making. 

Canada's experts chose to dismiss the evidence, apparently ignoring the issue of statistical power.

* Statistical power: Ability of a study to detect a real difference, if one exists. Power is affected by how big the difference is and sample size. If a difference is big, it's easier to detect. And large sample sizes make a real difference easier to detect. 

Canada v UK #3 (Efficacy and Quality of Life)
Here the two panels agreed. The studies showed insufficient evidence that pirfenidone provides clinical benefit for quality of life. Quality of life was measured with a 50-item questionnaire that measures distress due to respiratory symptoms, mobility and physical activity, and the psychosocial impact of the disease. 

Both panels found that in the studies Esbriet did not affect related health indicators such as dyspnea (shortness of breath), respiratory-related hospitalisation, need for supplementary oxygen, etc.

2. COST AND COST-EFFECTIVENESS
In both Canadian and UK assessments, the manufacturer submitted a confidential estimate of costs, which were analysed by the panels’ experts.

How medical and public health experts decide cost effectiveness is complex and one of life’s great mysteries. Voodoo economics is the term that comes to mind. The key terms are QALY, ICER / ICUR. (Stick with me. It won’t be too painful.)

QALY
QALY is a well recognized method that indicates how many extra years of life - of a reasonable quality - a person might gain from treatment. QALYs offer many opportunities for researchers to influence results, including what constitutes a reasonable quality of life. NICE explained its QALY calculation.

ICER / ICUR
ICER: The incremental cost-effectiveness ratio is the ratio between the difference in costs and the difference in benefits of two interventions per QALY. 

ICUR: Incremental cost-utility ratio is similar to ICER and is calculated as follows (where A & B are interventions, treatments, drugs, etc.):

Cost of A – Cost of  B
---------------------------------------------------------------
No. of QALYs produced by A –those produced by B

Canada vs UK #4
CDEC says the manufacturer reported that pirfenidone compared with placebo is associated with an ICUR of $143,617 per QALY. They found faults with the manufacturer’s cost analysis and thought true costs would be higher.

In contrast, the UK calculated its ICER by comparing Ebriet NOT to placebo but to ‘best supportive care’. The manufacturer's probabilistic ICER was £24,000 ($40,349 CDN) per QALY gained, which was less than the UK’s Evidence Review Group's assessment but ‘an acceptable cost-effectiveness estimate on which to begin to explore further considerations’.

So….assuming ICER and ICUR are the same, Canada’s cost effectiveness model concludes Esbriet is more than 3 times the cost of the UK’s. Huh?

Did Canada’s ICUR compare Esbriet to placebo but not consider actual treatment costs that IPF patients would incur if not on the drug?

Did Esbriet's manufacturer give different cost estimates to Canada vs the UK?

PERSPECTIVE on COSTS
Cost-effectiveness thresholds per QALY vary from country to country:

• UK: £20,000 - £30,000 (NICE)
• USA: $50,000 
• Australia: $52,400 
• Canada: $20,000 - $100,000 

Are these thresholds appropriate? Who knows?

BOTTOM LINE
CANADA
Canada's experts judged the data on Esbriet’s efficacy and costs to be inconsistent, untrustworthy, and insufficient, or as Brit football fans might say about an opposing club, ‘They’re shite, total shite!’ 

Yet CDEC allowed that, although individual patients may benefit from pirfenidone, they were unable to determine the clinical criteria that would accurately identify these patients in clinical practice. 

Can’t identify who may benefit? Then no one gets it. 

CDEC took the approach that any evidence that supported Esbriet was iffy. They decided to interpret all study results as the cup half empty. One can only wonder why.

UK
NICE’s approach was the cup is half full. UK experts accepted the positive RCT results of the one study and the pooled study results of both. They acknowledged that, because of small numbers of patients with IPF on Esbriet, it was unlikely that studies could ever show a different in mortality rates. They found Esbriet to be cost effective compared to best supportive care and their threshold for QALY costs. 

Can’t identify who may benefit? Then stop funding Esbreit for a patient who shows a significant decline in lung function over 12 months. 

So what does all this mean? 

To me, it's similar to Canada's blood experts in the 1980s deciding to use stocks of FVIII concentrate for hemophiliacs because they were probably all infected, which turned out not to be true. And what a pompous, cold-hearted decision to make with the lives of others. 

It’s also analogous to Canada’s blood experts deciding that surrogate tests implemented in the USA for non-A, non-B hepatitis (now hepatitis C) were not scientific enough for them. Inadequate sensitivity and specificity to use the lingo of diagnostic tests. 

In retrospect these expert judgements were huge miscalculations and cost the lives of many Canadians and suffering to thousands of others.

Yes, I know you cannot compare Canada's so-called 'tainted blood tragedy' to its decision not to fund IPF's only known treatment, Esbriet. But some aspects are similar. 

Canada’s blood experts put cost first then. And I suspect that CDEC has put costs first in the case of Esbriet to treat IPF. Its committee members would never admit it, even to themselves. But influence is subtle. Today, cost saving in Canada's health system is the pervasive culture. CDEC's decision no doubt pleases provincial governments. 

In contrast UK experts decided to put patients first. The Esbriet studies with all their limitations - especially because of the short 72 week duration and not enough patient numbers and time to show if Esbriet prolongs life - still show the drug provides a modest and real improvement. 

Some might call that balancing cost with patient-centred care, a principle that Canada’s medical community gives lip service to, but seldom implements. 

FOR FUN
'While My Guitar Gently Weeps' epitomizes how I feel about Canada’s decision not to fund Esbriet. The CDEC decision revives memories of earlier cost-based decisions, lacks compassion, and I suspect lets an inflated sense of scientific superiority blind our experts to the big picture. 

For interest, Harrison song was ranked #7 on Rolling Stone's list of the 100 Greatest Guitar Songs of All Time, and #10 on their list of The Beatles 100 Greatest Songs.

• While my guitar gently weeps (George Harrison with Eric Clapton on guitar and other celebs)

I look at the world and I notice it's turning
While my guitar gently weeps.
With every mistake we must surely be learning
Still my guitar gently weeps.

FURTHER READING

NICE Resources

• IPF overview
• Information for the public
• How pirfenidone guidance was produced
• Key documents

As always, comments are most welcome.

Those were the days (Musings on idiopathic pulmonary fibrosis)

Updated 14 Nov. 2013

This is the third of an ongoing series about idiopathic pulmonary fibrosis (IPF) and the refusal of Canadian provinces to fund the only known effective drug to treat it, pirfenidone (Esbriet).

This blog’s title comes from a catchy 1968 ditty, Those were the Days. 

The blog outlines some of the obstacles to funding Esbriet, or any expensive drug or treatment. 

At its core, it’s a tale of medical experts looking at the same facts and reaching different conclusions. To some readers that may seem impossible but it becomes understandable once you realize that

• Medical experts, like all humans, have biases
• Experts are affected by external influences and pressures
• Medicine is an art as well as a science
• When evidence is borderline, decisions are more susceptible to biases and political pressure
  

The prior blog ended with asking, ‘What to do?’ As you may expect, we’re not accepting the government’s decision without a fight. As Peter’s lung doc asked, we’ve become advocates, asked friends to participate (which they kindly and generously have), and plan to continue on a broader scale via this blog and our Twitter accounts

• grumblingonions
• bogeywheels

To some, getting public funding for IPF, or other pricey drugs, may seem a lost cause. Despite the obstacles, we don’t accept that. Indeed, as James Stewart said in ‘Mr. Smith goes to Washington’, lost causes may be the only ones worth fighting for, and this one is worth fighting for.

Funding Esbriet to treat IPF has many obstacles. Some relate to the milieu in which government decisions, including those on healthcare are made, e.g., social and economic factors. Others are harder to pinpoint, such as the pressures that influence scientists trying to play by the rules of evidence-based medicine. Sometimes, even ‘smoke and mirrors’ may play a role.

We’ve decided to briefly outline 7 obstacles. As you read the obstacles, please examine your feelings. What emotions do you feel (not think)? What's your gut reaction?

OBSTACLE 1: Not my problem

Dismissing relatively rare diseases is easy. Because they’re rare, we think they’ll never happen to us. Kinda like ignoring risky behaviours like smoking or unprotected sex or sex with multiple partners or drinking and driving. Won’t happen to me syndrome.

But it’s even more like laughing at getting a deadly disease from blood transfusion because today’s blood supply is so safe. Except if you do get a deadly, even a minor, transfusion-transmitted disease, guess what? Suddenly you do care. A lot.

That’s the case with idiopathic pulmonary fibrosis. No one much cares about it except

• Physicians who treat it (or try to, given Canada’s provincial governments won’t fund the only known effective treatment, pirfenidone)
• Patients who have it
• Their family and friends

Besides the public not caring, other obstacles exist to funding Esbriet.

OBSTACLE 2: It’s probably your fault

Some smug citizens may be in blame mode. It’s a lung disease? Probably caused it themselves. After all, that’s a factor with so many preventable diseases in which lifestyle choices play a role.

• Lung cancer, emphysema, stroke: All increased by smoking, even though they can happen to those who have never smoked
• Skin cancer: Too much time in the sun without a hat or sunscreen
• Breast, throat, liver cancer: All increased in those who drink alcohol. Yes, alcohol is a known carcinogen.
• Type 2 diabetes: Probably a lifetime of eating junk food, being a couch potato, and growing obese, never mind genetic factors
• Coronary artery disease: Too much fat in diet, too little exercise. Never mind that fit people, including runners, get it
• Sexually transmitted diseases: Unprotected sex, too many sex partners

Turns out that ~30% of all cancers are preventable (Source: WHO). 

Simple answers appeal to all of us, especially folks who are unaware of the influence of factors like genetics, stress, and unknown environmental exposures.

And it's so easy to ignore the cost to our health system of fitness buffs who run marathons, play soccer, downhill ski, etc.

For interest, cancer funding varies greatly: (2006 USA data)

• Breast ca receives the most funding per new case, $2,596 and by far the most $ per death (41,430 deaths), $13,452. 
• Prostate ca, the most common cancer, receives the least funding per new case ($1,318) but, per-death (27,350 deaths), it ranks second, with $11,298.
• Lung ca is the biggest cancer killer (162,460 deaths), yet per-death receives the least funding among major cancers ($1,630)

OBSTACLE 3. It’s only old people

IPF affects mainly seniors. And seniors are in the winter of life, soon to depart this world, even without a disease like IPF. 

Ageism often that means that what happens to us is less important than what happens to those younger. That our concerns can be ignored, that we can be dismissed as old foggies, fuddy duddies, past it, etc. 

It's only natural because those who are young don't want to think of what happens when we age, the deterioration of our physical bodies and inevitable death.

Does ageism exist in Canada and elsewhere? Based on our experience it does. Shows itself in many ways, every day, from how you are treated at the bank, who is served first in stores, to how advertisements focus on the young and how health care professionals speak louder to seniors, as if we were children and deaf. Often oldsters are invisible, at least that's how it can feel.

When it comes to IPF, it's easy to envisage government officials like @premierRedford and @FredHorneMLA

saying, 'They're old people who will die from the disease anyway. Why waste money on them?'

It matters not that the age-related tsunami cost to healthcare is a myth. The issue is multi-factorial with a passionate band of evidence-based medicine gurus leading the charge. So sure they are right, rigid to the core.

OBSTACLE 4: It costs too much

Then there’s the cost fanatics, often people on the right of the political spectrum but not totally, who believe that the less government does, the better. or that we need to balance the budget above all else. Their thinking is as follows:

If we, the taxpayers, will fund an expensive drug like Esbriet, it had better show a BIG improvement in quality of life, lung function, and even extend life. And ideally affect me, my family, or someone I know.

Such voters do not realize many drugs and diagnostic tests funded by government to diagnose and treat other diseases do next to nothing. 

We won’t go into specifics as the blog would become too long, but iffy government-funded tests and treatments exist. Many involve cancer. Cancer is scary, we might get it, whereas IPF, what’s that? It doesn't matter that millions, even billions, are spent, with minimal results.

OBSTACLE 5: Governments obsess about cost

Provincial government fear the aging population and worry about how they’ll fund long term care facilities and the increased use of drugs among seniors. To some, it's a tsunami is about to strike.

Accordingly, provincial governments are more than happy to see expensive drugs like Esbriet nixed by the Canadian Expert Drug Committee (CDEC).

Social and political pressures are the realities that face physicians and IPF patients seeking government funding for Esbriet.

Now for the biggest obstacle...

OBSTACLE 6: Canada's panel of experts said no to Esbriet

The Canadian Drug Expert Committee (CDEC), under the auspices of CADTH, decided that Canada should not fund Esbriet. 

Because all Canadians, especially those affected by IPF, should know who our CDEC experts are:

Dr. Robert Peterson (Chair), Dr. Lindsay Nicolle (Vice-Chair), Dr. Ahmed Bayoumi, Dr. Bruce Carleton, Ms. Cate Dobhran, Mr. Frank Gavin, Dr. John Hawboldt, Dr. Peter Jamieson, Dr. Julia Lowe, Dr. Kerry Mansell, Dr. Irvin Mayers, Dr. Yvonne Shevchuk, Dr. James Silvius, and Dr. Adil Virani

The CDEC decision gives our provinces a convenient out. We don’t need to pay for Esbriet, our experts recommend not funding it. As UK football fans might quip about the drug after reading CDEC’s decision, ‘It’s shite!’

BUT BE AWARE the UK’s NICE looked at the same facts and concluded that the

• UK’s NHS would fund pirfenidone

OBSTACLE 7: Healthcare a provincial responsibility

Because In Canada, provinces and territories are responsible for healthcare, it becomes difficult for one province to fund a drug when others don’t. Difficult, but not impossible.

It's easier if the drug is for a toddler with a really rare disease like Maroteaux-Lamy syndrome with significant morbidity and mortality (only 9 affected children in Canada), so the funding is a one-off.

Naglazyme is NOT approved by Health Canada and costs $300,000 or more per year for children. Because dosage is tied to weight, cost can rise to $1-million/yr for adults. Those on it are on it for life since the drug does not cure the illness but stops it from worsening.

It’s harder to get government funding if it’s for a rare disease like IPF with significant morbidity and mortality that affects 1000s of seniors. 

It doesn’t matter if Esbriet, like Naglazyme, doesn’t cure the disease but stops it from worsening, that Esbriet is approved by Health Canada, but Naglazyme is not. 

Who’s to say Canadians from other provinces wouldn't move to Alberta? Unlikely for most seniors but possible for some. 

BOTTOM LINE

Can you see that societal biases and politics are involved, indeed rampant, in Canada's drug funding decisions?

In the next blog we’ll explain why Canada and the UK made diametrically opposed decisions, focussing on what we see as the two most important issues:

• Contradictory studies (clinical trials)
• Contradictory interpretations of what’s a reasonable use of government money to improve health, prevent and slow illness 

FOR FUN

Two songs fit this blog's issue of our story about IPF and Esbriet. 

The first, Those were the days, speaks to our youthful enthusiasm and certainty that in Canada, with its universal healthcare, we'd always receive needed treatment and the ill would not be financially punished.

• Those were the Days (Mary Hopkins)

Those were the days my friend
We thought they'd never end
We'd sing and dance forever and a day
We'd live the life we choose
We'd fight and never lose
For we were young and sure to have our way.

The second song comes to grips with reality: 

• Money makes the world go round (Lisa Minnelli & Joel Grey from Cabaret)

As always, comments are most welcome.