New treatments: What benefits at what costs

Yesterday brought quite a bit of press coverage to a small biotechnology company in Cambridge called Vertex. All this attention was spurned by their gene therapy trial results in cystic fibrosis. The treatment, aimed at a genetic mutation present in about 4% of all CF sufferers, was able to improve the volume that a patient can force out of his lungs in 1 second by over 10%, from about 65% to 75%. Matthew Herper of Forbes on his blog, while being duly impressed by the results, also cautioned that the annual price tag for this medicine is likely to reach $250,000 per patient. So, what does all of this mean in the context of our ongoing national discussion about the value of therapies? Well, let's break things down a bit.

First, let's talk about CF. This is a genetic disorder that essentially makes mucus very sticky. Among its many effects, in its most familiar manifestation this mucus plugs up the airways making it difficult to breathe and predisposing the person to frequent and serious lung infections. When I was a resident back in the early '90s, I remember a devastating case of a young man in his late teens with CF whom we all knew so well from his frequent admissions for exacerbations. Though he was pretty high on the lung transplant list, he ended up succumbing to a devastating pneumonia in our ICU, leaving behind a devoted sister who had been fortunate enough to benefit from a transplant several years earlier. This was a typical course in those days: a brief life punctuated by frequent exacerbations, hospitalizations, antibiotics, gastrointestinal complications, and early death in the second or at best third decade of life with very little hope of procreation. Over the last 20 years things have changed dramatically in the treatment of CF: fewer exacerbations, much lengthened life expectancy and a good chance of having children. Yet we cannot attribute most of these changes to dramatic new breakthrough therapies. To be sure, while there have been tweaks to how we give antibiotics and how pancreatic enzymes are administered to replace the digestive enzymes that the pancreas in CF is unable to produce, most of the progress can be attributed to the increased attention to detail and the advent of almost ruthless care coordination at specialty centers. As a Fellow in the '90s I participated in a clinic where CF patients were transitioning from care by pediatric Pulmonologists to that by adult doctors. The CF specialist running this clinic did not only know all of his patients and their family members by names, but was available 24/7 to them and to his staff for consultation. This is the kind of dedication and vigilance necessary to improve the outcomes in CF.

Now, let's talk about the lesion addressed in the Vertex trial. The type of chronic lung disease caused by CF is called "obstructive." Simply put, it makes exhaling the air in the lungs difficult to do. On lung testing one manifestation of obstruction is the amount of air one is able to force out of his lungs in the first second of the effort, and this is called the FEV1, or forced expiratory volume in 1 second. Another important measure of the degree of obstruction is the amount of air that this volume expired in 1 second represents as a proportion of all of the air in the lungs that can be expired, known as the FVC or forced vital capacity. We say that if the FEV1/FVC ratio is under 75%, then obstruction is present. The size of FEV1 helps us understand how bad the obstruction is.

With this as a background, the primary outcome in many obstructive lung disease trials is the improvement in the FEV1. In the specific trial discussed, the average starting FEV1 in the intervention group was about 65%, which falls in the mild-to-moderate category of obstruction. What this means in terms of symptoms can vary widely. The 10% absolute improvement seen in the intervention group resulted in the average FEV1 of about 75% after treatment, definitely representing fairly mild obstruction (generally FEV1 over 80% is considered to be in the normal range). And this truly is impressive. However, equally interesting is the information that is not in the press coverage, largely based on press releases and sound bites from company executives, since the peer reviewed study is not available at this point. We are not told, but led to assume that, the control group started out on average with a similar deficit in lung function. We are informed that the treatment patients were 55% less likely than placebo patients to have an exacerbation of their disease, yet we do not know what the absolute numbers are; that is we are not told what proportion in each group had an exacerbation, how frequently or how severely. So, this 55%, in the absence of context, while an attention grabber, is not a substantive number. Herper does tell us that there was a remarkable difference in the weight gain (a desirable outcome in the CF population), on average 6.8 lb in the treatment vs. 0.9 lb in the placebo group. This is truly impressive, though it would be even more so if I knew that the trial was double blind, a piece of information I did not notice in any of the reports. Some of the reports have also alluded to symptomatic improvement in shortness of breath, though nowhere did I see this quantified.

The most important piece of data, however, is conspicuously absent from all the stories. What is the proportion of patients who responded to therapy? Why is this important? Well, we know that far from everyone responds to every treatment that they ostensibly qualify for; this is referred to as the heterogeneous treatment effect, or HTE. It is very likely that the 10% improvement in the FEV1 represents at once an inflated estimate referent to those non- or under-responders and a muted one for those patients with a terrific response. The question of a minimal clinically significant change in the FEV1 has haunted the lung trials community for a long time now. Yet, without setting some threshold for a minimum FEV1 improvement that correlates with a meaningful improvement in symptoms, one cannot quantify how well the drug works and hence articulate its value. This is crucial when trying to justify the ostensibly exorbitant price tag anticipated for this drug. How many patients will we need to treat in order to have one of them respond meaningfully with an improvement not just in a laboratory number, but also in their lives? If this targeted drug produces a desirable response even in 50% of all patients with the specific mutation it targets, then it means that we need to spend $500,000 annually to obtain a meaningful improvement in symptoms in one CF patient. But what if it only works this way in 20%? Then we will need to treat 5 patients with this drug to obtain 1 meaningful response at the price of $1.25 million annually. This becomes a bit more daunting, particularly given that the costs will have to be covered through some kind of public or pooled funds and given that this is one of many therapies in the pipeline likely to come with a similar conundrum.

I am not implying that improving a single life is not worth $1.25 million annually. In fact, it may well be a bargain. My point is that these are the serious discussions we need to have as a society, so that when the time comes to make these choices, the discussion will not be subverted by a few loud voices sensationalizing "death panel" slogans. Manufacturers need to know that they should disclose full data, not just selective tidbits that highlight benefits only, but also those difficult pieces of information that shed light on their costs. On our part, we need to understand the gargantuan effort and resources these companies expend to tame these elusive wild therapies that hold so much more promise in the abstract than they end up embodying.

We tread a fine line here. Information and how we assimilate it are the next frontier for cogent decision making. We need to get educated about this now because this train is leaving the station regardless of how we feel about it.