Sunday, May 17, 2009

ALS, the Rule of Rescue, and the FDA

The opening paragraph in "Fighting for a Last Chance at Life" in today's New York Times led me to expect what the Brits call "hanging crepe" - using imminent death to blast insurers as uncaring, profit-seekers and the FDA as a callous bueaucracy:
As Lou Gehrig’s disease sapped Joshua Thompson of his ability to move and speak last fall, he consistently summoned one question from within the prison of his own body. “Iplex,” he asked, in a whisper that pierced his mother’s heart. “When?”
Joshua, a vigorous, athletic, married 34 year old father was diagnosed with Amyotrophic Lateral Sclerosis in 2007. Kathy Thompson, Joshua's mother went onto the web, and learned about Iplex, a drug containing an insulin-like growth factor that in 2006 had been reported to stimulate growth of the nerve cells involved in ALS (in tissue culture). The growth factor had been tested on ALS patients and was found to be ineffective, but Iplex combined the growth factor with a protein that might get it into the nervous system more effectively. The New York Times article describes in rich detail the campaign Kathy orchestrated to make Iplex available, despite the lack of FDA approval or evidence - other than anecdotes from Italy, where the government provides it - for its effectiveness.

There are currently no effective treatments for ALS. It is regarded as a uniformly fatal condition. The desperate effort on the part of ALS patients and their families to try any approach about which they have hope is totally understandable. The public policy challenge is - how should a health system respond to patients in a "last chance" situation who want medications (or other interventions) they regard as promising but which have not been shown to be effective?

It's possible that the medication may prove to do more harm than good, but I don't see that as a reason to forbid access. As Kathy Thompson said when safety concerns were invoked - "what, exactly, is safe about ALS?" Patients who are competent to make decisions and who are fully informed about the risks and benefits of a treatment are entitled to decide whether they want to bear the risks for the chance of the gain.

The core issue involves considerations of the common good. If unproven medications are made available, patients in last chance situations will want to try them. I know that I would. But when this happens it is impossible to find out whether the medication really works. In the 1990s many states mandated insurance coverage for high dose chemotherapy and bone marrow transplant for women with advanced breast cancer. The availability of the treatment made it almost impossible to test its effectiveness. When results finally came in it emerged that the treatment was no better than the existing interventions, and often worse. Hundreds of millions of dollars were spent for what, on a population basis, was a net decrement in health compared to alternatives. (The chemotherapy story is told in detail in False Hope.)

As I read the story I thought - the FDA should make the drug available for what is called "compassionate use," but only in the context of a clinical trial. To my surprise and pleasure, that's exactly what the FDA did in March of this year. Here are the key sections of the FDA statement:
FDA's Decision

The FDA and Insmed [the manufacturer of Iplex] have agreed that access to Iplex for investigational use in patients with ALS will occur in two ways under Investigational New Drug applications (INDs):
1. Single-patient INDs requesting “compassionate use” of Iplex for treatment of named patients with ALS, received and date-stamped by FDA’s document room by close of business on March 6, 2009, will be allowed to proceed, and Insmed has agreed to supply Iplex to those patients; and
2. The remaining supply of Iplex, which is very limited, will be used by Insmed to conduct a clinical trial under an IND in which other patients with ALS who are interested in receiving Iplex treatment will be randomly assigned to receive drug through a lottery system.
All patients who receive Iplex under either a single-patient IND or in the Insmed clinical trial must be adequately informed by their treating physician of the possible benefits and risks of the treatment...

Rationale for FDA's Decision

...FDA has attempted to balance the needs of individual patients who are desperately seeking treatment options for this devastating disease with the need to learn if the drug is in fact beneficial, or harmful, in treating patients with ALS. These considerations were weighed over the last few weeks by FDA scientists and physicians, who held a series of meetings with Insmed and internal meetings to discuss the best path forward.


The FDA understands that ALS is a fatal disease with limited to no treatment options. We are very sympathetic to the desperate situation of patients with this terrible disease, and their families, and we remain committed to facilitating the development of effective drugs to combat ALS. Sometimes therapies that appear promising in the preclinical phase (before studies in humans) do not lead to benefits in patients...

The FDA is mindful of the need to strike a balance between access to unproven therapies for patients with limited treatment options, and the ethics of subjecting those patients to drugs with unacceptable risks or unconfirmed benefits. Today we have chosen a means to provide access to Iplex to as many patients as possible, consistent with all of the considerations discussed earlier.
The FDA has done an impressive piece of ethical analysis with regard to Iplex and ALS. It recognizes the dire circumstances of people like Joshua Thompson in last chance situations, the intensity of society's wish to rescue identifiable victims, and the importance of rigorous evaluation of new treatments on behalf of the common good. Hat's off to the FDA!


Anonymous said...

How much did Kathy's incredible devotion and hard work (and money in the family), influence the FDA, do you think?

Jim Sabin said...

Hello Anonymous -

My guess is that Kathy Thompson's extraordinarily devoted pursuit of (a) information about experimental treatments for ALS and then (b) strong advocacy for access to Iplex on a compassionate basis, (c) forced the question onto the FDA's agenda. I don't know how she and the other advocates responded to the FDA plan for a randomized trial. My guess about that is advocates were disappointed, perhaps bitterly so, that access to the drug wasn't given in an open ended way. But I think the FDA decision was correct. In my view, it recognizes the urgent situation ALS patients are in, and also the public need for good information on the drug, so that it can be made available if it is effective, but not approved if it has no positive impact or is actually harmful.



Anonymous said...

This shows the ongoing tension between the rule of rescue and our responsibility to be stewards of the resources given to us (including the opportunity to conduct clinical trials to find out what works). A related issue that is increasingly bothering me is the power of disease advocacy groups to leverage special treatment for their constituency.
This is most notably true of the cancer lobby. It is refreshing to see patients with an equally fatal but less prevalent disease get thoughtful treatment. In fact, you would be better off to be diagnosed with many types of cancer than with ALS. But we all instinctively fear getting cancer. Few people have nightmares about getting ALS. I am not trained as an ethicist, but favoring cancer patients over others with equally serious diseases appears to me to violate the principle of justice.

Jim Sabin said...

Dear Anonymous -

Thank you for your insightful comment!

Your comment proves an important point - one does not need formal training in ethics to be able to reflect insightfully about complex issues. All human beings are "ethicists" in that we consider questions of competing values and make decisions about how values conflicts can best be handled all the time.

I agree that the tension between the rule of rescue and our responsibilities as stewards is ongoing. I think it's a healthy tension. Trying to rescue our comrades is a fundamental good. So is recognizing collective needs and the common good. There aren't any easy answers. It would be a cruel society that simply turned its back on folks in dire situations. But it would also be a foolish and callous society that neglected the common good, as we in the U.S. have done by allowing health care expenditures to rocket out of sight.

I don't fault advocacy groups for fighting for their particular concern. I do fault them if they fail to recognize that others have legitimate claims, and that an honorable and just society will have to make choices. Cancer gets as much attention as it does because of its prevalence, but also because the image of cancer invading the body expresses our primitive fear of attack.

I would disagree with you in one way - you may not have studied ethics but you are an ethicist!



Anonymous said...

What do you think? -

I'd be intrigued to get both your opinions. To me there is no greater urgency than one's fight for life. And this urgency and rudimentary right to self-preservation is not to be defaced for the "common good." For is not making that common good a little less accurate balanced by allowing patients facing death to access these therapies as their last hope at survival?

: ) Love to hear your thoughts, Ryan

Jim Sabin said...

Hello Ryan -

Thanks for the link to your website. I see that your passionate focus is on access to "last chance" interventions for people who are at death's door.

As I indicated in this post, and here in another post about access to experimental therapies, I believe that several values should be considered in making policy. You are focused on possible extension of life as the overriding value. In my view, other values need to be considered as well, including the "common good," as reflected in scientific progress and stewardship of shared resources.

But even though I analyse the circumstances differently than you do, I think it's great that you have developed the website and ideas about legislation. And I especially liked the values you expressed, with such a strong emphasis on thoughtful, civil discussion and compassionate care.



Unknown said...

Hi Jim,

Thanks! I enjoyed reading your thoughts as well. I agree in that we need to consider "the societal benefits" at stake when it comes to enrollment in clinical trials -- and, that seems to be the biggest concern among scientists and clinicians.

I've been discussing this with a few folks, and we seem to come to the following conclusion: there needs to be a defined point where patients, who would be unable to enroll in experimental studies otherwise(b/c of certain characteristics like a two wk prognosis), would be able to get the same experimental therapy through another protocol.

The key is defining this point where the patient would no longer be eligible. This appears to be the logical balance I keep striking when it comes to this access.

What do you think?


P.S. - sorry it took so long to respond. feel free to email me at to ensure quicker responses. Thanks!

Jim Sabin said...

Hi Ryan -

Sorry for my own delay in responding - I've been distracted from the blog by the medical ethics class I teach that started recently.

I wouldn't want to say that scientists are concerned with societal benefits and not with individuals. In seeking to develop new treatments one envisions individuals in the future who might be helped and protection of subjects who might be harmed by the intervention that is being studied.

I personally would not support the idea that a caring society should guarantee experimental interventions to patients. As a society we're doing a very poor job ensuring access to simple, proven forms of treatment. Focusing on unproven interventions that may be (a) useless, (b) worse than the available alternatives or (c) actively harmful, would encourage our societal fantasy that we're doing fine with established forms of care and that new is better.

You probably noticed that I've used the word "experimental interventions" not "experimental treatments." We don't know whether something under study will end up being a "treatment." Not being eligible to participate in an experiment isn't the same as being denied treatment!

Thank you for your interest. And, again, my apologies for the slow response!