On Not Getting It...

Here is the scenario: you have cancer, and your doctor has told you there is no way to treat it. But there is an experimental drug that is being offered in a phase 1 study. Your doctor asks if you're interested.

You join the study because its your best shot. You know there are likely to be side effects–there always are with cancer drugs. You know the drug might not work–no cancer drug works all the time for all people.

If your doctor knew that entering the phase 1 study was unlikely to eradicate your cancer-- or even extend your life– would you want to be told, or would you prefer that the doctor keep this information from you?

The question came up in a recent research ethics committee (IRB) meeting I attended, in which a phase 1 cancer study consent form contained language to the effect of "you may or may not benefit from joining this study." I proposed that the language be changed to "this study is unlikely to significantly affect the course of your cancer." My preference was based on the following reasons:

1- "may or may not benefit" does not contain any information about probability. Indeed, there is a subtle rhetorical partity, wherebt most readers view "may" as having equal weight as "may not" such that they view this as suggesting a 50% probability of benefit.

2- two recent, large mete-analyses showed that studies of the type reviewed here result in tumor shrinkage for about 10% of patients. There is no evidence that tumor shrinkage in these studies actually translates to longer life or improved comfort. So, in fact, we do have information about probability of benefit.

3- Patients enter these studies not because of a desire to further cancer research, but rather, because they are seeking cure. This has been shown in numerous surveys.

4- Patients who enter these studies significantly overestimate the probability that they will benefit clinically. Also shown in numerous surveys.

5- Informed consent requires, at a minimum, that volunteers be provided information that a reasonable person would consider material to their decision to enroll.

A reasonable, terminal cancer patient would probably want to have some information about the probability that a drug that is likely to have strong side effects is unlikely to work against their cancer.

Incredibily, most of the members of my IRB disagreed, saying (among other things) that it would discourage patients (hmmm. I thought medical paternalism went out with Buicks with tailfins); that nothing in the original language implied benefit was a sure thing (yes, the original language made it very clear that instead of 100% chance of benefit, chance of benefit was somewhere between 0 and 99.999%);  that no one would enroll in the study with my language (wow! I thought our job was to protect volunteers, not investigators); that we've never done that before (let me make sure I understand this.  It's ok to withhold relevant information from volunteers, as long as you've done it before).

Yes, Virginia, the IRB system really is broken! (photo credit: Kenoir 2007)

Collins Resigns (part 2)

Nature ran an elegiac editorial in the June 5 edition on Collins' resignation. It provides a desiderata for future directors: "the new director will have to ensure that the implications and applications of those projects are fully explained to all concerned... genomics is now at the point where the science and technology are moving much faster than society's ability to assimilate and make sense of the information."

I'm not clear what is meant by "explained to all concerned."  At any rate, "all concerned" will arguably have a lot of explaining to do to any new director of NHGRI. As for society's "ability to make sense of the information," well yes- that's precisely the point.  If we can't make sense of the information, it seems that the technology isn't moving quite as fast as we might have thought.

This "run-away train" trope has been with us since the inception of the human genome project. But a brief consideration of medical applications from genome research provides good reason for patience. Exhibit A is genetic diagnostics, which have turned out to be a lot more complex and uncertain than originally thought. Exhibit B is, of course, gene transfer. Exhibit C is drug development. Despite large investments in genomic technology, pharmaceutical productivity seems to have declined. 

What can be said, at least, is that legislators have moved slow: Collins described recent passage of legislation against genetic discrimination as one of his proudest achievements.  I wish it hadn't taken Congress 15 years. (photo credit: Roby72 2007)

Also at ASGT: Collins Steps Down

Francis Collins spoke for the first time after announcing his resignation after fifteen years as director of the National Human Genome Research Institute. Collins presided over the completion of the human genome project, as well as a series of other genome sequence and other "big-science" programs like the HapMap.

Attendance at Collins' talk seemed surprisingly spotty. His speech did not particularly highlight gene transfer research; the subject was stacked like cord wood along with other genome project achievements like pharmacogenetics and drug target identification. Perhaps tellingly in terms of where he sees the biggest impact of genomics, Collins said he intends to write a book on personalized genomics.

Collins did, nevertheless, offer a tip of the hat to the Leber's Congenital Amaurosis study, saying he was "exhilarated" by it. To be continued...(photo credit: dawn m. armfield 2007)

Also Noted: Almost Licensed

Also noticeable at this year's ASGT meeting was what seemed to be a larger volume of phase 2 and 3 studies. One session was devoted to "late stage" clinical trials. I did not attend this– it conflicted with sessions on immunology and cancer gene transfer. Still, one observer told me, informally, that the first gene transfer product could very well be registered for commercial use in the U.S. within the next year.

Any truth to this?  The U.S. database of gene transfer trials lists 6 phase 3 gene transfer studies in the last two years; this represents 40% of all phase 3 gene transfer studies ever registered with the NIH. Three of these studies involve cancer; the other three are for various cardiovascular treatments.  I took a look at the abstract and press materials for the session I missed on late stage studies. In one case, the product only showed significant efficacy in women. In another, efficacy was significant only in populations with particular genetic profiles. But one needs to be very cautious interpreting efficacy claims that depend on subgroup analysis.

The third study was referenced above- it involved use of AAV for treatment of a rare genetic disease, LPL deficiency.  An interesting twist here: the researchers first developed the intervention in the Netherlands. They exhausted the entire Dutch population of LPL deficient patients for their first trial, which did not successfully correct the deficiency. The next trial was pursued in Quebec with a fresh patient pool. According to various conversations I had, this trial showed a lot of promise. Press materials for the company sponsor, Amsterdam Molecular Therapeutics, state "upon completion of the study the results will be part of the filing dossier for the marketing approval of Glybera(R)."

A number of other orphan disease studies, like ADA-SCID-show a lot of promise. What is badly needed now is  careful analysis of the ethical and policy challenges of gene transfer in the post-licensure era. My postings on biological generics give some hint of what I believe will emerge as a major challenge in this field: cost and access. (photo credit: home invasion tour 2007)

Also Hot: Diplomatic Immunity for Vectors

Also hot at the ASGT annual meeting: immunomodulation and gene transfer. The immune system has proven the bane of successful gene transfer (truth be told, there are other banes-like delivery). It confounds results. It causes toxicity. It stymies efficacy. It's unpredictable. It behaves one way in some tissues-the blood- and another way in other tissues- the gut.

Talk after talk was devoted to ways of better managing immune responses in gene transfer studies. This consisted of recruiting: cancer gene transfer researcher Steven Albelda spoke about ways to reduce inhibition of immune response within tumors so that immune-based strategies can work against cancer. Antonio Chiocca discussed how the immune system thwarts cancer virotherapy (that is, use of viruses that selectively infect and destroy tumor cells) and how, in his estimate, translating this approach will require dampening the immune response of patients.  Along a similar vein, researchers in Quebec and Netherlands showed encouraging results using short-term immunosuppression in a protocol using AAV vectors against a rare genetic disease, lipoprotein lipase deficiency. (photo credit: Miss Starr, Neutrophil migrating across bone marrow, 2007)

What's HOT: ASGT Annual Meeting

I've just returned from the annual American Society of Gene Therapy Meeting.  In the next several posts, I share my impressions on the state of the field in 2008.

What's Hot? Retinal gene transfer. The buzzzzzz of the meeting was the recent promising results for the Leber's Congenital Amaurosis study (discussed in previous posts). In one session, U of Florida researcher William Hauswirth shared results of a third LCA study using AAV.  His talk described results using functional MRI showing that visual centers in the brain are activated in LCA dogs following application of his vector. As for the results of the U Florida study, 3 volunteers received vector so far. No visual recovery was observed per se, though they saw large increases in light sensitivity. Hauswirth attributed the modest visual recovery results to the fact that only one section of the retina received vector.

In talking with many researchers not involved with this study, it's clear that the field sees this as the most exciting development of the year, and is putting its money on this horse to ride the field out of adversity. (photo credit: Chubby Bat 2007)