Prime Time for Embryonic Stem Cells?

According to a recent report in the Washington Post, researchers at Geron have received approval from FDA to initiate the first ever human trial involving stem cells derived from human embryos.  A story in the most recent issue of Nature provides more background.

Briefly, the study will involve transplanting tissues derived from human embryonic stem cells into patients who have recently suffered severe spinal cord injury. The principle behind the study is that the embryo-derived oligodendrocytes might repair myelin and restore the ability for nerves to transmit impulses.  According to the Nature report, Geron, submitted 22,000 pages of material to FDA, including data from 24 studies involving over 2000 animals.

So is the decision to initiate studies at this juncture prudent?  That's impossible to know without seeing the supporting data. What I can comment on, however, is the recurrence of a rhetoric that glosses trial initiation– rather than trial outcome– as a medical achievement in itself.  Whereas the former is a regulatory event, the latter is a clinical event. In my book about gene transfer, I argue that this sets up a cycle of expectation that is difficult to sustain given the scientific and clinical uncertainties. We saw this in the early days of gene transfer. Some examples of this "trial initiation"="medical achievement":

• "This... marks the dawn of a new era in medical therapeutics. This approach is one that reaches beyond pills and scalpels to achieve a new level of healing." (Thomas Okarma, Geron chief executive)

• "Today's news... is a milestone in the new era of hope..." (Amy Comstock Rick, Coalition for the Advancement of Medical Research)

• "This is what we've all been waiting for" (Robert Lanza, Advanced Cell Technology)

• "The announcement boosted the price of shares in [Geron]... up 56% from the day before the announcement" (Meridith Wadman, Nature, Jan 27, 2009)

I wish Geron, and the patients enrolled in this study, all the best.  But if embryonic stem cell work is anything like practically every other major medical advancement, be prepared for a very long, tough slog with lots of setbacks.  In one of the stories, Sean Tipton from the Coalition for the Advancement of Medical Research, commented  "This is a trial of one particular application, not a trial of all embryonic stem cells." That sounds just about right. (photo credit: no typographic man, UlamSpiral (negative), 2006)

Age of Risk: Biologicals

Approving new drugs is a risky business. Despite best efforts (and frankly, some less than best efforts), newly approved drugs frequently turn out to have unexpected toxicities. One example is unexpected heart toxicity associated with the use of the common pain-killers like rofecoxib (i.e. Vioxx).  Another is the surprising heart toxicity associated with the wonder drug for AML (a type of leukemia), imatinib mesylate (i.e. Gleevec).

According to a  2002 paper in JAMA, 8% of new drugs approved by FDA receive "black box" labels warning of toxicities that were not originally detected in drug trials. Another 3% are withdrawn from the market because of safety concerns. 

But what about biologics- vaccines, monoclonal antibodies, recombinant protein products, cell derived agents, etc.? There are a number of reasons why one might anticipate even higher rates of "unexpected" toxicities with this class of therapeutics. For one, they frequently cause immune reactions that are exceedingly difficult to anticipate in animal studies. For another, small alterations in production can dramatically change the composition and properties of a biologic product. For still another, biologics often have a very high degree of species specificity, limiting the predictive value of animal studies.

According to a recent report in JAMA led by Thijs Giezen (October 22/29, 2008), 24% of biologics approved for marketing in Europe received "black box" warnings.  For first-in-class agents, five of eight compounds were subject to regulatory action following approval.  A story in the January 2009 issue of Nature Biotechnology (Jim Kling) provides some perspective on these findings: most biologics are used to treat life threatening illnesses, which may make people more susceptible to toxic reactions (on the other hand, toxicity might be difficult to detect amidst the noise of disease course).

Bottom line: as translational researchers pursue biologics, uncertainty will continue to present a major challenges, necessitating new approaches to pharmacovigilence and trial design. (photo credit: teotwawki 2005)

What Will the New Year Bring?

My hope is that, with a new Presidential administration, certain research and ethics policies of the U.S. government might be revisited. One such policy is the FDA's replacement of the Declaration of Helsinki with the International Conference on Harmonization's Guideline for Good Clinical Practice (GCP) for foreign studies.  Recall that, in May, I lamented what at that time was a proposed policy change (it was finalized on October 27, 2008).

In the January 3 issue of Lancet, Charles Weijer, Eric Meslin, and I briefly lay out reasons why FDA's action is regrettable, and how GCP and Helsinki differ.  We urge the incoming administration to review this policy, and for medical societies to take action now and endorse Helsinki.  Our comment is featured, and is thus accessible for free at Lancet. (photo credit: Vilhelm Sjostrom, "Happy New Year 2009 from Helsinki, Finland," last seconds of 2008)