Clinical trials can be vexing, just ask anyone associated with Osiris Therapeutics, a leading stem cell therapeutic company. The company recently announced that their mid-stage, Phase II trials to treat chronic obstructive pulmonary disease (COPD) with adult stem cells (called Prochymal) did a great job reducing inflammation, but failed to improve pulmonary function. The 62 patients enrolled in the trial will be followed for two years in order to assess possible long term effects of the therapy. Nevertheless, these results reveal how complicated and unpredictable clinical trials can be.
COPD is really a combination of two maladies, chronic bronchitis and emphysema, rolled into one diagnosis. The disease commonly is caused by smoking, which triggers an abnormal inflammatory response in the lung in some individuals. In the larger airways, this inflammation causes chronic bronchitis, while in the microscopic lung sacks called alveoli, the inflammatory response causes emphysema, which is the destruction of the lung tissues where oxygen and carbon dioxide are exchanged. The result of this double inflammatory whammy is to limit the flow of air to and from the lungs causing shortness of breath. COPD is poorly reversible and usually gets progressively worse over time. In 1990, COPD was the third leading cause of death worldwide.
"...anyone would have predicted a priori that reducing lung inflammation would translate to improved lung function."
Given the central role of inflammation in the pathogenesis of COPD, anyone would have predicted a priori that reducing lung inflammation would translate to improved lung function. But, this is like believing that the baseball team with the most hits will automatically win the game. It is not uncommon for such surrogate measurements of efficacy to fail to predict the final outcome—the full game must still be played and the clinical trial done before the outcome can be certain.
Osiris is also testing Prochymal for its ability to treat other inflammatory diseases, so the reduced inflammation seeing in the COPD trial might be a good omen for these other maladies, even if Prochymal is of little benefit to patients with COPD. Unfortunately, however, last month Osiris was forced to discontinue enrollment in a phase III trial to treat the chronic inflammatory bowel condition known as Crohn’s disease. The reason for this, according to the company, is that patients on the placebo arm of the trial were doing unexpectedly well and interim data analysis indicated that this response would make it impossible to show a benefit of the Prochymal therapy. After examining the data with the FDA, it was concluded that that there was a potential “systematic design flaw” in the trial that “might be related to the fact that patients responding to the initial stem cell therapy were eligible to participate in a second, longer-term trial evaluating Prochymal as a maintenance therapy. Because the current standard for determining response of Crohn's patients to therapy is largely subjective, there may have been response bias to meet the eligibility requirements for continuation of therapy in the longer-term maintenance trial”.
Prochymal is a preparation of mesenchymal stem cells obtained from the bone marrow of healthy donors and specially formulated for intravenous infusion. In addition to Crohn’s disease, Prochymal also is being tested in two other Phase III studies to treat both acute and steroid-refractory graft-vs-host diseases (or GvHD). The FDA granted Prochymal Fast Track status for these and Crohn’s diseases and both the FDA and the European Medicines Agency granted Prochymal Orphan Drug status for GvHD. In addition to the COPD trail, Osiris is also conducting Phase II Prochymal trials for the treatment of acute myocardial infarction and type 1 diabetes. The therapy also is being developed as a potential treatment for acute radiation syndrome.
"...the company has a lot riding on Prochymal and can ill afford any further
clinical trial snafus."
Osiris also has another stem cell product in the pipeline, called Chrondrogen, which is being tested for its ability to regenerate cartilage. Last November, Genzyme paid Osiris $130 million upfront and promised up to $1.3 billion more in milestone and other payments to gain commercialization rights to Prochymal and Chondrogen outside the U.S. Osiris retains the rights to market these products in North America. Clearly, the company has a lot riding on Prochymal and can ill afford any further clinical trial snafus.
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© 2009 Steven S. Clark, PhD, some rights reserved. Articles contained herein, are meant to be distributed freely to interested parties. However, any use, including excerpts from any article, must credit Steven S. Clark and provide a link to the original article published in BioScience Biz.
Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, neither Steven S. Clark, nor other authors, assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.
Science and ethics in the embryonic stem cell debate
The Medieval philosopher, Boethius, tackled the esoteric question of what is a human and came to the conclusion that “human is born of human”. There is a certain circular, facile truth in this conclusion that reminds one of the modern right-to-life refrain that “life begins at conception”—an argument that seems as unsatisfying as any argument that has been reduced to a cliché. It is repeated so often and so glibly that the basis of the argument goes unexamined and unchallenged.
This “life begins at conception” reasoning, leads to a casuistic rhetoric where harvesting embryonic stem cells (ESCs) from a five day old human embryo called a blastocyst, for the purpose of treating human ailments, is akin to killing a living adult in order to harvest his organs to transplant into someone else. But how do we cross the chasm of logic to believe that a blastocyst is the moral equivalent of an adult human? This is an unexamined and unspoken conclusion that looks very different in the light of modern biology.
Before exploring the premises underlying the right-to-life position let me acknowledge that at this point, some will ask, why revisit this debate? Haven’t embryonic stem cells been rendered unimportant in the face of the research success of adult stem cells and in view of the fact that we can now reprogram adult cells to become stem-like, thereby avoiding the destruction of embryos to harvest ESCs?
Not so fast.
The fact is that we are rapidly driving, some would say careening, toward the day when ESCs will be used to treat patients. Despite the exciting advances in stem cell alternatives, ESCs still play a role that adult and reprogrammed adult cells cannot supplant—yet.
The FDA recently approved the first ESC clinical trial to treat patients with spinal cord injuries. The California Institute for Regenerative Medicine that oversees the $3 billion stem cell investment that came out of Proposition 72 in 2004, recently awarded grants specifically for supporting research leading to FDA applications to use ESCs for experimental therapeutics. A medical doctor in India claims to have treated a quadriplegic with human ESCs, with modest results. Doctors in other countries make similar claims, raising the specter of unregulated “stem cell” tourism and unfettered treatment of patients with insufficiently tested ESC therapies—unregulated clinical trials in reality.
As we rapidly approach the era of stem cell therapy, or regenerative medicine, if in fact we are not already there, the debate over whether this technology represents a “brave new world” or a Faustian bargain will only intensify and I believe it will do so very soon. At the moment, this debate seems to be in a latent period due to the recent discovery that adult cells can be reprogrammed into stem cells. Opponents of ESC research hope that this advance will negate their ethical concerns about destroying human embryos in order to obtain stem cells. After all, if you can pluck a skin cell from someone’s arm, put it in a broth and, presto, pull a stem cell out, why would anyone need or want to do research with stem cells obtained from an embryo? But, the inconvenient truth behind these reprogrammed cells has not been fully explained. The fact is that they, too, have the potential to develop into persons. A scientist at MIT reprogrammed a mature mouse blood cell into a stem cell and used it to derive a whole new mouse. Very recently, two groups in China reported doing the same thing beginning with mouse fibroblasts and ending up with cloned animals. Let us consider how this ability of these so-called induced pluripotent stem cells (iPS) affects the whole stem cell debate.
Unpacking the right-to-life argument
I’ll begin by unpacking the right-to-life argument that “life begins at conception. It is abundantly clear that when a sperm fertilizes an egg cell, a cellular entity is created that can grow into a fully developed person. So, in a sense one can indeed claim that “life” begins at fertilization. But this argument assumes, and leaves unstated, that society is, therefore, obligated to give the same level of respect to a fertilized egg as it gives to an adult human.
Thus, the underlying ethical argument here really is not about “when life begins” (indeed there is no precise time where this happens—it is a process lasting a couple of days), but about when is society obligated to give full respect to human life. This is the essential ethical issue on which the whole debate should focus.
Let me illustrate the idea this way: We all agree that a living woman deserves our full moral consideration; society cannot legitimately take her life or deny her other life-related freedoms without good cause, such as committing a crime. On the other hand, neither a live dog nor a clearly dead human elicit the same level of consideration from society. This means that simply being alive, as in the case of the dog, or simply having a human body, as in the case of the corpse, do not provide a sufficient basis for assigning the full moral consideration that we give the woman. It follows that there is something inherent in the adult woman that we all readily recognize, but that we, equally readily, do not see in a live dog or a dead person, which tells us she deserves a greater level of moral respect. This inherent worth in the woman that we all innately recognize is the crux behind making sense of the embryonic stem cell debate.
Viewed in this way, the question with ESC research becomes this: does a blastocyst that was created by a human (through in vitro fertilization) and that lives in a petri dish and lacks a brain, personal history, personality or any recognizable human trait is the moral equivalent of a living adult human that enjoys all these attributes? Do we innately recognize something in the blastocyst, like we do in the woman, which compels us to assign full moral recognition to a five-day old sphere of cells that is no larger than a period at the end of a sentence?
At this juncture, some will argue that the fertilized egg possesses a completely novel human genome that denotes a unique genetic human being, and that this makes it deserving of full moral consideration by society. But, this argument has this major problem; certainly, genetic makeup is necessary and sufficient for determining that an embryo is Homo sapien, but genetic makeup, no matter how unique, is not sufficient for determining moral standing. If it was, then skin cells, which have the same genes as the fertilized egg from which they came, should also have equal moral standing with the fertilized egg.
that, in fact, it is not a person at that time."
It also could be argued here that an important difference between a fertilized egg and a skin cell is that the former has the "potential" to develop into a mature human person, while the latter does not. But there are problems of both semantics and logic with this contention. For instance, "potential" describes something that can, but has not yet come into being. In other words, to acknowledge that a fertilized egg has potential to become a person means that, in fact, it is not a person at that time.
Furthermore, it is not logical to assume that “potential” confers any a priori obligation--while I may have the “potential” to become President, that obligates no one to play “Hail to the Chief” when I enter a room. So, based on potential, there is no compelling reason to afford a blastocyst the same obligation we offer the adult woman.
Conditional potential of stem cells
It also is important to understand that a thing’s “potential” can be altered by circumstance. Thomas Aquinas, the great Catholic theologian and philosopher, made this argument about “potential” many years ago. He explained that for potential to be present, a thing must have the capability of realizing that potential. Thus, a piece of paper has the potential to be burned, because it is burnable. Conversely, a bucket of water does not have the potential to be burned because it is not capable of being burned.
Certainly we now know that water can be given the potential to burn, but only under specific electrolytic conditions that separate oxygen and hydrogen from the water molecules. So, the conditional circumstances in which water exists determine its potential to be burned.
In the laboratory, human ESCs are harvested from a blastocyst that has only lived in a tissue culture dish. As long as a blastocyst lives in the petri dish, it has zero potential to become a person. This can only happen if someone intentionally inserts it into the womb of a woman who has been hormonally manipulated to mimic pregnancy. Only after these human efforts, like the human efforts needed to make water burnable, can the tissue culture organism then acquire the potential to become a person.
From animal cloning, which is now a common practice, we know that under the proper conditions, we can reprogram adult cells back to an embryonic state where they acquire the ability to grow into an embryo and a fully functioning animal. Therefore, modern science tells us that, like a blastocyst that lives in a petri dish, a blood cell that lives in your veins has conditional potential to develop into a person. Since we do not confer any special moral status to a blood cell what then compels us to confer such status to the blastocyst that was created in a laboratory and that lives in a petri dish or frozen in a liquid nitrogen tank? After all, they both have similar conditional potential to become a person.
Thus, like genetics, “potential” is not a sufficient basis to compel us to confer the same moral status to a fertilized egg that we reserve for a living person.
At what point do we give a developing embryo full moral consideration?
It, admittedly, is very hard, if not impossible, to know when we ought to bestow full moral protection to a developing human embryo. But, I submit that we can know when the embryo does not enjoy the same consideration we give to an adult. To illustrate this point, consider this thought experiment—you walk past a building and see a fire raging inside. Moreover, you also see a man struggling to get off the floor and escape the conflagration. You see that he is lying next to a tank that you know contains thousands of frozen human embryos. What would you do if you only had time to make one trip into the burning building?
Most of us would opt to rescue the man indicating that we recognize a greater moral responsibility to one anonymous living adult person than we do to a tank full of nascent persons. Indeed, most of us would opt to rescue a dog before the tank of embryos. In other words, we do not innately view thousands of five-day old embryos as moral equivalents to a single fully formed person any more than we view a live dog as the moral equivalent of the woman. To do so, we have to conjure up a special respect for embryos that is based on the imperfect arguments discussed above.
Unfortunately, poor Boethius, a Christian, ran afoul of the Visigoth rulers of Rome and was executed in an especially gruesome way. They wrapped a rope around his head, inserted a stout stick and twisted it until his skull burst. I suspect that when the right-to-life community becomes aware of the ability of reprogrammed adult cells to become people, the debate will flare once again generating Boethian-sized headaches on both sides.
© 2009 Steven S. Clark, PhD, all rights reserved.
Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, neither Steven S. Clark, nor other authors, assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.