Monday, December 20, 2010

More Gray Matter: Parkinson's Disease and Gene Transfer

Several groups are pursuing gene transfer strategies against Parkinson's disease. No small task, because for these approaches to work, investigators have to deliver vectors deep inside the brain using surgery. I have previously written that early phase studies using surgical delivery press the boundaries of acceptable risk, because patients can generally manage their disease adequately- though far from completely- with dopamine replacement, and study participation entails nontrivial surgical risks (by my calculations, about 0.5% chance of mortality, depending on the approach).

In the December issue of Lancet Neurology, Marks et al report results of a phase 2, sham controlled trial of CERE-120. The results were negative. That is, for the main measure in the study, improvement in symptoms at 12 months, patients receiving CERE-120 did not do significantly better than patients receiving sham. On the other hand, the product did not raise any major safety issues, apart from a hemorrhage during surgery in one patient.

The team performing the study has emphasized several "positive" outcomes. For one, patients receiving CERE-120 generally responded better than patients in the sham arm (though not significantly better- that is, differences may be attributable to chance). And on a secondary endpoint- response at 18 months- patients receiving CERE-120 did indeed perform significantly better. So did Ceregene score against Parkinson's disease? In an accompanying commentary, French Neurologist Alim Benabid says "the findings... provide the first clinical evidence of a clinical benefit of gene therapy in Parkinson's disease."

I ain't no neurologist, but I say: hold on a minute. When researchers start trials, they pick primary endpoints based on where they think they are most likely to succeed. In this case, the researchers picked improvement at 12 months, rather than at 18 months. From the looks of it, they backed the wrong horse- patients did significantly better at 18 rather than 12 months. What does this tell us? Success in a secondary endpoint might have occurred by chance, and the fact that researchers were unsuccessful on their primary endpoint indicates that they do not yet understand enough about their system to pick the "right" endpoints. So I see this as symptomatic of scientific uncertainty rather than a glimpse of medical destiny. [[One other issue to consider: it is possible that surgery itself (rather than gene transfer) may have caused symptomatic improvements.]]

The study was well reported and provides, yet again, evidence of the utility of sham comparator arms in studies involving Parkinson's disease. One disappointing feature, however, is that the authors did not report whether patients or clinicians could correctly guess their treatment allocation just prior to unblinding. Without this, it is difficult to exclude the possibility that any difference between groups- even at 18 months- was due to "placebo effect." (photo credit: Vin6, 2007)

Monday, November 29, 2010

Icarus, again: Adversity in another Gene Transfer Trial

Two weeks ago brought good news and bad news for gene transfer. First the good news. New England Journal of Medicine beatified a new gene transfer strategy for Wiskott-Aldrich Syndrome (WAS). WAS is a primary immunodeficiency that primarily affects boys. It is thus in the same family of disorders that have been, in varying degrees, successfully addressed using retroviral gene transfer. Like other immunodeficiencies, this represents relatively low hanging fruit for an approach like gene transfer, because scientists can access and target stem cells, and because corrected cells should be at a selective advantage for survival compared with uncorrected cells.

The NEJM article reported clinical, functional, and molecular outcomes for two boys in a trial based in Germany. Briefly the two boys were given a type of chemotherapy (in order to make space for genetically corrected cells), and then transplanted with “corrected” blood stem cells. The corrected blood stem cells contained a viral vector similar to those used in previous gene transfer trials of primary immune deficiency. The team saw: 1) stable levels of genetically corrected stem cells that expressed the WAS protein (indicating the genetically modified cells “took,” and produced WAS; 2) recovery of the function of a variety of immune cells; 3) reduction of disease symptoms, including improvement of eczema, and reduced severity of infections.

The article exhaustively ruled out events that have occurred in other, similar gene transfer trials in which children developed leukemias from the vector. Now the bad news. The same day NEJM published the results, American Society of Gene and Cell Therapy (the largest professional society devoted to gene transfer) released a statement saying that the German team just announceda serious adverse event in a gene therapy trial for Wiskott-Aldrich syndrome (WAS)”- one of the ten children in the German trial developed a leukemia.

And so continues the saga of gene transfer: three steps forward, one back. (photo credit: vk-red 2009)

Monday, September 20, 2010

Are Trials Necessary?

Today's New York Times ran a heartbreaking story by Amy Harmon about two cousins who developed melanoma. One was entered into a cancer clinical trial and received the investigational drug PLX4032. The other was ineligible for the trial, and therefore unable to access the experimental drug. Guess which cousin died?

The article is one in a series of Harmon articles that seems to raise questions about whether rules governing drug testing and research are depriving desperately ill patients timely access to curative therapy. In this article, the narrative takes aim at two practices: 1- the practice of including control groups within trials, and randomly determining that some patients will receive standard care that is widely regarded as inadequate; 2- excluding patient access to drugs that have not yet demonstrated unequivocal therapeutic advantage.

As with many of my blog entries, I preface this one by saying that I am not a cancer doc, and therefore not in a position to evaluate whether PLX4032 is the wonder drug this story makes it out to be. I also preface my comment on this article by acknowledging the incredible pain and anxiety that patients suffer when denied access to a trial, or when denied access to a preferred drug within a trial. These disclaimers aside, I found the tenor of this article very problematic.

First, the reason investigators randomly determine treatment choice in trials is because, at the outside of a well designed trial, there is genuine uncertainty about whether the new drug is better, the same, or worse than the (inadequate) standard treatment. Many doctors participate in trials because they fervently believe the new regimen is better than the standard one. But the evidence shows, again and again, that on average, new drugs outperform old ones in a small portion of instances (maybe around 15-20%). It is just as likely that new drugs will underperform standard treatments- making patients sicker perhaps, or failing to deliver as much punch. So one concern about the article is the premise that doctor's personal beliefs about which cancer drug will perform better in a randomized controlled trial carries some moral weight. The evidence shows doctors in the aggregate haven't a clue- which is why functional healthcare systems run trials.

A second troubling premise here is that there is no harm to allowing public consumption of drugs that are not yet validated in rigorous clinical trials. CEOs of many pharmaceutical companies perhaps may share this view. But the historical record shows otherwise: in fact, many patients are severely harmed when drugs are introduced into clinical use before they have been established as safe and effective. Perhaps a few readers out there may be familiar with thalidomide? Or autologous bone marrow transplantation for breast cancer? Ever considered the price tag on these new cancer drugs, and do you want your government or insurance company purchasing a potentially useless drug?

Still, article zeros in on an ethical tension that is very difficult to eradicate from clinical research. Patients want- and are entitled- to be treated as individuals. Physicians also prefer to treat patients as individuals. Clinical trials, however require that patients be treated as tokens of larger populations- that they be treated, in a sense, as "stand ins" for future patients. Randomization has not been shown to deprive patients of access to life preserving drugs. However, it does rob patients of fulfilling their desire to be treated as individuals and to exercise personal choice. And this is one of the reasons why the field of research ethics is endlessly fascinating, important, and nettlesome. (photo credit: travelingMango 2008).

Wednesday, August 4, 2010

Embryonic Stem Cell Trials Start Development

So, FDA has lifted a hold on the first ever clinical trial testing cells derived from human embyonic stem cells. The study- based in California and sponsored by the biotechnology company Geron (view press release here)- will administer cells derived from human embryos ("neural support cells") to ten patients with recent spinal cord injury with the primary aim of demonstrating safety. The same study had been initiated last year- but halted after safety concerns arose in rodent tests. According to news reports, Geron was able to deliver a clean package of studies to FDA. And so- roughly 20 years since the first ever gene transfer study, we now have the first ever human trial of embryo stem cell derived tissue.

Circumstances surrounding this study show all the signs of repeating phenomena surrounding other, highly publicized first in human trials. My book picks up on these signs as harbingers of challenge. Take, for example, the way the initiation of the study itself is seen as a milestone- as a visible sign of medical progress. This presents a regulatory decision as a stand in for study results; it confuses desire with results. And so, I worry when people like Alan Trounson, president of California Institute of Regenerative Medicine, say things like "I think it's a very important milestone for the whole industry... It's very important that they get on and treat the patients...." I also worry when I hear that share prices in Geron rose by 17% on news of the decision- as if permission to study a product is evidence of the product's promise.

The New York Times article reports that Advanced Cell Technology is seeking permission to test another embryonic stem cell derived tissue in human beings- this time for an eye condition. Approval of Geron's trial will surely blaze a path for the latter- though the ethical justification for proceeding in such research may prove more difficult than for spinal cord injury

(photo credit: Brennan G. Wills, 2010)

Thursday, June 17, 2010

Information: Stem Cell Tourism Redux (part 1)

The current issue of Kennedy Institute of Ethics Journal contains the first installment in a two part series on the ethics of stem cell tourism, by long time stem cell watcher Cynthia Cohen and Peter Cohen. The Cohens pull together a large body of news reports and internet posts on Russian and Indian private clinics offering stem cell interventions to foreign patients (who travel to these clinics because they cannot receive the nonvalidated interventions in their native countries).

They provide a very critical view of these clinics and the practice of offering nonvalidated stem cell interventions to large numbers of patients outside of clinical trials- a view that readers of this blog will recognize as one that I share: "those who travel to other countries for stem cell treatments enter into a sort of medical Russian roulette." I would add: they pay large sums to shady characters for the privilege.

The back end of the article takes issue with commentators who have offered a quasi-defense of stem cell tourism, viewing stem cell development as analogous to surgical innovation. These commentators have thus defended the idea of offering stem cells outside the trial context. According to the Cohens, these commentators "do not explain in what respects these interventions resemble surgical procedures and do not furnish reasons why clinical trials are not possible for them."

There is an intriguing theme in this article that ties in with my recent Science article. Namely, the Cohens are careful to point out that there are many legitimate stem cell scientists in Russia and India that have called on their governments to regulate stem cell clinics because their activities harm the reputation of unaffiliated stem cell researchers in the same country. More on how stem cell scientists have attempted to draw boundaries between their own work and that of these clinics in my next post... (photo credit: Alex McGibbon, (courtesy Banksy), 2006)

Wednesday, May 26, 2010

ASGCT, cont': Results on Fetal Tissue for Battens Presented

Robert Steiner, co-principal investigator in a fetal cell transplantation study involving the rare, fatal hereditary disease Neuronal Ceroid Lipofuscinosis (also known as Batten disease), presented results of a now completed phase 1 study. According to Steiner, the study involved the highest ever dose of stem cells delivered to the human brain. The trial involved six children with infantile and late-infantile forms of the disease.

Elsewhere, this safety study has been reported as "positive"- in the sense that there were no unexpected, stem cell related complications. Which is not to say the protocol was a picnic: the study involved (if I understood the presentation correctly) 14 trajectories to the brain, and an extended regime of immunosuppression that caused 23 adverse events. Steiner reported that none of the patients showed a clinical response- which is what one would expect in patients with such advanced forms of disease (hopefully, the research team conveyed the unexpectedness of clinical benefits to parents when they obtained informed consent).

Steiner also reported that, when one of the patients died due to natural course of illness, the family permitted the team to perform an autopsy. The autopsy ruled out the cell transplantation as a cause of mortality, and established that the tissues engrafted successfully. In the words of a press release, "By permitting the autopsy, the family allowed the researchers to learn very important details that will potentially benefit future patients."

Did the research team use the autopsy to determine whether the transplanted cells were expressing the therapeutic gene? If so, was the gene product taken up by surrounding tissues? Answering these questions would be key to maximizing the scientific value of the study, and thus redeeming the risks of surgery, immunosuppression, stem cell transplantation, and the many follow-up visits required of patients participating in the study. But from what I heard, the brain is in the hands of the company, and it is unclear whether they have performed these studies (and if so, whether the results will be reported). Let's hope the family's permission for autopsy allows the researchers to learn still more. (photo credit: dopamineharper 2009)

Tuesday, May 25, 2010

ASGCT, continued: Eyes on Stage

Predictably, the big presidential symposium at ASGCT reserved a slot for Jean Bennett, who led one of the three teams that have tested a gene transfer strategy for a rare genetic form of blindness, Leber's Congenital Amaurosis (LCA). Unpredictably, however, Bennett trotted out one of her "treated" patients, Cory Haas, along with his two parents, who sat up on the podium as Bennett went through her 45 minute presentation, which was titled "An Aye for Gene Therapy."

First, let me say that Bennett's results- as well as those of the other teams- continue to be very encouraging. In adults whose retinal tissues have degenerated, the approach has not restored vision, but it has also not raised any major safety concerns (apart from a surgical complication in one patient). In younger patients, the approach has shown safety with restoration of vision, and Bennett this time presented various functional data, along with neuroimaging data consistent with restoration of vision. And nothing that follows detracts from all the credit she and her team deserve for their smarts, scientific rigor, perseverance, and clinical accomplishments. Second, the family has agreed to go public, and this was not their first time on display. No doubt, they feel that putting themselves on display like his helps bring visibility to this important research. As well, they have their own battles to fight: only one eye has been corrected, and perhaps they feel that going public like this may help nudge regulatory authorities to clear the investigators to apply gene transfer to the second eye.

Nevertheless, I found Bennett's exhibition of her subject, and his parents, a case of poor judgment. And judging from one or two conversations with others in attendance, I was not alone. In my book, I warn against the perils of putting patients on display. It performs a rhetorical function that tends to neutralize critical thinking and indulge sentimentality. I found it particularly problematic that this would occur at a major scientific address: if there were skeptical questions to be asked (as there typically are at scientific meetings), who would dare ask them in front of a child and his parents? At any rate, Bennett used a short question and answer period following her talk by asking Corey and his parents a series of Diane Sawyer-like questions: "are you glad you joined the study?" "what was the most difficult part?" "do you have any questions?" She then elicited a round of applause "for the patients" from the >500 assembled attendees. Was the Q and A scripted? Was this a kind of victory lap for Bennett? Who knows.

Spectacular research, to be sure. But it makes for spectacle science as well. (photo credit: strangejourney 2009)

Saturday, May 22, 2010

ASGCT in Washington DC

Another year, another annual meeting of the American Society of Gene Therapy- now rechristened American Society of Gene AND CELL Therapy. The meeting ends today, and I am way behind in posts. There have been, to my knowledge, no startling new revelations about high impact trials or disastrous adverse events. The studies of Leber's Congenital Amaurosis- a rare genetic disorder causing blindness- continue to dazzle, with several groups presenting results showing consistent safety and functional recovery- especially in younger patients. The ADA-SCID data continue to show very encouraging results without any indication of the safety problems encountered using similar vectors. Same goes for the adrenoleukodystrophy study- now three children have received a lentivirus-based cell intervention. Again- no evidence that delivered cells are expanding in a way that would raise concerns about a malignancy, and the disease course for children appears to be significantly improved. Off, now, to catch a session on a new product for another genetic disease- LPL deficiency- which (by the title of the session) has been submitted for regulatory licensure. To be continued, with some ethical commentary... (photo credit: afagan 2007)

Monday, May 17, 2010

Conditions of Collaboration: Protecting the Integrity of the Scientific Enterprise

So what does it take to keep medical research a well-oiled enterprise that efficiently and effectively delivers cures? Lots of cooperation–or so I argue, along with co-authors Alex John London and Marina Emborg in a piece appearing in Science [a publicly accessible version of the essay is available at Science Progress]. Unfortunately, we argue, the way or system of drug development currently thinks about the ethics of clinical research does not presently place sufficient emphasis on the conditions necessary to sustain this cooperation.

Right now, oversight of clinical research is focused almost exclusively on protecting the personal interests of human subjects by obtaining valid informed consent and ensuring that risks are reasonable in relation to benefits. We suggest that this ostensibly private transaction between investigators and patient-volunteers has a public dimension in at least three ways. First, such private transactions inevitably draw on public resources. Second, such transactions have externalities- adverse events occurring on one trial have potential to disrupt collaborations elsewhere in the research system. Third, lax oversight of such private transactions creates conditions where consumers have difficulty identifying (and hence rewarding) producers of high quality goods (namely, trials that are well designed).

We suggest that, when considering whether to initiate highly innovative clinical trials that draw on such public goods, proper oversight and analysis must take into consideration factors that lie beyond the personal interests of human volunteers. (photo credit: McKillaboy, Cataglyphis velox 22, 2009)

Tuesday, May 11, 2010

Filing Cabinet Syndrome: The Effect of Nonpublication of Preclinical Research

Much has already been said about Filing Cabinet syndrome in medical research: the tendency of researchers to publish exciting results from clinical trials, and to stash null or negative findings safely away from public view in a filing cabinet. Nonpublication distorts the medical literature, because it prevents medical practitioners from accessing negative information about drugs. Recall that, back in 2004, attorney-general Eliot Spitzer sued Glaxo Smithkline for suppressing trial results that showed elevated risk of suicide for adolescents taking the antidepressant drug Paxil; this and several similar episodes led FDA, major medical journals, World Health Organization, World Medical Association, and others to require researchers to register clinical trials before they enroll any patients.

Yet important gaps remain. In the March 2010 issue of PLoS Biology, Emily S. Sena and coauthors provide the most detailed analysis yet of one of these gaps: nonpublication of preclinical (animal) studies. They aggregated results of 16 systematic reviews of preclinical studies involving acute ischaemic stroke, and used statistical methods to estimate the degree of publication bias, and the likely effect of publication bias on measured disease responses. Among other things, they found that 16% of animal experiments were not published, leading to a 31% overstatement of efficacy. The authors note: "we estimate that for the interventions described here, experiments involving some 3,600 animals have remained unpublished. We consider this practice to be unethical."

The authors urge that central registries of preclinical studies be established and maintained-- a call that is not likely to go heeded anytime soon by companies that have much at stake in the secrecy in preclinical research. But their proposal ought to be taken seriously by anyone committed not only to respecting animals used in medical research, but also protecting the welfare of human beings who might enroll in possibly unwarranted clinical research. (photo credit: amy allcock 2009)

Thursday, April 22, 2010

CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy

This month's issue of Molecular Therapy- the premium journal covering developments in gene transfer- reports two deaths in recent cancer gene transfer studies. Both studies involved a similar anti-cancer strategy, in which a patient's T cells are genetically modified to mount a strong and sudden immune attack against the patient's cancer (the particular genetic modification is known as "CAR," for chimeric antigen receptors). Both were phase 1 studies. Both patients died from what looks like "cytokine storm"- the same phenomenon that caused life threatening toxicity in the Tegenero TGN1412 study in 2005. In one case, the authors attribute death to the gene transfer; in the other, the authors categorize the death as possibly related to the gene transfer (the latter was previously described at ASGT in 2009).

In all likelihood, these patients (or at least, one of the patients) will be the third or fourth death in gene transfer that is clearly attributable to gene transfer. Don't expect too much public hand-wringing or media coverage, however: in both cases, the patients were adults and had terminal cancer. I have not made a careful study of these particular trials or the strategies they employ. So the following thoughts about these deaths should be read with caution:

1- Unpredictability: These deaths point, once again, to the unpredictability of strategies aimed at training the immune system to respond against tumors. Immune systems are notoriously difficult to model in animals, and as a result, every human study is essentially a shot in the dark. The authors of one of the reports sagely urge that phase 1 studies using similar strategies begin at low doses.

2-Where's the Toxicology? Neither report mentions anything about observing similar toxicities in preclinical studies. Indeed, neither report even mentions preclinical toxicology studies. One wonders why: were they done? how were they done? what was observed? For example, both studies involved immunosuppression co-interventions aimed at enhancing the effects of the T-cells (in one case, administration of the drug cyclophosphamide; in the other, use of nonmyeloablative conditioning). Were toxicology studies performed in animals receiving these immunosuppression treatments?

3-Did Investigators Give Preclinical Studies Their Best Shot at Producing Similar Toxicity? Both phase 1 studies were supported by preclinical studies using mice that lacked functional immune systems. One has to wonder how useful it is to test immunotherapies in mice that lack properly functioning immune systems. From what I can tell, in neither the first nor the second case did investigators perform preclinical studies that simultaneously delivered modified T-cells and immunosuppressive drugs.

4- Please: No More Gratuitous Appeals to the Integrity of the Investigators. An editorial by a leading expert on CARs accompanies the reports in Molecular Therapy and provides a very helpful summary and context of the events. It ends, however, with the statement "it is a great credit to all investigators involved that they have been so forthcoming in providing detailed reports of serious adverse events." I heard similar sentiments expressed when one of the deaths was presented at a scientific meeting last year. True- the research team did provide an unusually extensive report and investigation, including autopsy. However, careful and public reporting of serious adverse events is exactly what researchers are supposed to do in phase 1 studies involving highly innovative approaches; praising them for coming forward with this kind of information is a bit like congratulating Canada every time it holds a democratic election. One has to wonder whether there is a reserve of trial deaths that are never investigated or reported. (photo credit: Steve Kay 2008)

Tuesday, April 20, 2010

Testing Testing...: Personal Medicine, Breast Cancer, and Policy

Personalized medicine is supposed to usher an era in which treatments are tailored to individuals. And HER2 testing has long been seen as heralding the promise of personalized medicine: tumors that test positive for an amplified HER2 gene are more likely to be responsive to drugs, like trastuzumab, that block the HER2 receptor.

Some may see HER2 testing as foreshadowing a perfect future in which treatment decisions are coupled to molecular diagnostics. But Gina Kolata in the New York Times instead tells a story of shadows. Like all medical tests, HER2 testing is error prone: some tumors test positive when they are in fact negative, and others test negative when they are in fact positive. And some results are just plain ambiguous, with parts of the tumor being positive and other parts being negative. Kolata describes the challenges that women and their physicians confront when interpreting test results.

Most troubling in this story is the role, or lack thereof, played by regulatory agencies like the FDA. Quoting Kolata: "there is a proliferation of laboratories offering tests without F.D.A. oversight. But, for now, the agency has no specific plan to regulate the tests, in part because of lack of money." If FDA is not prepared to regulate tests because of resource constraints, and prescription decisions are likely to be increasingly coupled to diagnostic tests, it logically follows that FDA is not prepared to regulate the approval and use of newer generation, test-based drugs. In other words, FDA seems unable to establish the validity of labeling indications for drugs that rely on diagnostic tests. This can't be a good thing for patients, physicians, or third party payers (but is great for the makers of drugs and diagnostics, who thrive in this kind of clinical and regulatory uncertainty!) (photo credit: crafty dame, breast cancer cells, 2009)

Friday, April 16, 2010

Teaching Kills Blogging: Somewhat Recent Developments...

Dear Faithful Readers: Teaching has cut my blogging to a trickle, though the teaching has now begun to taper off. My silence is not for want of major developments in the last two months. Among a few highlights:

Obama picks members for his Bioethics advisory panel: White house recently announced membership of its "Presidential Commission for the Study of Bioethical Issues." The group is smaller than past Presidential panels. Its membership is lean on working bioethicists (3 or 4 who clearly fit the classic definition-- all others scientists, clinicians, federal employees, university administrators, or a disease advocate).

Health care reform (+ Translational Research) passes in the U.S.: Among the intriguing elements here is the relationship between reform and biomedical research. When Clinton proposed healthcare reform in the 1990s, there was much consternation in the research community that this would spell a retreat from investment in basic research. Indeed, failure to enact reform propelled a massive expansion of the NIH budget through the 1990s. This time around, healthcare reform has specifically integrated basic research. The law includes language creating a "Cures Acceleration Network" that would fund up to $15M/year in translational research (though the budget will depend on direct appropriation from Congress, and there is no certainty that it will be funded).

Gene Patents Voided: Following an ACLU challenge, a U.S. District Court Judge threw out Myriad Genetics' patent on BRCA1 and BRCA2 (genes associated with hereditary breast cancer; the company markets a $3K per pop test for mutations in the genes) by ruling that the genes are "products of nature." Products of nature are not patentable, though products purified from nature (e.g. enzymes, wood chemicals, etc.) are. The logic behind the decisions is that genes are better thought of as information rather than as chemicals, and that information extracted from the natural entities does not have distinct properties in the way that chemicals do. If ever there were a demonstration of the power of metaphors; suffice it to say, biotechnology companies will appeal. (photo credit: aurelian s 2008)

Monday, March 8, 2010

Ark, Troubled Waters, and Rainbows for Gene Transfer

This morning I awoke to a news report by National Public Radio's Joe Palca on promising developments in gene transfer. In it, Palca provided a good account of the field's travails, as well as some encouraging developments in the last few years. The story ended with the prediction that the coming "months and years" would bring landings for more common disorders like AIDS and cancer.

Coincidentally, the just released March issue of Nature Biotechnology ran a report on a front-runner for gene transfer commercialization: biotechnology company Ark Therapeutics gene transfer gliobastoma product Cerepro. The application for licensure of this product in Europe was unsuccessful (press release here). Recall that, last June, I described what seemed like unimpressive results from a phase 3 trial that were reported at an annual meeting of the American Society of Gene Therapy. Apparently, European drug regulators weren't impressed either (they cited flaws in trial design, including a small sample size and unconcealed allocation; Ark has asked the agency to re-examine their application).

But for those awaiting the first commercialization of a gene transfer product in a country with a robust drug regulatory system, there is still some indication that the rains may be subsiding: according to the report in Nature Biotechnology, Amsterdam Molecular Therapeutics has filed with EMEA for marketing authorization of their AAV product for a rare hereditary disorder, LPL deficiency; the company will soon file in Canada as well (the disorder is more prevalent in Quebec) (photo credit: Occhiovivo 2007)

Friday, February 26, 2010

Canada Human Research Ethics Policies: Take 2

In the Vancouver Olympics, Canada is tied for the most gold medals as of this writing. Will Canada also "own the podium" when it comes to providing a clear and effective voice for ethical human research?

Recall that, in a previous post, I mentioned that Canada was presently undertaking a major overhaul of its main research ethics policy- the Tricouncil Policy Statement. After issuing an intital draft, the panel charged with revising the document (PRE) released a second draft. In a few days, the comment period closes for this second draft. The policy will then be revised again and finalized.

I will be submitting comments on the new version, along with my research collaborators. Here are a few important problems that carry over from the previous version:

1) The draft, like the old version, does not quite get the foundations for research ethics right. As a consequence, principles like respect for persons or justice are made subservient to beneficence. This is not an obscure philosophical point: it sends a message to investigators and research ethics committees that these other principles matter less.

2) The application of justice in studies involving economically or socially disadvantaged populations is somewhat muddled. The draft defines justice in terms of what it is not, or what researchers should not do, rather than providing an affirmative description of what justice entails. Consider what it would mean if the application of "respect for persons" merely meant that researchers should avoid enrolling patients who did not consent, or that researchers should refrain from studies if risks are unacceptable.

3) The language on undue inducement has problems: The TCPS language implies that concerns about undue inducement arise out of a concern for risk (see point 1 above). It doesn't. It is unethical to pay individuals to override certain moral commitments (in government, we call this bribery), even in the absence of risk to the individual.

4) The chapter on clinical trials sends conflicting messages, and seems to imply that it is ok for doctors and institutions to put patients at medical disadvantage by enrolling them in research. Hard to imagine, if this is accepted, how conscientious doctors could ever participate in research, much less refer their patients to studies. Of particular concern, the chapter on clinical trials seems like it is trying to accommodate the unethical standards established by the International Council on Harmonization's Good Clinical Practice.

I hope the panel can correct these (and other) flaws, while preserving the many qualities contained in the proposed revisions. (photo credit: pmorgan 2004)

Transplanting Autoimmune Research

What's the difference between testing a typical small molecule drug, and testing a novel cell therapy strategy? And where might the latter raise ethical challenges that the former doesn't? These questions are extensively discussed in my book, and given human drama in a recent story by Jennifer Couzin-Frankel in the Feb 12, 2010 issue of Science ("Replacing an Immune System Gone Haywire").

Couzin-Frankel describes the numerous difficulties that researchers have faced in attempting to validate autologous bone marrow transplantation for the treatment of (often nonlethal but highly debilitating) autoimmune disorders like type 1 diabetes, Crohn's disease, and multiple sclerosis. The idea of this procedure is to "reset" the immune system by purging patients of their bone marrow cells, and then returning healthy bone marrow to them. The approach has shown some promise for certain autoimmune disorders. However, response is highly variable and unpredictable, and validating and applying bone marrow transplantation for autoimmune disorders is beset by numerous ethical and logistical difficulties.

A major one is the risk-benefit balance: bone marrow transplantation requires exposing patients to the dangers of the transplantation procedure (6.6% mortality in one report of lupus patients). And yet, the procedures appear to work better in patients whose disease is not yet advanced. Testing the procedure therefore requires recruiting more or less healthy, at risk patients (sometimes children) into studies that expose them to serious risk of mortality. Clinicians understandably balk at referring their patients to such studies, making recruitment very difficult.

A second challenge is funding: many of these approaches involve using the patient's own bone marrow cells. There is nothing to patent-- and hence, little commercial interest in bone marrow transplantation for autoimmune disorders. This deprives this promising line of research needed resources.

And all this creates the perfect storm for a series of ethical challenges not directly addressed in this article (but covered in my book and articles): the siting of such studies in low and middle-income settings. Prohibitive costs, plus extreme difficulty recruiting patients who are otherwise eligible for somewhat effective and extremely expensive monoclonal antibody therapies, makes the siting of such trials in economically disadvantaged settings very attractive. This gives rise to what I have elsewhere called "expedient" justification for recruitment. Not surprisingly, then, one of the first trials of the procedure was performed in Brazil, and the article closes by mentioning that ongoing trials involving high-income country researchers are recruiting from São Paulo, Prague, China, and Argentina. This is good news if people in those settings have a reasonable prospect of having widespread and affordable access to bone marrow transplantation once it becomes validated. But it is troubling indeed if people in these countries will be bearing considerable burdens for the sake of knowledge benefits that will primarily (or most expeditiously) accrue to patients in high-income settings. (photo credit: Wellcome Images, Compact Bone, 2009)

Saturday, February 13, 2010

Cooperation and Medical Research

Why do patients cooperate with medical researchers? So asks sociologists Mary Dixon-Woods and Carolyn Grant in a study analysis appearing in the June 2009 issue of Social Science and Medicine. You might think the answer is simple: they think they will benefit; they want to contribute to medical knowledge; or, they trust researchers who invite them. These are the simple and pat answers that have dominated the research ethics literature until now. However, Dixon-Woods and Tarrant probe deeper by asking why it is that patients feel safe and justified in joining research studies.

Using interviews from three different clinical studies, Dixon-Woods and Tarrant identify five recurring themes:

1- Research as Moral Act: Volunteers perceive participation as a moral act: they are willing to participate and cooperate only insofar as they are "able to defend the moral character" of their actions

2- Research as Risk: There was an awareness of risk and research scandals, and volunteers perceived a need to defend their choice to enter a study (rather than feeling like the choice was an obvious one that needed no explanation)

3- Trust in Regulation: Volunteers perceived that the research enterprise was regulated- that transgression of errant researchers would be "subject to punishment," though they had no familiarity at all with specific oversight structures

4- Signals of Trustworthiness: Participants sought "cues" and "signals" as to the values and trustworthiness of researchers. Informed consent, for example, was taken less as a substantive process than as a signal of the researcher's openness and integrity. Participants had strong expectations that researchers and affiliated institutions shared values of cooperation. And they saw the healthcare setting and affiliation of research personnel as "signaling" a kind of trustworthiness."

5- Trust of Professions: Building on item 4, participants made "swift" judgments about the trustworthiness of research personnel- not so much on the basis of their personal characteristics as their affiliation with trusted professions and institutions

The report helpfully contextualizes these findings within a broad sociological literature on giving, cooperation, and trust. Though the authors shy from offering specific prescription, two key themes emerge: oversight systems should focus on meeting these expectations; and regulation (whether external or internal to the profession), far from impeding research, creates social conditions in which patients can feel comfortable bearing risks imposed by strangers for the sake of strangers. (photocredit: Lucas 2008)