Lost in Translation

Tea Leaves: Predicting Risk and Benefit in Translation

2011-03-21T14:31:00.008-04:00

Every early phase trial begins with a series of predictions: that a new drug will show clinical utility down to road, that risks to study volunteers will be manageable, and perhaps, that patients in trials will benefit. Make a bad prediction here, and people potentially get hurt and resources wasted. So how good a job do we do with these predictions?

Hard to know, but given the high rate of failure in clinical translation, there are grounds for believing that various stakeholders go into early phase trials with an excess of optimism. In the current issue of PLoS Medicine, Alex London and I posit two problems with the way decision-makers make predictions in early phase trials. First, they underattend frequent and systematic flaws in the preclinical evidence base. Secondly, they draw on an overly narrow evidence base (what we call "evidential conservatism") that obscures an assessment of whether preclinical studies in a given research area are a reliable indicator of agent promise.

As an open access journal, readers are invited to view our article here. The article has garnered a decent amount of press- digestible summaries can also be found at the Scientist and Pittsburgh Gazette. Also check out a commentary commissioned by the journal editors. (photo credit: canopic 2010)

Dirty Windows of Drug Development

2011-02-08T20:24:00.007-05:00

Think of clinical trial data as a window on the efficacy and safety of a drug. Think of data protection and trade secrecy as soot. The above picture? This is the public view on drug safety and efficacy.

According to a recent report in Nature Biotechnology (Feb 2011), medicine may be getting some soapy water and a squeegee, thanks to several policy initiatives at drug regulatory authorities. In Europe, the main drug regulatory authority, EMA, recently issued a policy that will make publicly available "full clinical trial reports"-- even for drugs that are not approved for licensure.

The reforms roughly parallel a series of proposed policies at FDA under the FDA Transparency Initiative. Among the proposed items that would be publicly accessible: when an application has been submitted to the agency (or withdrawn); whether a significant safety issue triggered withdrawal, and reasons why the agency turned down an application.

Disclosure of such information carries some risk. Contrary to common belief, information disclosure does not level all power and influence, as some parties are better equipped to aggregate, analyze, and act on information. No doubt, such transparency will be used by various parties to harangue FDA for otherwise enlightened regulatory decisions.

However, what the public sees of safety and efficacy information- to mix metaphors- is merely the tip of the iceberg. The Nature Biotechnology report, for example, describes the case of Pfizer's SSRI drug Edronax. Published trials included data on 1600 patients, but in actuality, trials involved 4600 patients. When complete data sets were obtained and reviewed, the drug turned out to be no better than placebo, and possibly unsafe (read more here). [[Yet one more reason to wonder what Canadian Institute of Health Research was thinking when it appointed Medical Director of Pfizer Canada to its Governing Council.)]]

Any transparency reforms would provide a much better basis for a) circumventing ethically suspect information practices so that healthcare systems can assess the totality of evidence on drug safety and efficacy, and b) getting a better understanding of the drug development process- warts and all. (photo credit: Lulu Vision 2007).

More Gray Matter: Parkinson's Disease and Gene Transfer

2010-12-20T12:16:00.005-05:00

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)

Icarus, again: Adversity in another Gene Transfer Trial

2010-11-29T09:38:00.003-05:00

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 announced “a 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)

Are Trials Necessary?

2010-09-20T17:25:00.006-04:00

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).

Embryonic Stem Cell Trials Start Development

2010-08-04T17:48:00.008-04:00

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)

Information: Stem Cell Tourism Redux (part 1)

2010-06-17T11:05:00.009-04:00

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)

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

2010-05-26T16:54:00.002-04:00

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)

ASGCT, continued: Eyes on Stage

2010-05-25T10:35:00.006-04:00

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)

ASGCT in Washington DC

2010-05-22T09:26:00.003-04:00

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)

Conditions of Collaboration: Protecting the Integrity of the Scientific Enterprise

2010-05-17T22:11:00.006-04:00

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)

Filing Cabinet Syndrome: The Effect of Nonpublication of Preclinical Research

2010-05-11T13:35:00.005-04:00

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)

CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy

2010-04-22T10:24:00.008-04:00

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)

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

2010-04-20T18:57:00.005-04:00

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)

Teaching Kills Blogging: Somewhat Recent Developments...

2010-04-16T15:16:00.011-04:00

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)

Ark, Troubled Waters, and Rainbows for Gene Transfer

2010-03-08T18:06:00.002-05:00

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)

Canada Human Research Ethics Policies: Take 2

2010-02-26T11:55:00.004-05:00

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

2010-02-26T11:21:00.005-05:00

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)

Cooperation and Medical Research

2010-02-13T22:50:00.004-05:00

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)

Annus Mirabilis for Gene Transfer

2009-12-29T15:20:00.005-05:00

Time to review the year 2009 for cutting edge clinical research. For the field of gene transfer, it has been an annus mirabilis: a year that has seen very encouraging results in a wide variety of human clinical studies, as well as preclinical studies. Indeed, I regret that this blog has only been able to cover a few of the former, and very little of the latter. Here are a few highlights from clinical studies:

• in March 2009, Italian researchers reported major clinical improvement in eight of ten children participating in a gene transfer study involving ADA-SCID. [discussed here]

• in June 2009, researchers at Penn / Scheie Eye Institute reported very encouraging outcomes in three children with hereditary blindness, including evidence of visual recovery. [discussed here]

• in September 2009, researchers reported "marginal effectiveness" in preventing HIV infection for a gene transfer-based vaccine. These findings from this trial (the "RV144 trial") were unexpected after abysmal trial results involving a related strategy (the STEP trials). These are the first encouraging results from any HIV vaccine study conducted to date. [described here and here].

• in November 2009, researchers at Paris-Necker reported very encouraging outcomes in two children with adreno leukodystrophy who received a vector derived from lentiviruses [discussed here]

The decade began with a series of very inauspicious clinical outcomes in gene transfer, and a sharp abatement in the volume of clinical testing. The decade ends with several highly encouraging results from well designed and executed clinical trials. (photo credit: Xavier Luque 2009)

Finding Skew: Informed Consent and Bias in Clinical Trials

2009-12-04T17:20:00.005-05:00

Clinical researchers have long claimed that patients who enter clinical trials are better off medically than those who don't. I'm open to the notion that patients might derive personal meaning from trial participation, but I've always been dubious of the suggestion that trial participation in itself is therapeutically beneficial–above and beyond drugs received– in part because this has never been demonstrated in a convincing way. I've also worried about the way the "trial effect" has been occasionally mobilized to recruit patients, or to apologize for studies of dubious design. Last, I've worried about the ethical implications of the prospect that, in order to receive top quality care, patients should be enrolling in (or have access to) clinical trials.

One reason I have been skeptical of the "trial effect" is that trials do not enroll a random sample of patients. Ethical research requires informed consent, and if patients who consent to trials have different characteristics than those who decline, it seems plausible that they will have different medical courses. UK researchers led by Andrew Clark recently put this thesis to the test (Eur J Heart Failure; also reported in the December issue of Nature Medicine). In their study, they asked a large sample of patients whether they were willing to enter a clinical trial. They then followed the clinical course of patients who declined, and compared them with patients who consented to participation but were never enrolled in a clinical trial. They found that patients who accepted enrollment had better clinical outcomes- even when factors like age, other sicknesses, or drug use.

The finding raises a number of interesting questions about tensions between study validity and informed consent. It does not suggest that we should relax consent standards to reduce bias- though some may be tempted to view the study in this way. It does, however, raise questions about how findings in clinical trials should be interpreted when applying them in real clinical settings. And it provides another problem for those who are attached to the position that trial participation is, in itself, therapeutic. (photo credit: funkandjazz, Skew, 2007)

Expectation is a Vascular Condition: Thoughts on Media Coverage of "Liberation Procedures" for Multiple Sclerosis

2009-11-24T11:10:00.008-05:00

Disclaimer to all readers: I am not expert in multiple sclerosis. I am not intimately familiar with recent research findings on a novel surgical treatment ("liberation procedure") for multiple sclerosis that have received wide coverage in the Canadian media.

Now here are my "claimers:" recent media accounts of this novel approach border on the irresponsible, and point to serious problems with the way many media outlets cover translational clinical research. My second "claimer" is that such media coverage has important consequences for patients and the research community.

Finally, a point of clarification: my comments below concern the quality and consequences of media coverage, not the merits of the medical procedure discussed.

Here is the background: on November 20, the Globe and Mail ran a feature by veteran reporters André Picard and Avis Favaro titled "Researcher's labor of love leads to MS breakthrough." The story described a novel theory of an Italian researcher, Paolo Zamboni, that MS "is not, as widely believed, an autoimmune condition, but a vascular disease. More radically still, [an] experimental surgery offers hope that MS... can be cured and even largely prevented." Said Dr. Zamboni, "I am confident that this could be a revolution for the research and diagnosis of multiple sclerosis." The news story then describes an Italian study that performed the surgical procedure in 65 patients; the patients saw their disease virtually eradicated.

Like practically every other news article of this species, the reporters do two things. First, they truck out a few patients to proclaim the miracle cure (said one: "I don't remember what it's like to have MS"). Second, to establish credibility, the reporters throw in the perfunctory killjoy comments of a few scientists: "skeptics warn the evidence is too scant and speculative."

As observed on the excellent NPR program On the Media, media coverage of medical research and breakthroughs "overflow with optimism and excitement, offering hope for millions." According to long-time media analyst Gary Schwitzer, "What they don't overflow with is accuracy, context and journalistic responsibility." (Schwitzer, by the way, runs an excellent blog on health news coverage).

Here are some concerns I had about the Globe and Mail story:

• the story reports on clinical research findings. The story did not say, however, that the results have not been published and subjected to peer review.

• the story did not say whether the studies were well-designed: was there a control or placebo arm, for example? the story did not mention that placebo responses can be especially high in the setting of surgical interventions. Nor did it mention that placebo responses are often high in the context of remitting diseases like MS.

• the story wrapped logical fallacies within emotive proclamations. For example, what, precisely, could it possibly mean to say "I am confident this could be a revolution..."?

• the story was not linked in any way to any particular event. Usually reports like this follow from major scientific publications, or presentations at medical conferences. This story, however, is "free floating"- which makes it much more difficult to contextualize (why is it being reported now? how well have the findings been vetted? how did the researchers capture the attention of journalists?).

• the story contains statements that are deeply suspicious. One example is that Zamboni claims MS is not an autoimmune condition. Here is the very first line in the abstract of Professor Zamboni's most recent publication: "Multiple sclerosis is primarily an autoimmune disorder of unknown origin."

• the story did not address the correlation and causation problem. The story (and Zamboni) claim that vascular malformations cause MS symptoms, because the researcher discovered that many MS patients have "malformed or blocked" veins draining the brain. But an alternative explanation would be that malformations or blockages are themselves caused by MS- that they are symptomatic rather than causal. Any news coverage of correlation should always address the issue of cause.

And the consequences? Do a google search yourself on the procedure (CCVSI) to find out how much chatter there is among expectant patients, who (judging from discussions) are wondering whether they can travel to Italy to receive the "treatment." And today, the Globe and Mail reports that the MS Society of Canada- portrayed as sourpuss nabobs of negativism in the previous article- will now fund CCVSI "with significant research dollars" in response to "the overwhelming public response to the media stories."

Surely, more research, more trials, more basic science is needed. If indeed this approach is a promising as reported, it should be subject to rigorous clinical testing. But can anyone seriously argue that media coverage of this low quality should set the research agenda and decide how scarce research resources are allocated? (photo credit: xbloodsin, sepulcrum, 2008)

More on Lenti's, Gene Transfer and Adrenoleukodystrophy

2009-11-12T11:48:00.008-05:00

(...continued from the previous post). There are several features that make the recent Adrenoleukodystrophy (ALD) gene transfer study noteworthy.

1- A New Viral Vector Debuts: this is the first successful application of HIV-derived viruses in gene transfer (lentiviruses). These vectors have various advantages over retroviruses used in other protocols. One is that, in theory, at least, they are supposed to be safer. Previous trials of the same team (different disease) involving retroviruses triggered leukemia-like disorders in several volunteers. In this study, the authors do not detect any evidence that cells are poised to cause a malignancy. However, in a post this summer, I noted that another trial involving thalessemia and lentiviruses did, indeed, detect clonal enrichment. And the ALD study enrolled only two patients- if there were going to be safety problems detected, they'd need to be massive to be detected in so small a sample of patients. Thus, despite the encouraging findings in the ALD study, the safety of lentiviral gene transfer remains to be firmly established.

2- Prior Animal and Clinical Experience are Successfully Integrated: here is one instance where favorable clinical outcomes were achieved on the basis of limited preclinical evidence. Specifically, the authors previously tested their approach in mice, but because rodents do not develop the same pathology as human beings, they were uncertain whether the gene correction would be sufficient to correct the disorder in human patients. These animal studies were bootstrapped with extensive experience with bone marrow transplantation in children with ALD. Rarely is this transition from rodents into clinical applications so successful. All the more surprising- this is occurring within the realm of central nervous system disorders, which have a particularly high rate of failed drug development.

3- Patients in the Service of Science: This study will no doubt be perceived as a story of "science in the service of patients:" a team of clinicians applying cutting edge discoveries to do the best they can for their patients. But it is as much- perhaps more- a story of patients in the service of science. The study is notable for how well it used the occasion of ALD to make more fundamental discoveries. For example, in a "Perspective" piece that accompanies the published trial, Luigi Naldini describes this as what "may be a first glimpse of live [generation of new blood and immune cells at the level of DNA]." Naldini also notes how the study developed and applied new techniques for ruling out clonal dominance that "will likely become a gold standard." Also intriguing is the hint that this approach may be applicable for other disorders involving the central nervous system, and the finding that only a small amount of gene correction is needed to arrest the pathology. (photo credit: photobunny 2007)

Gene Transfer and Adrenoleukodystrophy: There Will Always Be Paris

2009-11-12T10:51:00.007-05:00

Last week's Science magazine reported what seems likely to count as one of gene transfer's greatest clinical successes to date: stabilization of adrenoleukodystrophy in two boys receiving genetically modified blood stem cells. Preliminary results of this study had been presented at this summer's American Society of Gene and Cell Therapy meeting.

Adrenoleukodystrophy (ALD) is a rare hereditary brain disorder in which a deficiency in a gene, ABCD1, causes degeneration of tissues (myelin) that insulate cells in the central nervous system. The disease is familiar to many because of its most famous patient, Lorenzo Odone, whose story was featured in the movie Lorenzo's Oil. Untreated, ALD is invariably fatal.

Because myelin cells originate from blood stem cells, researchers had previously used bone marrow transplantation to successfully halt progression of demyelination in ALD patients. However, bone marrow transplantation has two severe limitations: many patients lack matched bone marrow donors; second, even when a matched donor is available, the procedure is burdensome and risky.

In this most recent study, researchers at Hôpital Necker in Paris transplanted genetically modified bone marrow cells into two Spanish boys who lacked matched bone marrow donors. The boys were also given myeloablative conditioning- a type of chemotherapy that increases the likelihood that genetically modified cells will repopulate the bone marrow. The Science report showed:

1- genetically modified cells did, indeed, survive and were maintained at stable levels for two years.

2- the modified cells expressed the therapeutic gene, ABCD1, again for two years.

3- brain demyelination was halted after 14 months- the timing is similar to what would occur for patients receiving bone marrow transplantation.

4- the two boys did not appear to decline on various measures of neurological or verbal tests, as would almost certainly have occurred with the natural course of ALD.

5- the authors did not detect "clonal dominance" in their modified cells– that is, evidence that genetically modified cells were poised to cause a malignancy.

In an accompanying editorial, Luigi Naldini calls this study a "Comeback for Gene Therapy," describing it as a "long-sought rewarding achievement in the field of gene therapy." In my next post, I will discuss some implications, interpretations, and other interesting dimensions of this very encouraging study (photo credit: tgif28, chalk graffiti at Hopital Necker, 2009)

California Dreamin: CIRM Announces New Stem Cell Awards

2009-11-04T20:45:00.007-05:00

California's Institute for Regenerative Medicine just announced a series of large funding awards to fund translational research initiatives involving (mostly) stem cells. The projects funded are telling with respect to what was funded, and what they will attempt to achieve.

First, notwithstanding a press release containing the words "bringing stem cell therapies to the clinic," several projects are really dressed up gene transfer studies. Thus, one team will use gene transfer in hematopoietic stem cells for sickle cell anemia; another two will use gene transfer to stem cells for treating brain malignancies; another RNAi for HIV. All this is only further evidence that the field of stem cells is devouring gene transfer. Other projects are aimed more at getting "stem cells out of the clinic" by using small molecules or monoclonal antibodies to destroy stem cells causing malignancies.

Second is the sweeping ambition. As it stands today, only one clinical trial involving embryonic stem cell-derived tissues has been initiated. The projects funded under these awards are "explicitly expected to result in a filing with the FDA to begin a clinical trial." Given that these projects are funded for four years, CIRM seems to be banking on the prospect of at least a few of these initiating phase 1 trials within five years. Four of these proposals involve goals of implanting embryo-derived tissues, and two of these involve non-lethal conditions–macular degeneration and type I diabetes (technically, other awarded projects involve nonlethal, though extremely morbid conditions). Another involves implantation of embryo-derived tissues for Amyotrophic Lateral Sclerosis. It will be interesting to see how many of these meet their translational objectives, and how investigators will navigate the ethical, regulatory, and social complexity of initiating clinical testing. (photo credit: Michael Ransburg, 2008)

The Need for Speed: GAO Reports on Accelerated Approval

2009-11-01T22:26:00.007-05:00

Several blog posts ago, I wrote about the policy of accelerated approval (briefly, a mechanism whereby new drugs can be approved for sale by the FDA before definitive evidence of efficacy and safety are available). In that post, I reported on a recent paper where the authors claimed that, all things considered, accelerated approval enabled patients to get quicker access to life saving drugs without major adverse impacts on patient safety.

Last week, the Government Accounting Office issued a report on the subject that took a less favorable view of the program. Rules require that companies receiving accelerated approval for new drugs complete post-marketing studies confirming their efficacy. The GAO investigated the frequency with which companies fail to submit post-marketing trial data. They found that over a third of FDA-required post-marketing studies aimed at confirming efficacy had not yet been completed. Many of these studies might be incomplete because accelerated approval was only recently granted, and it can take as long as five years to complete requested studies. Disturbingly, however, the report found that a quarter of these studies had been incomplete for over five years; other studies have been completed but not yet reviewed by the agency. The figures are worse for other types of post-marketing studies requested by the agency.

The "poster boy" drug singled out in the GAO report is the hypertension drug Proamatine, which earned Shire Pharmaceuticals $257M since it was approved under accelerated approval 13 years ago. Apparently, the drug has not been subject to adequate confirmatory testing in all this time, though FDA has issued warning letters to the company over its promotion practices.

The report saves its criticism for the FDA, which it says has not reviewed sponsors' submissions in a timely manner, does not adequately monitor progress of post-marketing studies, and has neither specified conditions under which it would exercise its authority to withdraw drugs from market, nor has it ever exercised its authority to do so. But isn't some criticism also warranted for companies exploiting FDA's deficiencies? (photo credit: lindsay kay photography 2009)

Remembrance of Things Past: Fetal Tissue Transplantation and Parkinson's Disease

2009-10-28T20:45:00.003-04:00

In a recent article in Science magazine, Constance Holden reports that European researchers are contemplating a revival of fetal tissue transplantation for the treatment of Parkinson’s disease. As the article recounts, fetal transplants were subjected to sham controlled studies in the late 1990s; none performed better than sham, and several caused disabling dyskinesias. So should fetal tissue transplantation be revived, and if so, how?

The challenges seem all the more formidable today. We now understand that Parkinson’s disease is not restricted to the dopaminergic neurons in the basal ganglia, but instead involves diffuse pathology. And yet, studies will not involve implantation of tissues throughout the brain. As Holden’s article points out, previous fetal transplant studies revealed that brain pathology spreads to implanted tissues, suggesting that permanent responses may be difficult to achieve.

The ethical issues seem just as daunting. Deep brain stimulation has greatly improved the management of Parkinson’s for patients who are no longer responding to dopamine replacement. And yet, those pursuing fetal tissue transplantation will likely advocate pursuing trials in younger patients with less advanced disease. As pointed out by a European team of researchers, "A significant effort of bioethical research and conceptual clarification is required in anticipation of the first protocols involving human subjects." And in a recently published article in Movement Disorders, several coauthors and I outline various ethical challenges presented by such studies. These include a high degree of uncertainty about the safety of interventions, and a baseline risk associated with delivery that approaches levels of risk encountered in phase 1 cancer trials (for studies that involve eight inoculations to the brain, risk of intracerebral brain hemorrhage leading to permanent neurological deficits is on the order of 2%).

Advocates of the new wave of studies insist we know much more about the properties of fetal tissues than we did in the 1990s; they further note that such studies will provide a basis for later studies involving induced pluripotent stem cells and other tissues. Perhaps, but given the remaining uncertainties and promise of DBS, it’s hard to imagine how fetal graft experiments could credibly establish a claim of clinical equipoise with deep brain stimulation. For these reasons, a more prudent ethical course—if fetal transplant studies for Parkinson's are to be done at all—would be to pursue safety and feasibility studies in patients who are no longer responsive to standard care. Only once parameters are optimized and mechanisms well understood should clinicians consider studies in patients who are earlier in the disease process. (photo credit: Ethan Hein 2008)

Disclosure in Phase 1 Cancer Trials

2009-10-26T17:54:00.005-04:00

Followers of this blog may recall my continuing concern with the way informed consent is obtained in phase 1 trials involving patient-volunteers (typically, these patients have exhausted standard care options and enter phase 1 trials as a final shot at managing their disease). Language used by investigators in these studies is often suggestive of therapeutic benefit, even though meta-analyses of phase 1 studies show that chances of major clinical benefit in phase 1 studies are exceedingly low. In previous posts, I described my own experience with an ethics review committee that actually defended giving patients vague and almost meaningless information about the therapeutic benefits of phase 1 trial participation. Meantime, evidence from surveys indicate that phase 1 cancer patient-volunteers tend to overestimate the probability of therapeutic benefit.

In the July-August 2009 edition of the ethics journal IRB, Shlomo Koyfman and co-authors at NIH offer up a "Consent Form Template for Phase I Oncology Trials." Their recommendations are comprehensive and excellent. Among the items they recommend are:

• use of more therapeutically neutral language, like "research agent" instead of "therapy"

• disclosure of dose escalation design; in particular, the authors recommend that patients be informed about risks and benefits relative to the cohort they are entering.

• a statement (where appropriate) that patient-volunteers will not have the option of adjusting their dose assignment in the study

• a statement that "the chances that this agent will... allow you to live longer [is] very low."

One can quibble with various particulars (I think, for example, discussion of subtherapeutic dosing should be more explicit). But on the whole, these recommendations provide an excellent standard– along with NIH Guidance on Informed Consent for Gene Transfer Research– against which typical phase 1 cancer study consent forms should be measured. (photo credit: banlon1964)

Quack You! Medical Tourism and Stem Cells

2009-09-23T11:04:00.004-04:00

In the September 2009 issue of Nature Biotechnology, Jane Qiu reports on a thriving trade in nonvalidated stem cell interventions for incurable illnesses ("Trading on Hope"). The article provides numerous examples of overseas clinics that cater primarily to North American and European clientele in offering pricey, unproven stem cell transplants for incurable conditions like spinal cord injury, Parkinson's disease, and autism. Many of these clinics make extravagant claims in their promotion materials.

Encouragingly, policy makers are beginning to take notice. China, for example, has issued new regulations on clinical application of novel interventions; it requires licensing for clinics that provide unproven stem cells. India has issued guidelines on stem cell research and therapy. As noted previously in this blog, the scientific society ISSCR issued guidelines urging clinicians to offer nonvalidated stem cell interventions to patients only in the context of clinical trials designed to test safety and efficacy. Problem is (according to the article), guidelines are sporadically enforced, if that.

I think there is much more that governments and professional societies can and should do to stem this unethical conduct. Though most of these clinics are located outside of North American and Europe, some overseas clinics have reputable, North American / European scientists and clinicians on their advisory board or have partnerships with biotechnology companies that are based in North America / Europe. Examples include Stemedica (which includes several Stanford and UCSD faculty on its advisory board), and Theravitae (which has involved close collaboration with University of Pittsburgh clinicians), and Vescell (which includes Nobelist Aaron Ciechanover on its scientific advisory board). All of these companies offer stem cell interventions to large numbers of patients outside trials, and make claims that their interventions are effective when, in fact, they remain unproven.

1- Research ethics policies should condemn scientist-clinicians who travel or collaborate abroad in delivering nonvalidated, potentially risky interventions overseas outside the context of a clinical trial. Policies should state clearly the imperative of subjecting nonvalidated interventions to systematic study.

2- Institutions should not allow these clinics to trade on their reputations, and should sanction faculty members who are involved in such activities.

3- professional societies in medical fields (e.g. cardiology) and research areas (stem cells, gene transfer) should steward the standing and credibility of their research field by developing policies and standards that discourage inappropriate activities-- through social pressure-- by providing a benchmark against which the conduct of scientists and clinicians can be judged.

(photo credit: Insert Photographer Here, 2006)

Accelerated Approval: Safe at Any Speed?

2009-09-09T16:08:00.005-04:00

Drug regulatory authorities like the FDA have a mandate to protect public health by requiring and evaluating evidence of safety and efficacy before licensing new drugs for commercial sale. But for decades now, patient advocates have argued that FDA bureaucracy kills by keeping promising drugs from the IV's of terminal patients. In response to these criticisms, FDA and others have created new pathways for drug approval whereby drugs can be partially approved for sale on the basis of smaller, Phase 2 trials using surrogate endpoints (tumor shrinkage) instead of survival– provided drug companies confirm efficacy in subsequent trials.

This pathway, called "accelerated approval," is controversial because it allows companies to sell drugs whose efficacy and safety is not yet well established. True- the companies are obliged to run confirmatory studies, but a) how will confirmatory trials enroll enough subjects if patients know they might be randomized to standard, ineffective drugs, and they can get the drug outside a clinical trial? b) drug companies will not have sufficient incentive to run confirmatory studies once their drug is provisionally approved. c) drug companies stand to make lots of money selling unproven drugs to desperate patients in search of a cure.

In the most recent issue of Journal of Clinical Oncology, Elizabeth Richey and coauthors put these concerns to the test in an analysis "Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs." They find that:

• a very large percentage of new cancer drugs are initially approved under "accelerated approval." (37% approvals between 1995 and 2008)

• 63% of drugs receiving accelerated approval have their clinical benefit confirmed in subsequent studies

• drugs involving very rare cancers are often not subjected to confirmatory testing (42%); drugs for more common cancers are tested in confirmatory studies typically (71%-- though the percentage I calculated from their figures is actually higher- 86%)

• drugs receiving accelerated approval are twice as likely to receive black box warnings compared with drugs approved by the standard mechanism (21% vs. 10%)

• about half of non-orphan drugs approved under accelerated approval (47%) become first line treatment regimens in the National Comprehensive Cancer Network.

The authors see the glass half full on accelerated approval: to the title question of their article, the authors answer "Improved Access to Therapeutic Breakthroughs." (photo credit: Marxpix 2008)

Ted Kennedy: 1932 - 2009

2009-08-28T09:20:00.004-04:00

Ted Kennedy, who died two days ago, championed many of the issues covered in this blog, among them access to health care, funding for research, and a strong drug regulatory system. To those who care deeply about these issues, his indefatigable advocacy will be missed.

Among the many landmark laws and regulations that owe their origin to Kennedy are U.S. policies on human protections. Way back when, as a freshman Senator, Kennedy chaired Senate hearings that revealed human research abuses like those committed in the Tuskegee Syphilis Study. He went on to introduce some of the first legislation calling for formal regulation of human research. His initial bill would have given the federal government broad authority to regulate both public and private research. However, it was ultimately overtaken by a weaker bill that called for the creation of a National Commission. Ultimately, Kennedy supported the latter bill under the condition that the Department of Health, Education, and Welfare (now HHS) issue regulations. The reports of the National Commission continue to have a towering influence over research ethics, and the regulations following from this law (45 CFR 46) are virtually unchanged today (photo credit: John Mcnab 2007)

Everything You Always Wanted to Know About Clinical Research in China, But Were Afraid to Ask

2009-08-19T20:03:00.010-04:00

After scandals involving tainted toothpaste, poisonous pet food, adulterated milk, contaminated heparin, and counterfeit medicines, and a thriving trade in organs, one shudders to imagine how well human subjects are protected in drug studies performed in China. Apart from an occasional report in the medical literature, there is little easily accessible information about Chinese human protections: the regulations and laws, compliance and enforcement, and professional standards. This information would be interesting in its own right; however, it is all the more essential given trends towards trans-national trials.

A recent report issued the Medical Research Council (UK) provides some indication of China's system of human protections, and how researchers in countries like UK might proceed when locating trials in China. The executive summary finds that Chinese regulations substantially parallel those of the International Committee on Harmonization (ICH). Informed consent and independent ethics review is required for any study. However, the UK and China "differ greatly in their approaches to enforcing guidelines for the conduct of research at the national level. In China, although there is some scrutiny of clinical trials, there is comparatively little inspection or review of compliance." Other intriguing mentions are concerns about undue inducement in China: "the high costs of healthcare and medicines, and the dependence on local providers means that particular attention [for UK researchers pursuing studies in China] must be given to potential inducements to participate in research. Collaboration with China may offer attractive opportunities for large-scale recruitment, but potential UK collaborators must be alert to the risk that unethical inducements may be offered to potential participants. ... given the high cost of accessing health care in China, a ‘free health check’ may be a relatively greater inducement than it would be deemed to be in the UK."

A perusal of the Chinese regulations- at least the ones provided in this report- indicate the following:

• China places heavy emphasis on procedure (e.g. IRB review) and informed consent, rather than substance (e.g. prohibitions on certain practices; definitions of minimal risk; categories of patients)

• China seems to take a very permissive stand (like ICH) on the use of placebos. Indeed, there is no mention of studies involving placebo.

• There is no mention of justice considerations- for example, post-trial access or responsiveness.

(photo credit: 2 dogs, 07/03/25 12:32:09 Shanghai, 2007)

Help Wanted, Part 2

2009-08-08T22:41:00.004-04:00

So, what are some of the intriguing ethical questions of Kolata's August 2d article? Here is one: when researchers conduct studies and ethics committees review protocols, resource allocation is an important consideration. If, as Kolata alleges, mediocre trials siphon eligible patients away from good trials, then there is a case to be made that IRBs and investigators need to ponder carefully the effects proposed trials will have on other studies- even when proposed trials have a favorable direct benefit-risk balance for volunteers who enter them.

Second, if resource allocation is a key consideration in realms where patients are scarce, investigators (and IRBs) need reliable criteria for assessing the broader social value of study protocols. They further need some way of being able to compare one protocol against a body of others that are either underway or in the pipeline. The current system provides no straightforward way of doing this.

Third, if 50% of trials fail to recruit sufficient numbers to produce meaningful results, investigators, IRBs, DSMBs, and granting agencies are doing a lousy job ensuring high ethical standards in human research. It is well established that, for any study to redeem the burdens that volunteers endure on enrollment, it must produce valuable findings. It is disturbing, to say the least, that many volunteers enter studies that go nowhere, and that investigators, IRBs, and funding agencies are not realistically projecting recruitment.

Last, Kolata suggests that many cancer trials are merely aimed at "polishing a doctor's résumé." It would make a useful contribution to the field of cancer research- and bioethics- to measure the frequency of this practice. Meantime, this inability of IRBs to detect this kind of conduct, and stop it in its tracks, signals an important deficiency in human protections. Which leads me to my next post... (photo credit: ziggy fresh 2006)

Help Wanted- For the War on Cancer

2009-08-06T02:30:00.003-04:00

Earlier this week (Aug 2), Gina Kolata of the NYTimes ran a fascinating story about challenges recruiting patients to cancer clinical trials. The story contains interesting facts, credible claims, analysis, and unfortunately, some misleading conjectures. The problem of patient recruitment also invites some hard headed ethical analysis.

First the facts. According to the article, one in five National Cancer Institute-funded trials fails to enroll a single subject; half fail to recruit enough to produce meaningful results. Now some credible claims: many trials are "aimed at polishing a doctor's résumé, and produce meaningless results; many oncologists avoid cancer studies because they can be a money loser, and many patients shy away from trial participation- particularly when their cancer is less advanced and they can obtain treatment outside of trials.

The article, however, is swathed in some misleading conjectures. The article makes the suggestion that problems with recruitment are "one reason" and "the biggest barrier" to major strides in the "war on cancer" (hence the recruitment poster in the graphic above). Hard to reconcile this with Kolata's contention elsewhere that many trials are useless. It's also hard to square the claim with Kolata's point, earlier in the article, that trials involving really promising drugs usually have no problems with recruitment. In one famous case, a Phase 1 trial testing endostatin at Harvard received 1000 inquires from patients for 3 slots in the trial (Pop quiz: see if you can guess which New York Times reporter wrote an article on endostatin that many commentators criticized for sensationalizing the drug's promise?). Third, with only about 1 in 20 cancer drug candidates making it from phase 1 tests to FDA approval, a reasonable question to ask is whether preclinical researchers are validating their drug candidates properly. And finally, the article makes no mention of the fact that many studies have exceedingly narrow eligibility criteria. Many patients may be solicited for trial participation- but only a fraction meet eligibility criteria.

Still, Kolata's article is enlightening and raises a number of intriguing questions that demand ethical analysis. I'll discuss some of these in my next posting (photo credits: Joan Thewlis, 1918 Recruitment Poster, 2009).

Orange Light on Generics

2009-07-22T16:36:00.003-04:00

Last week, I blogged on the issue of generic biologics: should companies that make vaccines, monoclonal antibodies, cell therapies, etc. get 12 years of data exclusivity before competing companies begin offering generics? Or should they be held to the same standard as makers of drugs, who get five years of exclusivity?

Looks like the U.S. Senate is caving in to pressure from Pharma and the Biotech industry by opposing the Obama's "compromise" position: the Senate bill urges 12 years. But in today's New York Times, journalist Andrew Pollack suggests the exclusivity debate might not matter in the end: most biologics are protected by patents beyond 12 years after FDA approval. Meaning: short exclusivity periods advocated by various public interest groups would have no material impact on development of generic biologics, because generics would be prevented by patents. The article contains a graphic showing that patents on several leading biologics products extend well beyond 12 years.

So is this just a symbolic debate? I think not (disclaimer: I am not a health care economist!). Towards the end of the article, Pollack acknowledges that the exclusivity debate might matter where patents do not provide strong protection. That's a crucial issue for biologics. Intellectual property law around biologics is notoriously unstable and uncertain. And owing to their complex composition, generic manufacturers might plausibly argue that their products are biosimilar while not infringing patents. Advocates of the 12 year policy will argue that longer exclusivity is necessary to entice investors who might otherwise worry that lead products will not withstand patent challenges. Advocates of the shorter policy (like myself) will argue that we owe it to present day patients and their families to take that risk. (photo credit: sortofbreakit 2008).

Phased by Phase 0?

2009-07-17T17:47:00.004-04:00

Today, Lancet ran an editorial asking whether Phase 0 trials will become a "platform for drug development." The editorial responds to the first published 'phase 0' study, this June, in Journal of Clinical Oncology (Kummar et al). These studies involve delivering very small quantities of a new drug to test its properties before giving biologically active levels to patients. They promise to improve the efficiency of drug development by screening drug candidates before they are tested in larger, riskier phase 1 trials.

The Lancet editorial notes the potential of phase 0 studies, but raises questions about their ethics: "no therapeutic benefit can be conferred by the small doses in a phase 0 study, and while taking part, patients are not allowed to enrol in a trial with therapeutic intent." As I have argued in Journal of Law, Medicine, and Ethics, however, the former issue is a red herring: normal phase 1 trials routinely, and deliberately, deliver levels of drug that are too low to cause therapeutic response. Moveover, whether phase 1 trials in themselves have "therapeutic intent" is debatable.

There are, of course, many ethical concerns surrounding phase 0 studies. Chief among them is whether patients understand their nontherapeutic nature, and whether results are publicly reported (I predict that if phase 0 methods are taken up by the private sector, many results will languish in filing cabinets). But effective engagement with ethical issues in phase 0 cancer studies requires, in my view, that we take a more careful look at whether "therapeutic intent" is really the litmus that determines whether a study pursued in patients is ethical. (photo credit: w i n t e r t w i n e d 2009)

Generic Biologics

2009-07-14T14:26:00.004-04:00

Gene transfer, cell transplantation, monoclonal antibodies, enzyme replacements, tissue engineering all have great potential to improve health care. But will we be able to afford them? Various economists have shown that a large proportion of health care cost inflation is attributable to new technology, and the significant costs of development and production for drugs involving genes, cells, and large proteins- what regulators call "biologics"- provide grounds for concern that new biotech products will break the bank.

Questions about the affordability of biotech drugs are heating up in DC as Congress takes a look at generic biologics. Under current policy, there are no regulatory pathways for approving generic versions of biologics. This effectively means that companies that develop biologic drugs have a monopoly on them long after patents expire. Representative Henry Waxman, who previously sponsored legislation creating a pathway for generic drugs, is presently spearheading efforts to establish a way of reviewing and approving generic biologics as well.

The policy and economic issues here are profoundly complex, and much of the debate about legislation revolves around the issue of "data exclusivity." Briefly, this refers to the period after drug approval during which generic competitors are barred from using data from the innovator's clinical trials to apply for generic approval. In the U.S., for example, generic drug companies cannot file applications with FDA until five years after the new drug is approved by FDA. The aim of exclusivity is to reduce the economic impact of free rider generic companies that depend on trial data collected by the innovator.

The biotech industry, and many economists, argue that much longer periods of data exclusivity are required for biologics. They argue that without longer exclusivity periods (like 12 to 14 years), companies will have insufficient incentive to develop new biologics. Consumer advocates often argue otherwise, citing the mouth dropping costs associated with using many new biologics.

It remains to be seen who will prevail in this debate, but Waxman and the Obama administration appear inclined toward the consumer advocates, with the former urging a 5 year period, and the latter endorsing a "compromise" of 7 year exclusivity.

At stake is not simply question of markets and economics, but also one of ethics. Namely, should how should health care economies balance the need of current patients (who can ill afford expensive biologics) against those of future patients (who might benefit from greater innovation should exclusivity periods be extended)?

Sound ethical analysis must discount benefits accruing to future patients and consider the justice implications of excluding current patients from otherwise available treatment so that others in the future might benefit from new drugs. If implemented, the Obama administration's plan for generic biologics promises to reduce an important hurdle in ensuring an equitable future for cutting edge therapies. (photo credit: shazam791, a true generic brand, 2008)

Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors

2009-06-23T12:01:00.004-04:00

A few further observations from the American Society of Gene Therapy Meeting...

A recurrent theme in this blog is the frequency with which novel research fields encounter safety problems that confound laboratory predictions. One presentation at the 2009 ASGT meeting brought this point home.

Recall my entry on May 12 discussing various refinements to retroviral gene transfer that are aimed at reducing risk of malignancy. Researchers have postulated that HIV-derived lentiviral vectors might not cause the same leukemia-inducing mutations as retroviruses, and RAC recently passed a favorable judgment on a lentiviral vector gene transfer protocol for X-SCID.

How confident can we be that lentiviruses will not trigger leukemias? Some indication is provided in a May 2009 review by John Rossi in Molecular Therapy. It concluded "overall, the results of these [safety] analyses [of lentiviral vectors] are highly encouraging..." but "clearly, more careful analyses... are warranted in appropriate animal models."

At ASGT, researchers from France reported preliminary results from a phase 1 trial testing lentiviral vectors in patients with beta-thalassemia. The study involved two patients. Though no malignancies have been detected, tests in one patient showed signs that some cells were repopulating the patients blood much faster than others (what researchers call "clonal dominance"). This is a worrisome signal, as it might indicate a premalignant state.

The lessons here are not that lentiviral vectors are unsafe (we don't know whether this will lead to a malignancy), or that such vectors shouldn't be used in human beings (we can't say anything yet about the risk-benefit balance). Instead, I think the lesson is: in novel research areas, be very wary of anyone who makes emphatic claims that their system provides safe harbor. Expect the unexpected. (photo credit: dark matter, 2005)

The Vision Thing: Update on LCA

2009-05-30T02:17:00.005-04:00

Last year's "big ticket" item at ASGT was results from the first three patients in two gene transfer trials testing nearly identical products against a rare form of congenital blindness, Leber's Congenital Amaurosis (LCA). I previously blogged (here and here and here and elsewhere) on the controversial decision to move the intervention into children, given the novelty of the intervention, that the trial is primarily a safety study, and that blindness is not a fatal condition.

Today, Jean Bennett of University of Pennsylvania presented an update on the first three patients (previously reported in New England Journal of Medicine) plus results on the next three patients. Here's a synopsis. The first three patients continue to show dramatic improvement in objective measures like pupillometry (that is, their pupils are responding to flashes of light in a way that does not normally occur in patients with this form of blindness), and they show signs of improved vision.

The next three patients were children eight years or a bit older. Bennett showed dramatic footage of a child unable to find his way through a maze when using the uncorrected eye, and navigating a maze with relative ease with the corrected eye. She also showed data indicating retinal function in regions of the eye receiving vector. Improvements in vision were greater with the children than in the previous cohort- which she chalked up to the fact that retinal tissue was not as degenerated in younger patient-volunteers. The team did not observe any gene transfer-related adverse events.

The other two LCA trials were conspicuously missing from the meeting. Rumor has it that the Penn team has been far more successful recruiting patients with this rare disorder. Bennett flashed a slide at the beginning of her presentation showing that patients had been accrued from several continents- North America, Africa, Europe, and elsewhere. Patients in the second cohort, according to Bennett, are begging to have their second eye dosed. (photo credit: Ferran 2009).

Mice- Three Different Ones: Towards More Robust Preclinical Experiments

2009-05-29T13:41:00.003-04:00

One of the most exciting and intellectually compelling talks thus far at the American Society of Gene Therapy meeting was Pedro Lowenstein's. A preclinical researcher who works on gene transfer approaches to brain malignancies (among other things), Lowenstein asked the question: why do so many gene transfer interventions that look promising in the laboratory fail during clinical testing? His answer: preclinical studies lack "robustness."

In short, first-in-human trials are typically launched on the basis of a pivotal laboratory study showing statistically significant differences between treatment and control arms. In addition to decrying the "p-value" fetish- in which researchers, journal editors, and granting agencies view "statistical significance" as having magical qualities- Lowenstein also urged preclinical researchers to test the "nuances" and "robustness" of their systems before moving into human studies.

He provided numerous provocative examples where a single preclinical study showed very impressive, "significant" effects on treating cancer in mice. When the identical intervention was tried with seemingly small variations (e.g. different mouse strains used, different gene promotors tried, etc.), the "significant effects" vanished. In short, Lowenstein's answer to the question of why so many human trials fail to recapitulate major effects seen in laboratory studies is: we aren't designing and reviewing preclinical studies properly. Anyone (is there one?) who has followed this blog knows: I completely agree. This is an ethical issue in scientific clothing. (photo credit: Rick Eh, 2008)

ASGT in San Diego

2009-05-28T10:44:00.007-04:00

This year's annual meeting of the American Society of Gene Therapy is in San Diego. I've been to several interesting talks thus far, and plan to post entries on a few. For now, here's an overview of some major (or some not so major) clinical developments in gene transfer that are being reported at this meeting.

1- Last year, I predicted that the first gene transfer applications were nearing licensure. Not so fast. Because of concurrent sessions, I was unable to attend the entire talk given by Robert Shaw of the British biotech company Ark Therapeutics. Ark has developed a gene transfer approach, Cerepro, that uses adenovirus to treat malignant glioma (which is one of the most aggressive types of cancer). Ark recently applied to the European drug regulatory authority, EMEA, for registration of Cerepro. Why not FDA? Dunno (though the speaker stated that the review standards are more or less the same). The data behind the product are less than earth shaking. According to information available over the web [proviso- these data are from August 2008], the pivotal phase 3 study of Cerepro showed only a 42-day increase in survival for patients in the active drug arm. And the product caused "increases" in hemiparesis, aphasia, and fever.

2- Another somewhat discouraging indication of the challenges in reaching licensure for gene transfer products was a session titled "late stage industry clinical trials." To me, late stage means phase 3. But three talks centered on phase 1/2 studies, and none presented phase 3 results. The first talk was given by Ceregene on their Parkinson's disease product Cerepro. The product did not show any significant advantage over sham for their primary endpoint.

3- Last year, the "buzz" at ASGT was the preliminary results from three studies testing AAV vectors for a form of congenital blindness, LCA. I also discussed the somewhat ethically controversial decision to move this study into children. I will look forward to attending Jean Bennett's talk on Friday; her abstract reports that her LCA study has enrolled "9 children and young adults" ranging from age 8 to 26 years. The abstract claims improvement in "subjective and objective" measures of vision. To be continued... (photo credit: slack12, 2008)

A Cure? "Compassionate Use" and Drug Regulation

2009-05-17T12:11:00.005-04:00

Are government bureaucrats keeping dying patients from getting access to possibly life saving drugs? That's one way to read Margaret Talbot's story in the Sunday New York Times ("Fighting for a Last Chance at Life." May 17, 2009). Talbot describes how mother Kathy Thompson sought access to an unlicensed therapy Iplex for her Amyotrophic Lateral Sclerosis (ALS)- afflicted son, Joshua. The drug, Iplex, was not licensed by FDA for use against ALS, and an almost identical drug had failed two randomized controlled trials in patients with ALS.

Buoyed by anecdotal patient reports on web forums, Thompson sought compassionate use access from the FDA and was rebuffed. She ultimately engaged the Washington Legal Foundation to appeal FDA's rejection of Thompson's request for the drug. FDA relented, allowing the drug maker to run a trial of Iplex– recouping all costs from enrolled patients (about $100k/year).

There are a number of troubling features in this story. First, the article (or, at least Thomspson) makes FDA out to be a bunch of heartless bastards. Some, like the Washington Legal Foundation, view FDA's stringency as an affront to the "civil liberties of American Business" (to paraphrase Haley Barbour). But let's remember that, for over a half a century, FDA has played a critical role in public health by keeping unproven drugs out of the pharmacy. Grants of compassionate use seriously weaken the ability of the state to collect evidence of a drug's safety and efficacy, because they make enrollment in clinical trials much more difficult. So there need to be some pretty compelling policy reasons- backed by persuasive evidence- to grant exemptions.

Second, the article states "Many are Campaigning for the chance to be treated with drugs whose safety and effectiveness is not yet known." While Iplex itself hasn't been tested against ALS, its active ingredient has been tested in two large randomized controlled trials. Both failed to show any advantage over placebo.

Third, there's the business of allowing desperate patients to "buy" their slots in the trial approved by FDA. For starters, it's hard to imagine that a trial that included only "several dozen patients" is going to be of any use in measuring safety or efficacy (the two failed studies involved about 180 and 300 patients). As well, there is something unseemly about a "compassionate use" exemption that is priced at $100K.

ALS is an awful disease, and I feel for people like Thompson and her son. Surely, more and better care and research are needed for ALS sufferers. But where's the compassion in a program that ministers only all to the most wealthy and politically connected? More importantly, where's the compassion in undermining a system that ultimately protects us all from clinics that prey on the desperation of patients, and companies that sell unsafe, ineffective, and extremely expensive drugs? (photo credit: Monster 2007)

Basic Science and Pharmaceutical Productivity

2009-05-12T22:04:00.008-04:00

One of the great paradoxes of contemporary medicine has been a seeming inverse relationship between investment in basic science and registration of novel new drugs by regulatory agencies. The delay between basic science discoveries and clinical applications can be very long; many promising drug candidates are called on the basis of laboratory discovery, but few are chosen.

Cancer drugs, in particular, have one of the highest rates of failure as measured by the probability that a new drug entering phase 1 clinical testing will prove promising enough to eventually be registered by the FDA. One 2004 report pegged this figure at about 5%.

The question is: will such discouragingly low figures hold for new classes of cancer drugs that are entering clinical testing? According to Ian Walker and Herbie Newell in the January issue of Nature Reviews Drug Discovery, maybe not. Walter and Newell examined pharmaceutical development databases to determine probabilities that a particular class of new cancer drugs– protein kinase inhibitors– will survive from phase 1 testing through to registration (the wonder drug Gleevec is in this class). They found that 53% of new kinase inhibitors that enter phase 1 trials are ultimately licensed. They conclude that their analysis "further demonstrate[s] the benefits of developing molecularly targeted therapeutics for cancer."

Here are some concerns about their analysis. First, their figures for success from phase 1 to registration for all cancer drugs (not just kinase inhibitors) are roughly three times previous estimates. This bears explaining. A second concern is that this may represent a particularly successful class of molecularly targeted agents. Third and crucially, according to a recent Nature Reviews–Cancer report, there are 11 different kinase inhibitors approved by the FDA. Eleven divided by the sample used in this paper– 137 kinase inhibitor drugs entering phase 1 testing– yields 8%– a number very similar to the 5% success rate that has been quoted elsewhere. Last, some kinase inhibitors are "me-toos" or at least, very closely related (e.g. panitumumab and cetexumab)

Too early, I say, to conclude that the way we are doing basic and preclinical science is beginning to bear fruit in terms of pharmaceutical productivity. (photo credit: Night Heron, Pull Chain, 2007)

Yellow Light on Gene Transfer Studies

2009-05-12T16:37:00.006-04:00

Among the greatest heartbreaks in the field of gene transfer have been problems encountered in trials involving a rare, hereditary immune disorder, X-SCID (known popularly as "Bubble Boy" syndrome). As is well known, a team of researchers based in Paris– and then in London– successfully reversed severe immunodeficiencies in 20 or so children using retroviral gene transfer starting around year 2000. Shortly thereafter, however, the Paris team began observing rare leukemic disorders that were causally related to the gene transfer. To date, the Paris team has reported 4 cases of leukemia, with one leading to death. The London team has reported one leukemia.

In response to these events, the U.S. Recombinant DNA Advisory Committee (RAC) recommended that investigators only use retroviral gene transfer in the most severe situations– namely, where patients are ineligible for even high risk alternative care options like haploidentical stem cell transplantation. RAC's recommendations were stricter than those in the U.K., which allowed children to enter a study even if they were candidates for haploidentical transplants.

As reported in the current issue of Molecular Therapy, the RAC recently decided to liberalize its recommendations, allowing retroviral gene transfer in children who are eligible for halploidentical transplantation. RACs recommendations are still somewhat stricter than those of the UK, because the former recommends against retroviral gene transfer in children who are candidates for haploidentical transplantation but under 3.5 years age (children in this category respond better to haploidentical transplants). RAC additionally supported a similar trial involving a different vector that integrates its genome into the host's (lentiviral vectors, which are derived from HIV).

Is this gentle liberalization of standards justified? Some will argue that the benefits of haploidentical transplantation are variable and undependable, and that since initial leukemias have been reported, researchers have made progress in improving the safety of their vectors. All this might be true, if one were evaluating this as a clinical judgment.

However, the judgment is better viewed through the lens of research rather than therapy. Though laboratory testing indicates that new retroviral and lentiviral vectors are safer than the old ones, there remain substantial uncertainties. For example, current assays for determining the oncogenicity of integrating vectors are not well worked out. Neither the new retroviral vectors nor lentiviral vectors have been used in blood stem cell gene transfer in a pediatric population. The effect of lentiviral vectors on gene sequences near their integrating sites remains poorly understood. In short, the null hypothesis of new trials is that these new vectors are no better than the old ones.

What's the safest way to refute this null hypothesis and confirm what many think, on laboratory evidence, will be the case? In my view, the safest approach– for patients as well as the field in general, which stands to lose much from another major toxicity– is to begin with the most narrow medical indication possible, which means excluding children who stand a chance of benefiting from standard (albeit suboptimal) care. (photo credit: Jamelah 2007)

Toxic Waste?

2009-04-27T14:38:00.003-04:00

Before testing new drugs in human beings, drug developers must first perform a series of safety tests in animals. Unfortunately, these preclinical toxicology studies are typically protected as trade secrets. In fact, many countries have laws that specifically bar drug regulators from releasing preclinical toxicology data submitted by drug developers.

Unless you take the extreme view that animal experimentation raises no ethical concerns, this represents a terrible waste of animals and a failure of researchers to enable the sacrifice of animals to enrich the bank of human knowledge. As an afterthought, it's worth mentioning that this also comes with certain opportunity costs for human beings, since such nondisclosure potentially 1-frustrates efforts by researchers to improve their knowledge about drug safety, 2- results in duplicative expenditure of human resources.

It needn't be this way, and the field of gene transfer shows one modest way toxicology data could be published and pooled. Since it was established, the National Gene Vector Laboratories, at Indiana University, have invited gene transfer researchers to submit summary data on toxicology studies to their database (the laboratory recently was eliminated and replaced with the National Gene Vector Biorepository-- NGVB for short). As described by NGVB director Ken Cornetta and project coordinator Lorraine Matheson in Molecular Therapy (April 2009), the database is intended to provide a resource for researchers so that they can cross-reference toxicology experiments in their FDA filings and avoid duplicative studies. The authors also envision the database as a resource for grant reviewers.

The database contains 27 toxicology studies in all. This number seems small when you consider the volume of gene transfer studies pursued since the database was established. The fact that every institution that has contributed to the database is a nonprofit suggests that the private sector has not taken an interest in this worthy resource. One question I have is how many private companies have used data contained in this databank in their FDA filings (this should be easy to determine).

These questions aside, other fields should create similar resources to pool data and create opportunities for data linkage. I would go so far as to say that ethics policies should require that, at a minimum, such summary data be published on a public database. The failure to do so seem a toxic waste for animals, scientists, funders, and patients alike. (photo credit: drp, Waste Not, 2004)

The Biotechnology of Neglect

2009-04-13T13:01:00.005-04:00

What can the biotechnology industry do for neglected diseases (infectious diseases that, because they primarily afflict low-income countries, are not heavily researched in the public or private sector)? Biotechnology enthusiasts might answer "everything," ignoring the dearth of research and development incentives for small biotechnology firms, much less the major challenges presented by the manufacture, distribution, purchase, and administration of biotechnology products. Critics might answer "nothing," drawing attention to the existing availability of simple, low cost interventions against diarrheal diseases, tuberculosis, etc..

A recent article puts forward a series of proposals on the biotechnology sector and neglected disease. In the April 2009 issue of Nature Biotechnology (Leveraging biotech's drug discovery expertise for neglected diseases), authors Joanna Lowell and Christopher Earl (of BIO Ventures for Global Health) argue that biotechnology companies can play a "pivotal role" in developing small-molecule drugs against neglected diseases. Noting that many neglected diseases involve drug targets that are similar to those for high-income country diseases, Lowell and Earl suggest that companies can simultaneously advance their primary objectives while supporting development of drugs for neglected diseases.

They offer several reasons why biotechnology companies might do so. First is "the chance to prove technology platforms." Companies might "leverage" philanthropic support to test biologic pathways of relevance to drugs targeting more affluent markets (I will note, without comment, that such a proposal would need to think through justice concerns). Second is employee morale: initiating such research is an important way of attracting and retaining talented and idealistic scientists. Third is "sustaining underutilized discovery platforms." Once companies have discovered a lead compound, drug discovery platforms can potentially languish. Using this dormant capacity helps companies maintain their drug discovery platforms so that they will be available in the future.

I leave it to readers to decide the soundness of the proposals. On the one hand, the idea that biotechnology companies can derive benefits from pursuing neglected disease research seems plausible, as does the notion that the biotechnology sector has much to offer low-income countries (curiously, the article centers on small molecule drugs rather than vaccines). The authors cite a number of examples to support their claims, and BIO Ventures for Global Health has received a "seal of approval" (e.g. generous funding) from the Bill and Melinda Gates Foundation.

On the other hand, are struggling biotechnologies likely to embrace this-- especially given today's credit markets? One can be forgiven for wondering whether this is merely a PR ploy for a biotechnology industry that has sought contentious policies like strong intellectual property protections. BIO Ventures for Global Health is, after all, an arm of the biotechnology trade association, BIO. (photo credit: ViaMoi, Neglect, 2007)

Guinea Pig Nation?

2009-04-08T11:20:00.007-04:00

Here is an irresistible news headline: "Public Policy That Makes Test Subjects of Us All."(New York Times, April 6, 2009). Then you open to the story only to discover, to your disappointment, that the piece is written by John Tierney, probably the most uninformed and underqualified members of the NYTimes staff.

His argument is ridiculous: that the New York City mayor's initiative to "pressure" the food industry to cut salt amounts to a big experiment that would normally have to undergo IRB review and informed consent (never mind that the initiative is not an experiment designed to further knowledge. Never mind that the initiative is not aimed at generalizable knowledge, or that public health initiatives grounded in a state-based interest that are enacted by elected leaders have the "consent of the governed").

But in the most recent issue of JAMA, a news story (Bridget M. Kuehn, "Rare Neurological Condition Linked to Newer Monoclonal Antibody Biologics," April 8, 2009) reminds us that, in some small sense, licensure of novel biologics makes guinea pigs of us all. The report describes how FDA recently issued an advisory on the psoriasis drug efalizumab after reports emerged that it may be associated with a risk of developing a rare and fatal brainwasting disease (progressive multifocal leukoencephalopathy, or PML). FDA had previously issued warnings on two similar, immunomodulating drugs, and established a restricted distribution system for a third (natalizumab-- for multiple sclerosis).

In the case of natalizumab, cases of PML occurred in pre-marketing clinical trials. For the other drugs, knowledge of the risk emerged only after drug licensing. Risk of PML was totally unexpected, and is a reminder of the high degree of uncertainty surrounding interventions directed at the immune system.

Premarketing clinical trials are statistically powered only to detect common, "signature" adverse events. As we move into an era of biologics-based pharmaceuticals (and accelerated approval), expect that many adverse events will only be discovered once a drug is in widespread use. Robust systems of pharmacovigilence will be especially critical (photo credit: Peter Guthrie, 2006).

Red Handed: An Independent Review of IRBs

2009-03-27T23:23:00.005-04:00

A decade or so ago, the Government Accounting Office published a series of reports faulting human protections at VA hospitals, raising concerns about HHS oversight of human research, and urging continued vigilance in human research.

After a seeming pendulum swing toward protections bashing (witness the outpouring of condemnation after OHRP sanctioned a team of researchers investigating ways to cut infection rates in intensive care units, or the Tricouncil draft policy's use of the phrase "over-protection"), a recent GAO report may show a revival of concerns about independent review operations.

In it, GAO reports the result of a "sting" operation in which a sham device study was presented to three private IRBs. The IRBs were selected on the basis of having "less burdensome initial paperwork requirements." Two of the IRBs rejected the protocol, describing it as "awful" and "the riskiest thing I've ever seen on this board." But one– identified in a New York Times article as Coast Independent Review Board (whose webpage lists "speed" as the first selling point), unanimously approved the protocol, characterizing it as "probably very safe."

Congress, GAO, and press reports are framing this as evidence of flaws in private IRB review. I'm actually impressed that the glass is 2/3 full. And without suggesting endorsement of the private IRB model, I actually wonder how well academic medical center IRBs-- most of whose members are salaried by an institution with a significant financial and professional stake in seeing research protocols approved-- would have performed. (photo credit: laughing squid, 2008)

Centralized Revue

2009-03-27T12:49:00.003-04:00

In the most recent issue of Molecular Therapy, U Penn researcher Hildegrund Ertl provides a strong and eloquent defense of the Recombinant DNA Advisory Committee (RAC). RAC was initially formed to evaluate the safety of studies involving recombinant DNA. In the last decade, however, its most visible function has been to provide advise to researchers pursuing novel gene transfer protocols in human beings.

Many researchers resent RAC, viewing it as yet another layer of oversight for their clinical studies. Understandably, they question whether it makes sense to have a separate review track for gene transfer. Other scientists and ethicists might question whether gene transfer is so exceptional as to be singled out for separate review, but would nevertheless argue that the RAC model should be extended to other ethically contentious areas of medical research. Nevertheless, the RAC model of centralized review of trial protocols has yet to be extended to comparably novel and contentious human clinical research areas like cell transfer, embryonic stem cell research, or tissue engineering.

Ertl provides a clear and persuasive description of RAC's role in improving gene transfer trial safety, enhancing scientific value of studies, and ensuring appropriate informed consent practices. But the structure of her argument embeds three assumptions that, in my view, need to be questioned.

1- Why demand solid preclinical evidence? Ertl answers "if such data are not available, the risk outweighs the potential benefit for human volunteers– and that is not acceptable." I would argue that preclinical evidence is of greater use in improving the scientific value of clinical studies.

2- How are risks justified in early phase studies? In the above quote, Ertl seems to suggest the answer is therapeutic benefit for the volunteer. In my view, risks in first-in-human trials are justified by the potential for scientific gain, not direct medical benefit.

3- What is the purview of ethics? Ertl, like many others, partitions "technical" concerns like study validity / value / preclinical evidence from "ethical" concerns like informed consent and conflict of interest. But why is the former any less ethical than the latter, given that technical questions implicate problems of risk-benefit balance and the ultimate ends of research. In my view, there is no clear division between the technical and ethical, and few if any decisions in designing and executing clinical protocols are devoid of ethical content. (photo credit: 416style, 2005)

Departing Milano Stazione? ADA-SCID and Gene Transfer

2009-03-10T13:00:00.005-04:00

Greetings after a hiatus for teaching, grants, committees, book deadlines, wiping runny noses, and more. Much has happened since my last posting, and in the next two or three weeks, I hope to catch up.

First item on the agenda is a Jan 29 report in New England Journal of Medicine (NEJM) describing successful reconstitution of immune function in eight of ten children receiving gene transfer for adenosine deaminase severe combined immune deficiency (ADA-SCID). The paper follows on a previous report in Science, 2002, and almost certainly counts as gene transfer's greatest clinical accomplishment to date.

I have previously argued in Lancet and Developing World Bioethics, as well as in my forthcoming book, that this study raised important justice concerns because it recruited volunteers from economically disadvantaged settings without clearly fulfilling the requirement, articulated in the Declaration of Helinki, of responsiveness. The NEJM article does not say where subsequent volunteers were recruited, though the fact that all but one new volunteer received PEG-ADA (a very expensive standard of care available only in high-income countries) suggests that later patients were not economically disadvantaged.

Rather than dwell on justice, I'd like to focus on the significance of this study. As indicated, eight of ten children with a life threatening immune disorder had their immune systems reconstituted. Five of these children had T-cell counts that were "above the lower limits of normal." These children were able to enjoy normal social relations parents and other children.

There do not appear to have been any adverse events relating to the gene transfer vector. A major concern was the possibility that gene transfer might trigger a leukemia-like syndrome observed in two X-SCID studies. Blood tests of children in this ADA-SCID study, however, do not evidence of either the leukemia syndrome or its precursors– at least within the time frame of the study (median follow-up of 4 years; range: 1.8-8 years).

So is ADA-SCID gene transfer ready to leave Milan and conquer ADA-SCID? For children lacking haplo-identical bone marrow donors, maybe so given the morbidity associated with marrow transplantation. Still, there are lingering concerns. First, though these results are encouraging, risks of malignancy remain unquantified. Second, this gene transfer regime requires several ancillary treatments- like bone marrow conditioning- that expose patients to risk of infection until the gene transfer intervention kicks in. Several volunteers in this study developed infections and neutropenia, for example. In an accompanying editorial in NEJM, Donald Kohn and Fabio Candotti describe several ways that retroviral gene transfer to blood stem cells might be made safer. Last, it is important to remember that ADA-SCID is a multi-system disorder, with neurological, skeletal, and other effects. Though this approach seems to address what is by far the largest cause of morbidity and mortality in children with ADA-SCID, it does eradicate their condition.

The results of Aiuti et al have been widely celebrated in the gene transfer community. Kohn and Candotti's editorial, for example, is titled "Gene Therapy Fulfilling its Promise." More than any single gene transfer study I can think of, this one seems to have earned the vindicating headlines. (photo credit: Paolo Margari, Milano Sazione Centrale Ferrovi, 2008)

Found Figures: Picking up the Pieces after an HIV Vaccine Trial Fails

2009-02-03T14:53:00.004-05:00

In the November 29, 2008 issue of Lancet, two reports (plus a commentary) report the famously disappointing outcome of a recent placebo-controlled study testing adenoviral vector-based vaccines against HIV. News reports over a year ago reported that the study was halted after an interim analysis failed to show any prospect of proving effective. More troubling, subgroup analysis suggested that vaccine recipients who had high pre-existing immunity to the adenoviral vectors showed higher rates of sero-conversion compared with placebo. As this vaccine was among the most promising and advanced in terms of development, these results were seen as a major setback.

The recent Lancet reports paint a complicated picture: if I read them correctly, the inference that vector might enhance sero-conversion is muddied by the finding that circumcision status might also have played a role in sero-conversion (men with higher rates of adenoviral immunity were also, coincidentally, less likely to be circumcised).

What is clear, from what I gather, is that this is a good example where rigorous preclinical testing, coupled with rigorous trial design, permits meaningful interpretation of (unfortunately) negative human trial results. As Merlin Robb notes in a commentary accompanying the Lancet reports "the predictive value of the non-human SHIV-challenge model is not supported by this experience. The benchmarks for advancing candidate vaccines to efficacy testing and the priorities for vaccine research have been re-examined."

Well-designed studies, supported by rigorous preclinical testing, should always produce valuable, findings– like the unexpected "found figures" in the bark of a tree (photo credit: Readwalker, Found figures, 2006)

Prime Time for Embryonic Stem Cells?

2009-01-29T22:33:00.004-05:00

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

2009-01-19T11:47:00.003-05:00

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?

2009-01-06T20:11:00.005-05:00

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)

Stems and Blossoms (part 2): Really Informed Consent

2008-12-29T20:59:00.007-05:00

There is a strain within the clinical and bioethics community that takes a minimal view of informed consent: investigators are supposed to provide requisite information to volunteers; if research subjects fail to comprehend this information, pity for them. This view brings to mind a memorable exchange between Inspector Clouseau and a hotel clerk (Clouseau: "does your dog bite?" Clerk: "No." Clouseau then extends a hand; the dog lunges at him. "I thought you said your dog doesn't bite." Clerk: "Zat is not my dog.")

The ISSCR guidelines take a bold stand on informed consent. "Investigators involved in clinical research must carefully assess whether participants understand the essential aspects of the study." The guidelines go on to state "ideally, the subject's comprehension of information should be assessed through a written test or an oral quiz during the time of obtaining consent." Once again, ISSCR shows vision here in going well beyond the legalistic conception of informed consent described above.

The ISSCR guidelines also urge researchers to:

• explain possible irreversibility of some toxicities

• describe the sources of stem cells

• inform patients that researchers "do not know whether they will work as hoped"

These laudable recommendations aside, I might have hoped for more guarded language about the therapeutic value of early phase studies. For one, the guidelines use mostly "therapeutic" language, for example, using the aspirational term "cell therapy" instead of the neutral term "cell transfer." Second, the third item above logically means that the probability of benefit is less than 100%; experience tells us, however, that when interventions are highly novel, major therapeutic benefits for early phase trials are very improbable. (photo credit: Helen K, Stems, 2008)

Stems and Blossoms (part 1): Justice

2008-12-28T17:54:00.007-05:00

Shortly before I left for holiday, the International Society for Stem Cell Research (ISSCR) issued a policy paper, "Guidelines for the Clinical Translation of Stem Cells," outlining ethical and scientific considerations for researchers designing translational trials involving stem cells (whether stem cell derived, adult, or embryonic).

In my opinion, the document wins the award for most forward thinking and comprehensive statement on the ethics of a translational enterprise. It shows that the stem cell research leadership has closely studied mistakes made by translational researchers in other highly innovative fields. But the guidelines do more than look backwards; they proactively contemplate fairness and justice considerations as well. Here are a few justice-related excerpts:

On responsiveness: "The ISSCR strongly discourages conduct of trials in a foreign country solely to benefit patients in the home country of the sponsoring agency. The test therapy, if approved, should realistically be expected to become available to the population participating in the clinical trial through existing health systems or those developed on a permanent basis in connection with the trial."

On reasonable availability: "As far as possible, groups or individuals who participate in clinical stem cell research should be in a position to benefit from the results of this research."

On diversity: "Stem cell collections with genetically diverse sources of cell lines should be established"

On access and licensing: "Commercial companies, subject to their financial capability, should offer affordable therapeutic interventions to persons living in resource-poor countries who would otherwise be wholly excluded from benefiting from that stem cell-based therapy. Academic and other institutions that are licensing stem cell therapeutics and diagnostic inventions should incorporate this requirement in their intellectual property license"

On review: "Regulatory and oversight agencies (local, national, and international) must explicitly include the consideration of social justice principles into their evaluations."

On trial participation: "... the sponsor and principal investigator have an ethical responsibility to make good faith, reasonable efforts whenever possible to secure sufficient funding so that no person who meets eligibility criteria is prevented from being considered for enrollment because of his or her inability to cover the costs of the experimental treatment."

In upcoming posts, I will comment on other aspects of the ISSCR guidelines. (photo credit: Helen K, Stems, 2008)

GenetEx Cathedra

2008-12-13T19:22:00.008-05:00

On December 12, the Catholic Church issued what the New York Times called "the most sweeping document on bioethical issues," its Dignitas Personae. The document– the summary of which is available on the web– is dominated by discussion of in vitro fertilization, embyro research, and stem cells. But there is a section on gene transfer– and following on my previous post, the degree to which gene transfer has receded from the public discussion is striking (for example, gene transfer gets nary a mention in the New York Times coverage on Friday).

Here is what the document has to say about gene transfer. It defines "gene therapy" in a rather un-(small-'c')atholic way, as "techniques of genetic engineering applied to human beings for therapeutic purpses, that is to say, with the aim of curing gentically based diseases." This excludes lots of what goes on in gene transfer, like cancer and cardiovascular disease gene transfer and gene marking. It also excludes much of what is morally contested about gene transfer– namely, enhancement applications. About "somatic gene therapy," the statement says that "in order to proceed to a therapeutic intervention, it is necessary to establish beforehand that the person being treated will not be exposed to risks to his health or physical integrity which are excessive or disproportionate to the gravity of the pathology for which a cure is sought. The informed consent of the patient or his legitimate representative is also required." Nothing startling about this statement. But a careful reading raises interesting questions. What, for example, is meant by "establish beforehand?" What type and degree of evidence is required? Are gene transfer applications not aimed at "therapeutic intervention," like gene marking or vaccines, exempt? Another question: why the word "cure" given that few if any gene transfer strategies actually cure. Why not the more inclusive "treat?"

The statement on germ line cell therapy is somewhat intriguing. The document stops far short of categorically condemning such practices, and instead advises against them given that "the risks... are considerable and as yet not fully controllable." In principle, then, the Catholic Church does not oppose germline gene transfer applied surgically to adults, fetuses, gametes, and embryos provided risks are manageable. But it is hard to imagine how these risks could be reduced for embryos without research that destroys embryos. It is also hard to imagine how the safety of gamete gene transfer could be established without the creation of "injured" embryos. If my analysis is correct, embryonic and gamete germline gene transfer are obliquely banned, leaving permissible application of germline gene transfer to fetuses with genetic illness provided benefits outweigh risks.

The document goes on to warn against "genetic engineering... with the presumed aim of improving and strengthening the gene pool." Such techniques "promote a 'eugenic mentality';" many disabilities activists (and medicalsocial constructivists) will be heartened by the admonition that these techniques "introduce an 'indirect social stigma with regard to people who lack certain qualities, while privileging qualities that happen to be appreciated by a certain culture or society...." Still, one wonders what, exactly, this condemns other than heavy handed state, or large collective efforts, to improve the gene pool (that is, genetic engineering with the aim of creating individuals who can fly, see in the dark, or think more clearly is not explicitly banned).

Somewhat surprisingly, the document contains no language on somatic gene transfer applied towards the ends of enhancement, though the spirit of the prohibition on cosmetic germline alteration would seem to rule out the use of such techniques. (photo credit: Vatican stairs, tintalle* 2007)

Soft Cells and C-Sections

2008-12-10T11:57:00.003-05:00

The American Society of Gene Therapy is renaming itself: "American Society of Gene and Cell Therapy" (membership has yet to finalize the name change." The European Society of Gene Therapy has already done so: "European Society of Gene and Cell Therapy."

Why is gene transfer going cellular? The publicly stated reasons are two fold. First is a recognition that gene transfer has always involved "cell transfer." For instance, ADA-SCID and X-SCID protocols-- for that matter, all ex vivo protocols– involve modifying cells outside the body, and returning them to the volunteer.

A second reason is to have a more "inclusive" society, and an "expanded membership base." I suspect this partly reflects a concern that cell-types might affiliate with groups like ISCT (International Society of Cell Therapy), which has a "gene therapy" committee, or perhaps also ISSCR (International Society of Stem Cell Research).

Of course, this raises the question of what ASGCT means by "CT." Does the society intend "American Society of Gene AND Cell Therapy," or is it "OR Cell Therapy (which would include protocols that do not involve genetic modification). I can't help but wonder what the realignment will mean for gene transfer. Since its founding, "gene transfer" has represented a kind of "invisible college" - an international network of collaborations and co-citations with a common set of concerns. Does renaming represent the demise of the gene transfer invisible college, as "genes" are absorbed under the more powerful social category of "cells?" Or does it represent a promising extension of the network? Is this simply a reflection that in the first decade of the 21st century, "cells" are, in terms of scientific capital, what "genes" were to the 1990s? (photo credit: I like 2008)

Northern Lights? Canada and the New Tricouncil Draft

2008-12-08T10:45:00.004-05:00

Since it's issuance in 1998, Canada's Tricouncil Policy Statement (Canada's policy on the ethics of human research) has had an influence on the practice of research ethics that has outsized Canada's population. The three research councils– CIHR, NSERC, and SSHRC– are presently revising the Tricouncil, and a few days ago, a revised draft was presented on the CIHR web site.

There is much to commend the newest version. There are also a number of disappointments. I won't dwell on these here, however. Instead, I will focus on Tricouncil's revised language on phase 1 and gene transfer research.

The revised Tricouncil contains a definition of phase 1 that, in my view, is somewhat outmoded and not much of an improvement on the old version. Both emphasize the role of phase 1 in toxicity and dose determination, but do not encompass the many other purposes to which phase 1 trials are put (e.g. for deciding whether to pursue phase 2, for gathering evidence of biological effects, etc.). On the other hand, the new Tricouncil requires prospective registration of all trials– including phase 1. And it contains a lengthy discussion of "therapeutic misconception," which it defines as "the tendency of trial participants to believe that the primary intention of research tests and interventions is to provide a therapeutic benefit to the patient-participant." The document urges research ethics boards and researchers to "emphasize which specific elements of a clinical study are required for research purposes, as well as the differences between research and the standard clinical care they might otherwise receive." Bravo.

The new Tricouncil also, for the most part, replaces the old language of "gene therapy" with the more neutral "gene transfer." In a section on "Gene Transfer," the new draft warns about therapeutic misconception. It shrinks from any ethical statement on germline modification by deferrinng to Canada's Assisted Human Reproduction Act. The remainder of the text notes the irreversibility of genetic alterations (not quite accurate), the potentially latent nature of gene transfer risks (a point I agree with), and states that research and ethical debate is evolving rapidly (a point I mostly agree with). Somewhat disappointingly, there is no mention of the need for centralized, transparent, or specialized review of such protocols.

On balance, these two sets of modifications are pretty good, though rather than anticipate the issues that are likely to arise in the next 5-10 years while this draft is in force, I worry a little that instead the draft represents a policy that I and others wish we might have had in the previous 5-10 years. Onwards and upwards! (photo credit: Studiolit 2006)

Sourgene

2008-12-04T21:34:00.004-05:00

Heaven help those perseverant souls who pursue translational research on neurodegnerative disorders. New interventions in this area have just about the highest failure rate of any area of medical research. And last week, yet another promising strategy was shown ineffective in a phase II study.

The trial in question was testing Ceregene's gene transfer strategy against Parkinson's Disease (PD). Ceregene was second out of the gate testing gene transfer against PD (the first was Neurologix). In April 2008, I wrote about their phase 1 study results, which on the one hand seemed to suggest safety, while on the other hand did not show signs of a dose-effect nor a change in dopamine metabolism by imaging. For me, the most troubling aspect of this protocol was its aggressiveness: researchers delivered vector along eight needle tracks to deep brain structures. Based on surgical complication rates in the published literature, the risk of causing permanent neurological deficits from cerebral hemorrhage was on the order of 7% in this study- and that's not including the additional risk associated with the vector itself.

On November 26, Ceregene announced results of its sham controlled phase II study of CERE-120. First the good news: the press release described CERE-120 as "safe and well tolerated." The bad news is that the investigators saw no difference in outcomes between the sham and active arms. The press release does not say whether any adverse events were reported; nor does it say anything about surgical complications. In the next few weeks, expect to see data on why, precisely, the strategy might have failed. (photo credit: bebob717 2006).