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 Among the proposed items that would be publicly accessible: when an application has been submitted to the agency (or withdrawn); whether a significant safety issue triggered withdrawal, and reasons why the agency turned down an application.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).
@Manual{stream2011-56,
title = {Dirty Windows of Drug Development},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2011,
month = feb,
day = 9,
url = {http://www.translationalethics.com/2011/02/09/dirty-windows-of-drug-development/}
}
MLA
Jonathan Kimmelman. "Dirty Windows of Drug Development" Web blog post. STREAM research. 09 Feb 2011. Web. 29 Apr 2024. <http://www.translationalethics.com/2011/02/09/dirty-windows-of-drug-development/>
APA
Jonathan Kimmelman. (2011, Feb 09). Dirty Windows of Drug Development [Web log post]. Retrieved from http://www.translationalethics.com/2011/02/09/dirty-windows-of-drug-development/
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 andprovides 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)
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title = {CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy},
journal = {STREAM research},
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month = apr,
day = 22,
url = {http://www.translationalethics.com/2010/04/22/car-accidents-unexpected-and-serious-toxicity-in-gene-transfer-immunotherapy/}
}
MLA
Jonathan Kimmelman. "CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy" Web blog post. STREAM research. 22 Apr 2010. Web. 29 Apr 2024. <http://www.translationalethics.com/2010/04/22/car-accidents-unexpected-and-serious-toxicity-in-gene-transfer-immunotherapy/>
APA
Jonathan Kimmelman. (2010, Apr 22). CAR Accidents: Unexpected and Serious Toxicity in Gene Transfer Immunotherapy [Web log post]. Retrieved from http://www.translationalethics.com/2010/04/22/car-accidents-unexpected-and-serious-toxicity-in-gene-transfer-immunotherapy/
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).
Jonathan Kimmelman. "Guinea Pig Nation?" Web blog post. STREAM research. 08 Apr 2009. Web. 29 Apr 2024. <http://www.translationalethics.com/2009/04/08/guinea-pig-nation/>
APA
Jonathan Kimmelman. (2009, Apr 08). Guinea Pig Nation? [Web log post]. Retrieved from http://www.translationalethics.com/2009/04/08/guinea-pig-nation/
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)
@Manual{stream2009-112,
title = {Age of Risk: Biologicals},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2009,
month = jan,
day = 19,
url = {http://www.translationalethics.com/2009/01/19/age-of-risk-biologicals/}
}
MLA
Jonathan Kimmelman. "Age of Risk: Biologicals" Web blog post. STREAM research. 19 Jan 2009. Web. 29 Apr 2024. <http://www.translationalethics.com/2009/01/19/age-of-risk-biologicals/>
APA
Jonathan Kimmelman. (2009, Jan 19). Age of Risk: Biologicals [Web log post]. Retrieved from http://www.translationalethics.com/2009/01/19/age-of-risk-biologicals/
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.
