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)
@Manual{stream2011-54,
title = {Tea Leaves: Predicting Risk and Benefit in Translation},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2011,
month = mar,
day = 21,
url = {http://www.translationalethics.com/2011/03/21/tea-leaves-predicting-risk-and-benefit-in-translation/}
}
MLA
Jonathan Kimmelman. "Tea Leaves: Predicting Risk and Benefit in Translation" Web blog post. STREAM research. 21 Mar 2011. Web. 29 Apr 2024. <http://www.translationalethics.com/2011/03/21/tea-leaves-predicting-risk-and-benefit-in-translation/>
APA
Jonathan Kimmelman. (2011, Mar 21). Tea Leaves: Predicting Risk and Benefit in Translation [Web log post]. Retrieved from http://www.translationalethics.com/2011/03/21/tea-leaves-predicting-risk-and-benefit-in-translation/
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/
The October 2008 issue of Nature Reviews–Drug Discovery contains a very informative perspective piece on how drug regulators negotiate uncertainty, risk, and benefit when making approval decisions (“Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma”). I have long argued that novel biologics like gene transfer will require creative approaches from regulators, because on the one hand many types of adverse events might be latent and unpredictable, while on the other hand, many novel biologics will target highly morbid or lethal conditions like primary immunodeficiencies.
The authors (Hans-Georg Eichler et al) are all employees of drug regulatory agencies in Europe. Not surprisingly, then, the article is balanced and presents drug agencies as making appropriate trade-offs between patient access and public safety. The article studiously avoids any criticism of pharmaceutical companies. And it makes some questionable claims. For example, in several passages it suggests that drug regulation is increasingly “risk averse” (it seems to me the opposite, but who knows?). Another is that the article contains ample evidence that premature approval has had important costs in terms of health and economics. Nowhere does it provide clear evidence or anecdotes that delay of approval, or restrictive evidentiary standards have had important public health or economic impacts (it might, but if you are going to suggest that the balance is appropriately struck, one needs a clear picture of the benefit side of the equation).
The article contains a number of observations and policy approaches that cry out for careful ethical analysis. Here are two:
1- Drug regulatory agencies accept greater uncertainty about safety and efficacy when new drugs address serious, unmet health needs. Thus, new cancer drugs can be approved on a weaker evidentiary base than new acid reflux drugs (in several instances, new drugs were approved on the basis of uncontrolled, surrogate endpoints (e.g. gefitinib). Why should evidentiary standards be relaxed in this way? And to what degree? If the disease is serious enough and standard care non-existent, then what is the basis for any drug regulation?
2- The article states that “rare drug reactions will continue to be identified only after wider use in the market,” and that more sophisticated approaches to drug safety will increasingly “blur the line between pre-marketing and post-marketing activities.” How will this affect ethics review and oversight? How will privacy protections be maintained in this gulf-stream of flowing health data? How will trial registries absorb and respond to post-marketing studies?
This article contains multitudes– I highly recommend it to anyone interested, as I am, in the problem of uncertainty, risk, and drug regulation (photo credit: Alincolnt, schedule 5, 2006)
@Manual{stream2008-127,
title = {The Future of Pharmaceutical Regulation},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = oct,
day = 28,
url = {http://www.translationalethics.com/2008/10/28/the-future-of-pharmaceutical-regulation/}
}
MLA
Jonathan Kimmelman. "The Future of Pharmaceutical Regulation" Web blog post. STREAM research. 28 Oct 2008. Web. 29 Apr 2024. <http://www.translationalethics.com/2008/10/28/the-future-of-pharmaceutical-regulation/>
APA
Jonathan Kimmelman. (2008, Oct 28). The Future of Pharmaceutical Regulation [Web log post]. Retrieved from http://www.translationalethics.com/2008/10/28/the-future-of-pharmaceutical-regulation/
When gene transfer researchers perform an experiment, how do they measure the dose of their vectors? For that matter, when investigators perform a study using any novel biologic, how have they characterized their agents?
Few would think the questions are ethically significant. But consider the fact that research teams often use different techniques to determine vector dosage, and as a consequence, results from different human and animal studies cannot be compared with each other.
In the July issue of Molecular Therapy, Richard Snyder and Philippe Moullier outline international efforts to estabish reference standards for AAV vectors (a class of viral vectors widely used in gene transfer studies). After about six years (and nearly twice that of trials using human beings), reference standards for two serotypes (AAV2 and AAV8) will soon be available. The authors describe a number of logistic and funding problems for establishing reference standards. Not mentioned are the numerous sociological challenges with herding feline-like researchers.
In my book, I argue that standards represent a critical vehicle for risk management in novel research arenas: small-scale human safety studies have limited value unless results can be linked up with other human studies to identify trends. Standard setting, and the octopus–like extension of standards into all preclinical and clinical studies–thus have important ethical implications. IRBs reviewing early phase novel agent protocols should be on the alert where study agents are not characterized using reference standards (photo credit: Roadsidepictures, 2007)
@Manual{stream2008-133,
title = {The Octopus of Reference Standards},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = sep,
day = 23,
url = {http://www.translationalethics.com/2008/09/23/the-octopus-of-reference-standards/}
}
MLA
Jonathan Kimmelman. "The Octopus of Reference Standards" Web blog post. STREAM research. 23 Sep 2008. Web. 29 Apr 2024. <http://www.translationalethics.com/2008/09/23/the-octopus-of-reference-standards/>
APA
Jonathan Kimmelman. (2008, Sep 23). The Octopus of Reference Standards [Web log post]. Retrieved from http://www.translationalethics.com/2008/09/23/the-octopus-of-reference-standards/
Most cancer patients who enter phase 1 clinical trials are motivated by the prospect of controlling their cancer. Increasingly, however, such studies, in the words of one ethicist, “take without giving in return” by involving biopsy procedures in which tissue is collected before and during the study in order to gauge whether a new drug is having intended biological effects. Such procedures are potentially burdensome, and offer no direct benefits for patients.
So is it ethical for clinical investigators to “stick it to” their research subjects? Depends in part on the level of risk. In the August 20, 2008 issue of Journal of Clinical Oncology, Aaron P. Brown and coworkers at NIH performed a literature review examining the complication rate for research biopsies in the context of studies involving radiotherapy (“Performing Nondiagnostic Research Biopsies in Irradiated Tissue: A Review of Scientific, Clinical, and Ethical Considerations”). One might expect to find higher than usual complication rates in this context, because irradiation can interfere with wound healing.
Here is what they found. Of 29 eligible studies, only 3 (!!) actively evaluated adverse events related to biopsy (another 16 reported adverse events– but not specifically related to biopsy) These 3 studies reported a total of 17 adverse events.
Here is what the authors concluded: “Limited data suggest that biopsies can be performed in irradiated tissues without clinically significant excess risk.”
The authors sagely argue that “all clinical trials that perform biopsies in combination with other therapies should actively study and report complications.” But with their specific study question- the complication rate of tissue biopsies- so underexposed, the their conclusions are dodgy. (photo credit: Moominsean 2006)
@Manual{stream2008-137,
title = {In the Dark?},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = sep,
day = 11,
url = {http://www.translationalethics.com/2008/09/11/in-the-dark/}
}
MLA
Jonathan Kimmelman. "In the Dark?" Web blog post. STREAM research. 11 Sep 2008. Web. 29 Apr 2024. <http://www.translationalethics.com/2008/09/11/in-the-dark/>
APA
Jonathan Kimmelman. (2008, Sep 11). In the Dark? [Web log post]. Retrieved from http://www.translationalethics.com/2008/09/11/in-the-dark/
