FDA: Lapdog or Listener?

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Sociology of Health and Illness sociologist John Abraham (photo credit: eddiemcfish 2008)

BibTeX

@Manual{stream2011-55,
    title = {FDA: Lapdog or Listener?},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2011,
    month = feb,
    day = 27,
    url = {http://www.translationalethics.com/2011/02/27/fda-lapdog-or-listener/}
}

MLA

Jonathan Kimmelman. "FDA: Lapdog or Listener?" Web blog post. STREAM research. 27 Feb 2011. Web. 20 Nov 2017. <http://www.translationalethics.com/2011/02/27/fda-lapdog-or-listener/>

APA

Jonathan Kimmelman. (2011, Feb 27). FDA: Lapdog or Listener? [Web log post]. Retrieved from http://www.translationalethics.com/2011/02/27/fda-lapdog-or-listener/


Dirty Windows of Drug Development

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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 Among the proposed items that would be publicly accessible: when an application has been submitted to the agency (or withdrawn); whether a significant safety issue triggered withdrawal, and reasons why the agency turned down an application.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).

BibTeX

@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. 20 Nov 2017. <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/


The Need for Speed: GAO Reports on Accelerated Approval

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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)

BibTeX

@Manual{stream2009-81,
    title = {The Need for Speed: GAO Reports on Accelerated Approval},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = nov,
    day = 2,
    url = {http://www.translationalethics.com/2009/11/02/the-need-for-speed-gao-reports-on-accelerated-approval/}
}

MLA

Jonathan Kimmelman. "The Need for Speed: GAO Reports on Accelerated Approval" Web blog post. STREAM research. 02 Nov 2009. Web. 20 Nov 2017. <http://www.translationalethics.com/2009/11/02/the-need-for-speed-gao-reports-on-accelerated-approval/>

APA

Jonathan Kimmelman. (2009, Nov 02). The Need for Speed: GAO Reports on Accelerated Approval [Web log post]. Retrieved from http://www.translationalethics.com/2009/11/02/the-need-for-speed-gao-reports-on-accelerated-approval/


Age of Risk: Biologicals

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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)

BibTeX

@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. 20 Nov 2017. <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/


Goodbye, Helsinki

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According to recent news reports, the U.S. FDA recently decided to abandon its endorsement of the Declaration of Helsinki when sponsors submit clinical trial data obtained overseas.


The Declaration of Helsinki (DoH)- which was first adopted in 1964- is the World Medical Association’s statement on ethical requirements for human experimentation.  According to an editorial in Nature (22 May 2008), 85 countries have endorsed the DoH.

The FDA had long ago began distancing itself from the DoH when it refused to endorse revisions to the statement that followed controversies over the use of placebos in HIV mother-to-child transmission studies.  But the FDA has now opted to slam shut a door it had, for years, left ajar.

Helsinki is an imperfect document.  Certain paragraphs– particularly those involving international research– have continued to provoke heated debate.  But it is arguably the most influential, multilateral statement on ethical human experimentation, and it speaks clearly to considerations of justice when high income countries pursue trials in resource-poor settings.

Shame on FDA, and the U.S. government, for favoring parochial interests over international policy and, indeed, human rights. (photo credit: sobergeorge 2007)

BibTeX

@Manual{stream2008-153,
    title = {Goodbye, Helsinki},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = may,
    day = 23,
    url = {http://www.translationalethics.com/2008/05/23/goodbye-helsinki/}
}

MLA

Jonathan Kimmelman. "Goodbye, Helsinki" Web blog post. STREAM research. 23 May 2008. Web. 20 Nov 2017. <http://www.translationalethics.com/2008/05/23/goodbye-helsinki/>

APA

Jonathan Kimmelman. (2008, May 23). Goodbye, Helsinki [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/23/goodbye-helsinki/


Teddy’s Frowning

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This blog primarily covers the ethics of translational clinical trials. Products tested in such studies, should they progress towards licensure, will eventually fall under the oversight of drug regulatory agencies like the FDA. How prepared will the FDA be to protect the public once these highly complex interventions are introduced to clinical practice? And when they are tested in early phase trials, how much should IRBs be reassured by the fact that sponsors can show a letter of “no objection”?


The FDA has long been considered the world’s “gold standard” for the evaluation of drug safety and efficacy. But here is a list of NYTimes headlines over the last 6 months that suggest that standards at the agency have fallen.

Panel’s Bipartisan View: FDA is Underfinanced (April 16, 2008). Headline says it all

Drug Makers Near Old Goal: A Legal Shield (April 6, 2008). Reporting that, if the FDA screws up its review, courts are increasingly reluctant to allow injured parties to sue drug and device manufacturers.

Tainted Drugs Put Focus on the FDA (March 17, 2008).  FDA violated its own safety rules in not inspecting overseas drug manufacturing facilities.

Justices Shield Medical Devices from Lawsuits (February 21, 2008).  Reporting that the Supreme Court found that device manufacturers have immunity from tort litigation if the FDA approves them– even though FDA standards on device approval are notoriously weak.

FDA Seeks to Broaden Range of Use for Drugs (February 16, 2008).  Reporting on proposed FDA guidelines that, more or less, would allow drug makers to promote applications of their drugs that have not yet been reviewed or approved by the FDA.

FDA in Crisis: It Needs More Money and Talent (February 3, 2008).  Editorial.

Advisors Say FDA’s Flaws Put Lives at Risk (December 1, 2007).  Reporting that an FDA Science Board report stated that “FDA’s inability to keep up with scientific advances means that American lives are at risk.”

FDA Tests on Devices Scrutinized (October 23, 2007).  Reporting on a letter from Congressman Waxman to the FDA questioning the rigor of their review of a Medtronic implantable defibrillator. (photocredit: sluggerwv 2008, though probably lifted from someone else)

BibTeX

@Manual{stream2008-160,
    title = {Teddy’s Frowning},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = apr,
    day = 17,
    url = {http://www.translationalethics.com/2008/04/17/teddys-frowning/}
}

MLA

Jonathan Kimmelman. "Teddy’s Frowning" Web blog post. STREAM research. 17 Apr 2008. Web. 20 Nov 2017. <http://www.translationalethics.com/2008/04/17/teddys-frowning/>

APA

Jonathan Kimmelman. (2008, Apr 17). Teddy’s Frowning [Web log post]. Retrieved from http://www.translationalethics.com/2008/04/17/teddys-frowning/


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