Overseas clinical trials of pharmaceuticals — the globalization of guinea pigs

(WARNING: this isn’t going to be pretty…)

In the 1940s, the US Government deliberately infected mentally ill and incarcerated Guatemalans with syphilis – almost 700 people in total.  The study design included arranging sexual encounters between prostitutes known to be infected and the male participants [you just can’t make stuff like this up].  After 2 years, the study was determined to be “useless” and was subsequently abandoned and forgotten in the Guatemalan rainforest.  As were the participants and their families.

Until last October, that is, when Wellesley College medical researcher Susan Reverby rediscovered it.   Against all odds, she managed to break the story.

It was kind of a big deal. 

Obama called the president of Guatemala on the phone, and Hillary gave a speech about it:

Although these events occurred more than 64 years ago, we are outraged that such reprehensible research could have occurred under the guise of public health…We deeply regret that it happened, and we apologize to all the individuals who were affected by such abhorrent research practices.

(Hillary Rodham Clinton, Secretary of State; 10/1/2011)

Let me translate that for you:

Although these events occurred more than 64 years ago,

[something like this could never happen today]

we are outraged that such reprehensible research could have occurred under the guise of public health…

[However, under the guise of “stopping Latin American communist/socialist/populism” and “protecting American business interests”[1] loss of Guatemalan lives was totally cool by America in the past, so… why is this such a big deal?]

We deeply regret that it happened, and we apologize to all the individuals who were affected by such abhorrent research practices.

[but in no way are we interested in offering support, reparations, monetary assistance, further treatment, etc. at this time.]. 

(Hillary, with a little help from ALT)

 

The emphasis remained on “this could never happen today;” when Obama spoke with President Colon, he “reaffirmed the United States’ unwavering commitment to ensure that all human medical studies conducted today meet exacting U.S. and international legal and ethical standards,” a White House statement said.  Obama also charged the “Presidential Commission for the Study of Bioethical Issues” with researching the issue, particularly in the context of international clinical studies/trials. 

    

This just in: It could happen.

The Commission came back on Tuesday with its official report: despite 1000s of rules and regulations to prevent these human rights violations from happening, they could happen.

What they forgot to mention is that they do happen.  ALL THE TIME. 

A couple examples:

• Grudziadz, Poland; 2007 – residents of a homeless shelter received as little as $2 to take part in a flu-vaccine experiment.  The subjects thought they were getting a regular flu shot (staff, of course, deny this).  Regardless, participants were getting a H5N1 bird-flu vaccine, not a typical flu vaccine.  At least 20 of them died. [more information here]
• India and 11 countries; 2002-2004 – Ketek, FDA-approved only as an antibiotic for treating respiratory-tract infections, is tested on nearly 4000 infants and toddlers as a preventative measure for ear infections and tonsillitis.  At least 12 deaths and 93 “severe adverse events” occurred before the trial was halted and the medication given a black box warning. [more here]
• Santiago del Estero, Argentina; 2008 – A vaccine, Synflorix, is tested on local children, toddlers, and infants by Glaxo-Smith-Klein.  14 infants enrolled died; their parents (some of them unable to read) did not understand that their children were in an experiment.  Local doctors received $350 for each child they enrolled in the study. [more here]

These are not anomalies, attributable to the rare cruel/evil researcher, a few “bad apples” in an otherwise ethically and scientifically rigorous community.  Nope; these kinds of research abuses are system-wide, and overseas clinical trials in countries where human research protections are easily overlooked are essential building blocks of the pharmaceutical industry’s business model.

This doesn’t come as a surprise to anyone familiar with the growing trend in overseas clinical trials (particularly for drugs with questionable – at best – efficacy). 

Frankly, I am most worried about the drug trials that get done elsewhere now, which we have little control over.

(Susan Reverby; researcher who broke the Guatemalan syphilis trial story, when asked to cite any ongoing experimental practices that gave her pause)

    

Like a tumor, so it grows…

Between 1990 and 2008 the number of clinical trials for pharmaceuticals being conducted overseas increased from 271 to 6485; that’s over 2000%!  In 2008 alone, 80% of the applications submitted to the FDA for new drugs contained data from foreign clinical trials.  While traditional clinical trial host countries – like the United States, Britain, Germany, and Australia – are hosting less and less per year, 24 of the 25 fastest growing countries are from the “developing world.”  Check out some of these average annual growth rates (from 2008):

• 47% – China
• 33% – Russia
• 26.9% – Argentina
• 24.6% – Czech Republic
• 19.6% – India

This map also puts it in perspective:

[citation: Theirs, F.A., Sinskey, A.J., & Berndt, E.R. (2008).  Trends in the globalization of clinical trials.  Nature, 7; pp 13-15.]

What makes overseas trials so attractive to pharmaceutical companies?  Aside from the above-mentioned lack of human research subjects protections, there are a host of reasons.  Overseas clinical trials are cheaper; the contractor’s fee is cheaper, you can pay the participants and researchers pennies compared to the dollars of American trials, follow-up care and treatments are not required, etc.  In developing countries there are larger populations willing to participate because they have limited access to medical care.  Many more people are “drug naïve” (ie, they aren’t currently taking and have never taken medications) – and drug naïve populations typically yield better results than American test subjects whose systems have already been chemically manipulated.  It’s quicker to do a clinical trial overseas (again, because of the lack of regulation), and that means you don’t have to deal with long term side effects showing up in the results.

Another important factor is this interesting loophole: if American clinical trials show a drug has no benefit, the FDA will still accept overseas clinical trials as adequate proof during the approval process.  Certain countries have proven themselves invaluable when it comes to delivering positive results quickly for questionable drugs; they’re known as “rescue countries.”  Hungary, Morocco, Tunisia, Turkey, and Poland are a few notable examples  [more information on rescue countries in this book].

  

But Obama said…!

Yeah.  Didn’t Obama say that the United States has an “unwavering commitment to ensure that all human medical studies conducted today meet exacting U.S. and international legal and ethical standards?”  Yup.  He did.  On the phone with el presidente Colon de la República de Guatemala.  I hope he wasn’t bluffing, because Latin Americans take their machísmo pretty seriously – decades of dictatorship will do that.

 

 

When Obama said “US legal and ethical standards,” he could only have been referring to the FDA.  And on their website, they clearly state that overseas clinical trials will be accepted if they either a. comply with FDA regulations [insert complicated number here] or b. comply with the Declaration of Helsinki, which is essentially the international standard (though not international law) for human subjects research; medical trials in particular.

The first draft of the Declaration of Helsinki was released in 1969.  A few minor revisions brings us up to the 1989 version, which is the version the FDA officially acknowledges (read it here).

But here’s the thing: the Declaration has been revised several times since them (the most recent version is from 2008; read it here).  Some of those revisions were specifically made to address the movement of pharmaceutical trials overseas, and all of them are, presumably, rather inconvenient for the FDA and the pharmaceutical companies it partners with.  Here are a few of the key points from the 2008 version that are missing from the 1989 edition:

• Investigators must disclose funding, sponsors, and other potential conflicts of interest to both research ethics committees and study participants
• Study design must be disclosed publicly
• Post-study, participants must be given access to treatment
• Authors must report results accurately, and publish or make public negative findings
• Research, notably that in developing countries must benefit and be responsive to health needs of populations in which it is done

Now the 1989 version still has some good stuff in it; the physician’s ultimate responsibility is the safety of the patient, NOT the success of the drug trial.  This is stated explicitly: even though the participant has given consent, it is the physician’s responsibility to make sure no harm comes to him.  Additionally, the declaration spells out pretty strict guidelines about informed consent: participants need to know study design, potential risks and benefits, and the ultimate purpose of the study.  They have the right to withdraw at any time, for any reason.  And if they are unable to give consent (ie, deemed incompetent) the only way they can be included in the study is if the study COULD NOT be done with competent individuals and the research entails only “minimal risk” and “minimal burden.”

Unfortunately, these conditions aren’t being met in the United States, let alone internationally. 

Are you feeling shocked, angry, outraged?  Is your heart aching for the children of Santiago del Estero, the homeless of Grudziadz, and for everyone who trusted that the data collected by pharmaceutical companies was a fair and accurate representation of a drug’s efficacy and potential risk?  Are you ready for something to CHANGE?

Good. 

Let’s do this.

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