Say you have high blood pressure. There's a new blockbuster drug on the market, and your doctor lets you know about a new clinical trial you can join that is testing the new treatment against an old tried-and-true one. What's not to like? You're going to be taking, under the care of experts, one of two U.S. Food and Drug Administration–approved medications.

What you might not know—even after you sign up for the trial and have inked the informed-consent form—is that scattered reports are starting to suggest that the new medication might occasionally cause severe side effects. And the real reason the trial is being conducted with these previously released drugs is to test whether the new medication really is a lot riskier to everyone or just to a subset of patients.

If you found that out, would you still sign up for the trial? The problem is that many patients—and often even the institutional review boards that approve the trials—are never informed of these lingering questions.

This is one of the big ethical holes often left open in post-market trials, says Ruth Faden, director of the Johns Hopkins Berman Institute of Bioethics, who co-authored a new essay on this topic in The New England Journal of Medicine, which was published online August 22. She and a team of co-authors released a formal Institute of Medicine (IOM) report earlier this year recommending that the FDA improve this and other ethical aspects of post-market trials—especially those it requires.

This issue hit the headlines two years ago, when the FDA suddenly restricted the use of Avandia, a drug that had been approved to treat diabetes.  It had become clear that patients in post-market trials were at increased risk for heart attack and stroke—risks about which drugmaker GlaxoSmithKline knew but had not informed patients.

When patients sign up for clinical trials to test an experimental drug, procedure or device, they give their informed consent after doctors counsel them about the risks and uncertainty associated with a not-yet-approved intervention. Volunteers are often more than willing to accept those risks if the experimental intervention offers potentially more promising treatment for their condition, compared with what is on the market.

The benefits of signing up for a trial testing a drug that is already on the market are less clear. Patients and their doctors will already have the option to choose that same drug without being part of a study, ideally taking any known risks into consideration. If they sign up for a trial, however, they will be randomized into groups and required to take one of the test therapies—especially if one is suspected to cause occasional severe side effects—"Now you've got this heightened ethical obligation toward these people," Faden says. "They need to understand why this particular trial is being conducted." This step is often lacking in post-market trials, especially those conducted by the pharmaceutical companies and their contractors, she notes.

With so many new therapies being fast-tracked through the FDA approval process, post-release vigilance is becoming increasingly important, Faden and her colleagues noted in the piece. And when suspicion arises that a new medication might be causing more harm than it is worth, a large, formal, randomized controlled clinical trial is necessary. But informing patients fully of the risks they are taking is ethically imperative, the researchers concluded. "That's a hard sell," but potential trial participants would need to knowingly shoulder the risks to hopefully help others down the road.

4 Comments

1. 1. jgrosay 06:05 PM 8/23/12

   Helsinki declaration dates to the 70s, written informed consent is mandatory, and both the hospital Ethical Review Committees and the Health Regulatory Authorities have facilities and personnel devoted to the quality assurance and the control of the fulfillment of rules of every clinical trial (CT). I was aware of an informed consent text in the 80s for a CT that spoke about "this drug has been linked to side effects, specially in women, including death..." My feeling is that the overall tone of the article doesn't reflect actual facts, and documents, including package inserts and informed consent handouts are there to be read. Just take some time, and ask about the things you don't clearly understand if you've offered participating in a Clinical trial, your doctor has a legal obligation to fully inform you, and will do it with great pleasure, and remember, you can withdraw at any time from a clinical trial you accepted to participate in without having any obligation to give an explanation, although for sure, they'll ask you for the reason why, but if you don't want to answer, you can shut and go away, nobody bad will result for you, at least coming from the people making the clinical trial, your disease may be a different thing, as outcomes rarely are 100% positive, but Niels Bohr said, "It's extremely difficult making predictions, specially about the future". Yeah, in some cases post-marketing trails do overlap with the commercial promotion of new drugs, seeding campaigns and stuff like this, so it's good checking in the governments' databases for CTs if you're offered a real one, every decent trial has an official trial number, and the sponsor must be known, or just a doctor is being paid for prescribing the drug in a payment for case way, it won't be the first time this has happened. Pharmaco-surveillance, or data gathering about side effects not known before the drug was put for sale, as the number of patients in phases I, II and III sometimes misses rare side effects, is not exactly a clinical trial, and probably the only issues would be around the confidentiality of data, and the protection of the patient's privacy. Drug makers must report for legal reasons any serious side effect of they drugs they are aware of, so it's supposed that health regulatory authorities have the same info about safety of a drug as its producer, the costs of non-compliance of this rule would be so enormous in the case of a legal suit, that nobody can even think in making hiding drug safety data an actual choice.

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2. 2. nyog@shaw.ca in reply to jgrosay 02:14 PM 8/30/12

   Re: "...documents, including package inserts and informed consent handouts are there to be read." Expecting an increasingly non-science-literate population to read the materials mentioned constitutes being in complicit denial about what is entailed in communicating risk to trial participants. I conduct research with human subjects, and have created a plain language statement, including relevant potential risks, which we read through aloud with our participants, pausing to ask questions to make sure they have understood. This process is costly in terms of the paid time for my interviewers, and annoys some of the participants, but generates a much higher likelihood of TRULY informed consent.

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3. 3. dragonasbreath 03:01 AM 2/9/13

   Those inserts all read the same. Almost word for word.
   And it is very hard to tell what is ACTUALLY likely to happen for this drug or that drug - the best way is still to monitor yourself when taking a new drug, and letting your doc know if there are any issues.
   
   Another thing they REALLY need to update - you enter these trials at your own risk. If they cause you to have a heart attack requiring multiple bypass surgery - the trail folk are not going to pay for it. And chances are your insurance will also refuse to pay for it because it was the result of a drug trial you voluntarily entered rather than a natural-for-you medical condition.
   And the medical/insurance industry is still not wild about doing that kind of thing without money up front.
   
   You can easily have full disclosure and word it in such a way (and in such find print) that few if any of your participants will read it and understand it if they DO read it.

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4. 4. jgrosay 04:52 PM 2/9/13

   Both of you are right, but handouts and package inserts don't come out of the blue, the doctor must always be there, and has a legal obligation to duly answer any question the patient may have. The actual practice may differ in some cases, but is the doctor and the HRA's responsibility to guarantee a fair flow of info to the person screened as a candidate for entering as volunteer in a CT, if some people, icluding doctors, behave unproperly, it's their responsitibity, and it's the Sponsor, HRAs and ERBs task looking for violations of rules that put in danger the patient's autonomy or safety, as in other fields, neither the Commands that Moshe's announced, nor the Codes, nor Commow Law made mankind perfect; if rules were needed, it was because abuses existed that harmed third parties, or innocent bywatchers, even when it was said that sin entered the world because of the law, as before the law, there was sin, but it was not imputed. I have no direct contact with patients on Clinical Trials since I left a Pharmaceutical Company in 1988, so I don't know the situation of actual info provided to patients as of today. Salut +

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