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Catch-22, Clinical Trial Edition: Protecting Women and Children

Cartoon: why don't we test drugs on women and children?

“I remember wheeling down this long, narrow corridor into my office, just a confused, scared mess, but I had to confront him.” Phil Vardy was a young medical researcher in Sydney that day in 1982. The man he had to confront was his boss, one of Australia’s most prominent doctors, William McBride.

He had just seen an article McBride published suggesting an ingredient in the drug Bendectin caused birth defects – with fabricated defects and experimental pregnant rabbits that didn’t exist either.

Vardy’s confrontation with McBride did not go well, and “small battles led to bigger ones which led to bigger ones.” It would cost Vardy his job and his marriage. After a decade of media storms and public enquiries establishing fraud, McBride lost his license to practice medicine.

I was a maternity consumer advocate in Australia then, and watching what happened to Bendectin and the women who needed it was a long slow revelation.

McBride was very famous back then. In 1961, he had sent a letter to The Lancet reporting limb malformations associated with the drug Thalidomide. The pendulum swung overnight from under-awareness and inadequate protection to hyper-vigilance, emotion and hype about drug safety in pregnancy.

In the wake of Thalidomide, Bendectin inevitably came in the firing line. In some countries up to a third of all pregnant women had taken the drug – over 30 million by the early 1980s.

That number of women would be expected to give birth to over a million babies with some kind of congenital abnormality – by coincidence alone. So the potential for people to point the finger of blame at this drug was sky-high.

The National Enquirer and other media spread the word. The Public Citizen’s Health Research Group (unsuccessfully) petitioned the FDA in 1980 and 1982 to remove its marketing approval. Bendectin, they argued, didn’t work and was “unsafe for human use.”

Bendectin did work and was never proven to be harmful, but it caused a lot of litigation. McBride – his fraud not yet revealed – was a prominent medical expert for many plaintiffs.

The case against the drug was made up of flimsy science and selective choices of studies. Even without junk and fraud, it’s risky to look at some studies in isolation, rather than systematic reviews of all strong evidence. Litigation over Bendectin led the Supreme Court to set a new standard for scientific evidence and testimony.

But the drug was off the market by 1983 purely for commercial reasons. Defending it was just too expensive. This quote in the New York Times shows what Bendectin was up against:

Hundreds of thousands of pregnant women and their unborn children will be spared the risk of exposure to this questionably effective and unsafe drug.

With Bendectin gone, the rate of congenital abnormalities didn’t fall. The ratio of hospitalization of pregnant women for nausea and vomiting almost doubled in the US (from about 7 per thousand to 13). There aren’t very effective non-drug alternatives, so many women used drugs not approved for pregnancy. There’s no strong concern about these drugs, but questions remain.

In 2013, 30 years after the end of Bendectin, Diclegis was approved by the FDA for the treatment of nausea and vomiting in pregnancy. It’s a new formulation of Bendectin’s key ingredients. With a couple of trials now, so far so good.

It’s still occasionally in the news: the 2017 publication of a large unpublished trial of Bendectin from the 1970s brought more “doubts cast” media coverage. And then there was the Kim Kardashian episode: a deal she made with the manufacturer to promote the drug in social media when she was pregnant broke FDA rules.

Diclectin still seems to be approved only in the US and Canada, though.

We still have a larger problem.

We don’t have adequate evidence of the effects of drugs women need to use when they’re pregnant. We became more concerned about protecting people from the risks of research than the risks of not doing research.

Animal studies can’t resolve the problem. Some drugs cause birth defects only in humans, or only in some animals and not in humans. Surveillance only gets us so far. Such as finding out too late that a particular type of hypertensive drug in pregnancy was sometimes fatal for the baby.

The problem leaked out to partially affect all women. Women of childbearing age or even all women have often been excluded from drug research – just in case. Yet differences in body weight, metabolism and more between men and women can affect drug response and ideal dosing in critical ways. It’s a problem the FDA and NIH target these days. A study of FDA approvals for new drugs between 2011 and 2013 found women were well-enough represented in pivotal trials – so that’s encouraging. But writing in 2012, Melanie Chan and colleagues concluded:

The teratogenic risk of more than 80% of 468 drugs released in the USA over the last 20 years remains to be clarified.

And most pregnant women take at least some prescription medicine during pregnancy. What does this add up to? Situations like this:

No firm conclusions about optimal interventions for managing asthma in pregnancy can be made.

Children are in a similar boat, too. By the late 1990s, children were described as “therapeutic orphans”, because there were so few safety and efficacy studies in children. And legislative efforts to try to improve the situation began.

While pregnant women face the added complication of litigation, they are also – along with children – among the populations designated as vulnerable to exploitation in research. And that has left them more vulnerable to medical harm.

It’s the Catch-22 of clinical trials.

 

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This is an updated version of a guest post that originally appeared at Scientific American in 2013.

 

The cartoon is my own (CC BY-NC-ND license). (More cartoons at Statistically Funny and on Tumblr.)

 

* The thoughts Hilda Bastian expresses here at Absolutely Maybe are personal, and do not necessarily reflect the views of the National Institutes of Health or the U.S. Department of Health and Human Services.

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