clinical trials


Economist Heidi Williams, Genius Award Winner, On Invisible Drug Industry Incentives

Last week, as she was sitting in her office at MIT, 34-year-old economist Heidi Williams got an unexpected phone call. It was from the John D. and Catherine T. MacArthur Foundation, telling her that she had just been awarded a so-called “Genius Award” — a no-strings-attached $625,000 grant that celebrates “the creative potential” of its fellows.

Williams, an assistant professor of economics at MIT, researches how invisible economic incentives affect the kind of cures that the medical industry produces. Her research has found that researchers are more likely to develop cures for late-stage cancer patients than early-stage patients, for instance, and that intellectual property law can limit innovation in genome research.

Radio Boston’s Anthony Brooks spoke with Williams about her research and her award (the interview airs in an upcoming show). Their conversation, edited:

AB: Tell us how you got the news about this award, and your reaction to it.

HW: I got a phone call from an area code that I recognized as a Chicago number. And I was just completely speechless when I answered the phone and talked to them. I’m very early in my career, and I was just completely overwhelmed to hear that I had received a fellowship.

Talk to me about these invisible economic incentives that affect the cures that the medical industry produces. Can you explain how this works?

Researchers working on drug treatments often come up with a lot of ideas, but if you talk to them, many of those ideas just never reach patients. Sometimes you hear anecdotes about the reason why those products never got developed — because of misaligned incentives in the patent systems or because of misaligned incentives in the policy system more generally. I try to explain why some promising scientific leads never get developed into new drugs or medical technologies that consumers or patients actually have access to.

Why are there incentives for late-stage cancer treatment for example, but few for early-stage cancer, or even cancer prevention? What incentives control that?

When new drugs come to market in the U.S., they need to show the U.S. government evidence that the drugs are safe and effective by showing evidence that the drug improves survival. When you need to show that a drug improves survival for patients that are very sick and will die relatively quickly, you can show that in a randomized clinical trial much more quickly than if you need to show evidence that a drug improves the survival of patients that have a longer life expectancy.

Longer clinical trials take more time and cost more money, but also, biotech and pharmaceutical companies almost always file for patent protection before they start their clinical trials. And so every additional amount of time that they’re spending in clinical trials is less time that they have for their patent to actually be generating profits for them once their drug is on the market. Continue reading

The Complex Interplay Of Genetics And The Placebo Response

Why do some people respond to placebos while others don’t?

One possible answer: genetics.

A provocative new paper introducing the concept of a “placebome” — that is, the complex interplay between genetics and an individual’s response to placebos — raises questions that might ultimately lead to changes in how clinical studies of drugs are evaluated.

Indeed, researchers from Harvard Medical School suggest that genes, and genetic variation, might play a far bigger role in the placebo response than previously thought.

That the placebo effect is an actual physiological response is well established. But the new report, a research review, looks specifically at the placebo response in the context of drug studies, where some participants get the active medication while others get a placebo, or non-active version of the drug.

The new findings, “call into question whether or not the outcomes in a drug treatment arm of a clinical trial are limited to the effect of the drug on the condition,” says Kathryn Hall, an integrative medicine fellow in the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center, and one of the study authors.

Instant Vantage/flickr

Instant Vantage/flickr

Several neurotransmitters, such as dopamine, appear to be involved in the placebo response, Hall said, and variation in the genes in these pathways appears to change our response to placebo. So different people with different genotypes respond differently to placebos.

But Hall takes it one step further. “When you are in a trial you don’t know if you are getting the drug or the placebo, so not just the people in the placebo arm can have placebo responses. We are curious about the drugs’ effect on the placebo response.”

It’s all a bit tough to wrap your brain around, so I asked Hall to give me an example. Here’s what she said:

In the literature we see several studies in which in the placebo arm one group of people with a certain genotype have a strong placebo response and the other group has a weak placebo response. And when we look at the drug treatment arm, we see the outcomes are reversed, the people who had the strong response in the placebo arm now have a low response and the people who didn’t have a response in the placebo arm now have a strong response. The historical interpretation of these results has been that only one group of people responds to the drug and we’re pointing out that it’s more complicated than that. It’s that one group responded to the placebo and that response is eliminated in the drug treatment arm.

What all this means in the real world is still hard to know. But in their paper published this week in the journal, Trends in Molecular Medicine, the researchers offer these three key takeaways in the abstract:

•The predisposition to respond to placebo treatment may be in part a stable heritable trait.

•Candidate placebo response pathways may interact with drugs to modify outcomes in the drug treatment arms of clinical trials.

•Genomic analysis of randomized placebo and no-treatment controlled trials are needed to fully realize the potential of the placebome.

Continue reading

Debating Vitamin D: Leading Docs Still Wrangling On Best Dose For Patients

(Suzanne Schroeter/Flickr)

(Suzanne Schroeter/Flickr)

The message on vitamin D is pretty clear if you talk to Dr. JoAnn E. Manson, M.D., chief of the preventive medicine division at Brigham and Women’s Hospital in Boston, who is leading the largest clinical trial in the world investigating the potential health benefits of vitamin D. It boils down to this: Curb Your Enthusiasm. At least for the time being. Even in the midst of a hellish winter when you may be tempted to take an extra dose of the so-called “Sunshine Vitamin” for a boost.

In a commentary piece published this week in the Journal of the American Medical Association, Dr. Manson urges caution. She says that even though the public has become smitten with vitamin D, its growing popularity has led to mega-dosing that’s not backed by the current evidence. “More isn’t always better, more is sometimes worse,” Manson said in an interview. “We don’t yet have the answers, so we shouldn’t make assumptions.” But, she adds, in a couple of years, gold-standard evidence on whether higher doses of vitamin D are good for you should be out.

But get on the phone with Dr. Michael F. Holick, Ph.D., M.D., a leading vitamin D proponent, endocrinologist at Boston Medical Center and professor at Boston University School of Medicine, and you’ll get a totally different, but equally clear message. Vitamin D deficiency and insufficiency are far more widespread than certain professional medical groups suggest, Holick says, and dosing at higher levels shows “no evidence of toxicity.”

How did we get here and what’s a patient to do?

Here’s a little background:

In debates over nutrition, vitamin D is one of those supplements that’s drawn both passionate supporters and equally aggressive skeptics over the years. And, like coffee, chocolate and red wine, it’s often the subject of studies that can make your head spin: it’s good for you…until it’s not.

The current vitamin D guidelines from the Institute of Medicine recommend 600 IU’s per day for adults up to 70 years old and 800 IU’s per day for those over 70. “This,” writes Manson in her JAMA piece “is equivalent to 3 to 4 daily servings of fortified foods such as milk, yogurt, soy beverages, orange juice, or cereal, plus fatty fish twice per week. These amounts are adequate for at least 97.5% of U.S. and Canadian residents, she says, and it’s good even in the bleakest, darkest season, “even if you’re in Antartica in winter.” Continue reading

First Treatment Found For Rapid-Aging Disease In Children


Researchers have found the first treatment for progeria, a rare “rapid aging” disease in children. (Courtesy of the Progeria Research Foundation)

I first heard of progeria in “When Bad Things Happen To Good People,” by Harold Kushner. The author, a Natick rabbi, lost his 14-year-old son to the disease, a rare genetic defect that causes accelerated aging and effectively turns children into little old people, afflicted by strokes and heart attacks. They die young, of old age.

So my first reaction to today’s big news about the first promising treatment for progeria was: “Now at least the bad things that happen to some good people may not be quite so bad.”

A paper just published in the Proceedings of The National Academy of Sciences reports on a clinical trial for the first known treatment for progeria, and the findings are highly promising. The drug used, Lonafarnib, originally aimed at fighting cancer, appeared to help with weight, bone structure, and most importantly, artery health in 28 children with progeria.

That the drug appeared not only to slow but to reverse some aspects of damage to the children’s blood vessels “is a tremendous breakthrough, because cardiovascular disease is the ultimate cause of death in children with progeria,” said Dr. Leslie Gordon in the press release. She is the lead author of the study, medical director for the Progeria Research Foundation, and the mother of a child with progeria. (She’s also affiliated with Boston Children’s Hospital, Harvard, Brown and Hasbro Children’s Hospital.)

I challenged her on “breakthrough” — I tend to be so cautious with that word that I’m downright allergic to it. Her justification:

“This is a 100% fatal pediatric disease and we had no idea whether it could be influenced in any way by any drug treatment.’

“I do think it can be called a breakthrough, and the reason is that prior to this study finding, we had no idea whether we could offer anything for progeria at all. This is a 100% fatal pediatric disease and we had no idea whether it could be influenced in any way by any drug treatment.

So to me, the breakthrough here is that we have findings that show that progeria can be altered. Not only in the rate of weight gain but that the vasculature can be influenced and the bone can be influenced. That’s a real breakthrough that gives us tremendous hope that by finding more treatments and more ways to get at the disease process in progeria — with the protein called progerin — that we can actually have an impact on the disease.”

The clinical trial was only 2-1/2 years long, she noted, so it is not yet known whether the drug’s benefits will translate into longer lives. But “the breakthrough element is really, ‘Oh my gosh, for the first time, we know the disease can be influenced.'”

I also spoke today with Dr. Mark Kieran, senior author of the progeria study and director of pediatric medical neuro-oncology at Boston Children’s Hospital and Dana Farber Cancer Institute. Our conversation, lightly edited:

So it sounds like this is one of those times when science works just as it’s supposed to: Researchers found the gene, figured out what it did, and then corrected it, at least partially?? Continue reading