Clinical Trials

In response to recent questioning of the integrity of the dissemination of results in biomedical literature, three medical researchers from Stanford and Duke University are pointing to the need for increased access to data from clinical research.

In a viewpoint article published online today in JAMA Internal Medicine, the authors, Robert Califf, MD, and Jonathan McCall of Duke, and Robert Harrington, MD, of Stanford, write that it’s time for both industry and academia to “catch up to other areas of society:”

The liberation of information once held in secret has toppled regimes and transformed societal expectations regarding progress and possibilities. Access to data from clinical research should be truly democratized.

The goal of clinical research should be to add to the body of evidence that can guide decisions about personal health and health policies, the authors write - but things like selective omission of important findings, inaccuracies in published studies, and the use of unreliable data systems are all hindering this. Harrington and his colleagues outline the critical issues that need to be addressed - issues that concern “(1) the value of the research question, (2) the quality of the execution of the research, and (3) the complete and balanced presentation of all relevant data in the publication” - and sound a hopeful note:

The good news is that powerful tools exist to address and potentially surmount these issues. These tools are the ClinicalTrials.gov registry and the ongoing movement toward data transparency.

ClinicalTrials.gov was originally created to provide researchers, physicians, and the public with ready access to information on clinical trials. More recently, legal requirements to register studies have expanded to encompass the reporting of results, including adverse events, within 1 year of ascertainment of the last primary end point. These requirements are designed to ensure that findings from almost all trials relevant to US medical practice that involve a drug or device are available in a single, accessible public registry. If the requirements of ClinicalTrials.gov and other international registries are maintained and strengthened in areas where they are currently deficient, the benefits should be substantial…

Previously: Research shows small studies may overestimate the effects of many medical interventions, Outing bias in scientific research, A critical look at the difficulty of publishing “negative” results, Examining the impact of unpublished research on medicine and Testing medical ‘truths’

A recent blog entry on the Huffington Post focuses on an issue I haven’t seen much written about: the role of caregivers in the clinical-trial process. Noting that the caregiver “is the closest and most constant observer of the patient,” writer Tory Zellick outlines how caregivers can help study investigators by, for example, reporting any side-effects or changes experienced by their loved one during the trial. She also offers a few suggestions, courtesy of the National Alliance for Caregiving, on how trial leaders can better partner with caregivers:

• Speak not only in patient-centered language, but also caregiver-centered language. For example, when discussing protocol, ask the caregiver whether she is able and/or willing to perform certain duties.

• Support the caregiver in figuring out the most effective and realistic way to comply with protocol requirements.

• Explain the medical jargon used throughout the clinical trial. The caregiver needs to understand what the researcher is saying, so as to effectively communicate this information to the patient.

• Guide the caregiver on being an effective observer- explicitly stating what to look out for, how to identify it and how to respond to it.

• Prepare the caregiver and patient for the emotional aspect of ending treatment, at the conclusion of a clinical trial.

Previously: Advice for caregivers and patients about clinical trials and Clinical trials: My next good chance

This last winter has been a tough one for my small rural community. Every time I turned around, more people were sniffling and sneezing, coughing and feverish. We’ve all been just as likely to compare doctors’ recommendations as our children’s report cards, and more than one of my friends walked away from the physician with a prescription for a Z-pack: a five-day regimen of an antibiotic called Zithromax that’s effective in treating many common infections.

Last week, however, the Food and Drug Administration strengthened their warning about Zithromax: Mounting evidence has shown that the drug can be dangerous for people with certain preexisting heart conditions, or those who may be taking other drugs that affect the heart’s rhythm.

How could such a common medication carry such risks? It’s simple, explain Stanford scientists. The current methods of testing a prospective new drug’s heart safety profile depend primarily on the use of non-heart cells that are genetically modified to mimic some aspects of real ones. But they’re no substitute for the real thing. Unfortunately, the “real thing” is hard to get. After all, we’re not all lining up for heart biopsies so scientists can have a steady supply of material on which to test each drug.

Today cardiologist Joseph Wu, MD, PhD, medical student Andrew Lee, and postdocs Ping Liang, PhD, and Feng Lan, PhD, published some really exciting new work in the journal Circulation (subscription required) that presents an alternative. In short, the researchers collected painless skin samples from patients with one of three inherited cardiac conditions, as well as from healthy family members. They then used induced pluripotent stem, or iPS, cell technology to convert the skin cells in the laboratory into functioning heart cells that reflected each patient’s specific heart aliment. Finally, they tested the response of the cells to specific medications - some of which have been shown to be relatively safe for the heart and another that had been withdrawn from the market due to unexpected cardiotoxicity. As Lee explained in our release:

It’s clear that individual patients will respond uniquely to specific drugs. If you have a hereditary disease or a problem with your ion channels, you’re going to respond differently than members of the general population. Even companies relying on genetically normal human embryonic-stem-cell-derived cardiac cells won’t be able to see all these effects. But our ‘clinical trial in a dish’ with patient-specific iPS cells allows us to model this personalized response and identify high-risk groups who should not receive the drug.

The researchers found that the heart cells in the dish responded in much the same way to the medications as did human patients. They anticipate that this type of “clinical trial in a dish” may become a standard method of testing drugs for cardiotoxicity on healthy and diseased hearts. It may also allow researchers and clinicians to test the effect of combinations of drugs while limiting the risk to real patients. Although none of my antibiotic-toting friends have been harmed by Zithromax (and thank goodness, we all seem to be feeling a bit better!), who would argue with better, faster and safer testing of all drugs? According to Wu:

Our hope is that, instead of a physician using a patient as a guinea pig, trying one medication after another until something is found to be effective, this method will one day lead to personalized drug screening to find out exactly which medication is the best for you.

I’m really excited about this research, and in this use for iPS cells in general. We’ll likely be hearing more about this approach; earlier this week Wu, who co-directs the Stanford Cardiovascular Institute, received$1.44 million from the California Institute for Regenerative Medicine to collect tissue samples to create iPS cells from several hundred patients with idiopathic familial dilated cardiomyopathy - that is, members of families with a predisposition to develop enlarged and weakened hearts without an obvious cause.

Previously: Sudden cardiac death has a cellular cause, say Stanford researchers, New leaders in heart medicine at Stanford and Lab-made heart cells mimic common cardiac disease in Stanford study
Photo by kaibara87

We’ve written here about the food-allergy work being done by Kari Nadeau, MD, PhD. But what’s it like for the parents of children with severe allergies who participate in one of Nadeau’s trials? As the kids are gradually exposed to foods they are highly allergic to, how do their moms and dads feel? That was the focus today of an NBC online piece, which includes excerpts from e-mails written by a mom of one study participant. A few of the passages jumped out at me:

January 27, 2012: Tessa will officially start the clinical trial at Stanford Hospital Friday morning!

This journey we are about to embark on is a massive one … and not to be underestimated. Not only is the time commitment great … this will be physically and emotionally taxing on Tessa as well. It will be scary for her (and us) at times as she will be reacting to the foods all throughout. Kids can have anything from stomachaches to hives to vomiting, etc.

We were in bed tonight and [Tessa] said “Mommy, I am scared. What if I can’t tell that I am having a reaction and it gets out of control like the last two times when I almost died?” It was a heart-wrenching conversation.

…

February 26, 2012: Tessa is now up to the equivalent of … about one ounce of milk, four peanuts, [and] three whole crackers.

She has now had three home doses at this level and has not even had the slightest reaction (knock on wood) … I watched her eating crackers with her friends the other day … which was a very weird sight to see her eating “normal” food socially like that among friends… and had to make sure that her friends were very clear that she is only able to eat this food because of the drug she is on [Xolair, which suppresses the allergic reaction].

Mentally she is doing very well, too … In fact, she is the one that keeps telling me to “chillax”.

…

April 10, 2012: … There were a few extra M&M’s on the side and Tessa asked me to eat them and I said, “No thank you” and she insisted that I eat them. It was the first time in nine years that I have ever eaten anything “unsafe” in front of Tessa. It was a very odd moment and a feeling that I just don’t think I will ever get used to.

The article accompanied a Today Show segment during which Nadeau talked more about her work. And, as a reminder, she’s taking questions about food allergies this week as part of our Ask Stanford Medicine series.

Previously: Ask Stanford Med: Pediatric immunologist taking questions on children’s food allergy research and Searching for a cure for pediatric food allergies

Pediatric surgeons have been slow to adopt a technique that could keep their patients safer during a common but risky hospital procedure. But the Stanford scientist behind a new study of the procedure hopes his new research findings will provide the push they need to change their ways.

The procedure is insertion of a central venous catheter, a type of intravenous line that gives access to the largest vein in the body. It’s used when the a peripheral IV (the kind that goes in the patient’s hand or arm) is not appropriate - for instance, if a patient needs to receive a large volume of IV fluid, or needs a chemotherapy drug that could damage small veins. Inserting a central line requires poking a needle deep inside the body, into one of three major veins that feed to the very biggest vein, the vena cava. Once the needle is in the vein, it provides a pathway for threading in the catheter.

Since 2010, the American College of Surgeons has recommended that surgeons use ultrasound to see what they’re doing during this procedure. The new study provides fresh, kid-focused evidence that this is the right thing to do, as our press release on the research explains:

“Although it’s a common procedure and is sometimes perceived as benign, it’s not,” said Sanjeev Dutta, MD, senior author of the new study. “We found that, even in the hands of experienced pediatric surgeons, the use of ultrasound can mitigate the risk of complications when placing central lines.” Dutta is a pediatric surgeon at Packard Children’s and an associate professor of surgery at the School of Medicine. The research was published online today in the Journal of the American College of Surgeons.

In the study, when pediatric surgeons used ultrasound, they were able to successfully guide the needle safely into a vein 65 percent of the time on the first try, and 95 percent of the time within three tries. In contrast, when they used only anatomic landmarks to guide insertion, success rates were 45 percent on the first attempt and 74 percent after three attempts. Previous research has shown that needle placement into a vein for central line insertion is associated with few complications if it succeeds on the first try, but after three attempts, the risk of complications jumps sharply. Complications of a failed insertion can include bleeding in the chest cavity, lung puncture that causes air to be trapped in the chest cavity, puncture of the carotid artery and, rarely, fatal complications such as strokes

In case you missed it yesterday, NPR had a segment discussing the importance of having more diversity among participants of clinical trials:

…[A]ccording to the National Cancer Institute, African-Americans only accounted for 9.2 percent of the patients involved in its clinical trials, even though African-Americans are more likely than any other racial group to die of the disease.

But bringing more African-Americans into clinical trials means overcoming decades of suspicion and distrust.

The reporter goes on to talk with Junius Hayes, a retired federal worker and the first African-American participant in a clinical trial for a potential prostate-cancer treatment. When asked if anyone in his family discouraged him from being part of the trial, he said:

No, but if they knew about it they would say no. They would say no because of trust. We just don’t trust people to experiment with us. The black male - just like the while male - they don’t want to go to the doctor anyway, regardless of your race. When you put the color - we grew up going through Jim Crow. And when you come up going through Jim Crow days we weren’t educated. So it’s education has a lot to do with the disparity in the participation.

Research published online yesterday in the New England Journal of Medicine shows a novel anti-clotting drug to be superior at preventing blood clots during coronary stenting procedures compared to the currently used medication.

The study included about 11,000 patients from 153 centers around the world and was led by co-investigators Robert Harrington, MD, chair of the Department of Medicine at Stanford, and Deepak Bhatt, MD, at Harvard. The results of the trial, which were presented at the American College of Cardiology conference in San Francisco yesterday, showed that the drug, called cangrelor, reduced the odds of negative outcomes from stenting procedures such as blood clots, heart attacks and strokes, by 22 percent when compared to the routinely used anti-platelet drug clopidogrel (tradename Plavix).

We need a very potent agent to prevent clotting when we are putting things in the heart artery like wires and stents. We want a fast acting reversible agent, which is why a drug like cangrelor could be useful and why we tested it.

Coronary artery stents are used in the majority of patients who undergo percutaneous coronary intervention (PCI). In the United States, an estimated 600,000 of these procedures are done per year on patients who suffer from coronary artery disease, which causes arteries to become narrowed or blocked.

In our press release, Bhatt comments on why the discovery of a new drug like this is important to patients. He said, “We need a very potent agent to prevent clotting when we are putting things in the heart artery like wires and stents. We want a fast acting reversible agent, which is why a drug like cangrelor could be useful and why we tested it.”

Food allergies affect one in every 13 American kids, yet when a child is diagnosed, modern medicine can’t do much to help. As parents of newly diagnosed kids quickly learn, the standard advice is to avoid allergy triggers completely, since that’s the only surefire way to prevent life-threatening episodes of anaphylactic shock. Many of the common allergy triggers - such as wheat, cow’s milk, soy, eggs and peanuts - are so ubiquitous that avoidance becomes a herculean task. Families have to be extra-cautious about everything from restaurant meals and school events to birthday parties and sleepovers at friends’ homes. In addition to the stress they cause for affected families, food allergies take a big medical toll. They’re responsible for 90,000 episodes of anaphylactic shock each year and 2,000 hospitalizations.

It’s hard enough if your child is allergic to just one food. But a growing number of children have severe allergies to multiple foods. Fortunately, a scientist at Stanford and Lucile Packard Children’s Hospital is working to help these kids. Building on a body of work - her own and others’ - demonstrating that it’s possible to safely desensitize children to a single food allergen, Kari Nadeau, MD, PhD, is now trying to find treatments that will address multiple food allergies simultaneously. Her quest is described in a new feature in this week’s New York Times Magazine:

Could patients be desensitized to more than one allergen at a time? No one had ever tried it, but more than a third of children with food allergies are allergic to more than one food. If it was safe to give patients x milligrams of one allergen, would it be safe to give them one-fifth of x milligrams of five different allergens, as long as the total dose remained the same? That would assume that allergens function in a linear, additive fashion — rather than a multiplicative one; it was also possible that they could interact with one another to produce a more severe reaction.

Nadeau experimented with blood samples of allergic patients and was encouraged to see that the allergens seemed not to interact with one another. She consulted with senior colleagues in the field to see if anyone would collaborate on a multiallergen study, but no one was interested. Scientifically the results would be harder to interpret than single-allergen trials. Moreover, each allergen would require getting separate F.D.A. approval, and it was difficult to get even one application approved. When she found herself home sick in bed with a virus for a few days in 2011, she decided she would “knock them all out” and wrote 13 Investigational New Drug Applications, each 90 or so pages long, and soon received F.D.A. approval for each one.

The entire story is a fascinating behind-the-scenes look at the science of immunology, and well worth reading. Those interested in learning more about Nadeau’s ongoing projects should check out her research group’s website.

Previously: Helping kids cope with allergies, New hope for people with severe milk allergies and Researchers find mechanism for destruction of key allergy-inducing complexes
Photo by Steve Fisch

An article in today’s New York Times highlights just-published work by Massachusetts General Hospital researchers and Stanford genomics expert Ron Davis, PhD, in which the scientists presented “stunning evidence that the mouse model has been totally misleading for at least three major killers - sepsis, burns and trauma.” As a result, according to the Times article, “years and billions of dollars have been wasted following false leads.”

The newspaper story is referring to a Proceedings of the National Academy of Sciences study that writer Gina Kolata says may help explain why every one of nearly 150 drugs tested at huge expense in patients with sepsis has failed.

This work goes back several years, with Davis and his associates finding patterns of gene activity that seemed to predict which sepsis victims will live and which will die. The researchers tried to publish their results in several journals but were initially rebuffed because they hadn’t tested their findings in mice to see if the same things happened, according to the article:

“They were so used to doing mouse studies that they thought that was how you validate things,” [Davis] said. “They are so ingrained in trying to cure mice that they forget we are trying to cure humans.”

“That started us thinking,” he continued. “Is it the same in the mouse or not?” The group decided to look, expecting to find some similarities…

But when the investigators looked, there were none at all. In fact, some genes that were “turned on” by sepsis in mice were “turned off” in humans. Further, in humans, similar genes were activated by sepsis, trauma and burns - three conditions in which the immune system overreacts and inflicts more damage to the body than the bacteria, knock to the head or house fire, respectively, that originally caused the problem. But in mice, these three different types of stimuli trigger three quite different gene-activation patterns.

So, a drug that might work in a human could have the opposite effect in a mouse. And vice versa.

The man/mouse mismatch, intriguingly, shows up in other places, too. For instance, a recent study led by Stanford immunologist Mark Davis, PhD, suggests that experimental mice - who spend their entire lives in artificial, ultra-germ-free environments - may be a poor model for adult humans’ more battle-hardened immune systems, which have acquired quite a bit of savoir faire.

And in another study a few months back, Stanford drug-development expert Gary Peltz, MD, PhD, developed mice with humanized livers, explicitly to address another disparity that can easily result in costly failures of new drugs in clinical trials: Mice’s livers, being different from ours, often metabolize new experimental drugs quite differently from the way ours would.

Previously: Professor Ronald Davis wins 2011 genetics prize from the Gruber Foundation, Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before and Fortune teller: Mice with “humanized” livers predict HCV drug candidate’s behavior in humans
Photo by gliuoo

In a 2011 cover story for Stanford Medicine magazine, my colleague Krista Conger outlined one of the big hurdles in getting new cancer treatments to patients: the clinical-trial process. And, more specifically, the dearth of people enrolled in trials. “We’re going to have to get around the problem that less than 5 percent of adult cancer patients who could be participating in clinical trials are enrolled in one,” Phil Lavori, PhD, chair of the Department of Health Research and Policy, is quoted as saying. “The rate of participation is abysmal.”

I was reminded of this late last week when coming across findings of a new study from the University of Michigan. Researchers there conducted a survey and found that only 11 percent of adults and 5 percent of children had ever participated in medical research (not just cancer-related). In addition, as outlined in a release, only “64 [percent] of adults said they were aware of opportunities to participate in medical research, while only 12 [percent] of parents said they were aware of opportunities for their children to participate.”

In a bit of good news, the researchers did find a significantly greater level of awareness about trials from survey respondents living within 100 miles of four specific Clinical and Translational Science Awards locations. (CTSAs, like Stanford’s Spectrum, are NIH-funded programs designed to improve clinical and translational research.) As the researchers point out in their paper, these higher levels of awareness “merit investigation” to identify what these programs are doing right, and how their approaches might be used elsewhere.

Previously: Advice for caregivers and patients about clinical trials, Patients share clinical trial experiences at Stanford and Clinical trials: My next good chance