Published by
Stanford Medicine

Category

Clinical Trials

Applied Biotechnology, Ask Stanford Med, Clinical Trials, Research, Stanford News

SPARKing a global movement

SPARKing a global movement

browser-98386_1280

Many academic researchers are tenacious, spending years in the lab studying the processes that lead to human diseases in hopes of developing treatments. But they often underestimate how difficult it is to translate their successful discovery into a drug that will be used in the clinic.

That’s why Daria Mochly-Rosen, PhD, founded SPARK, a hands-on training program that helps scientists move their discoveries from bench to bedside. SPARK depends on a unique partnership between university and industry experts and executives to provide the necessary education and mentorship to researchers in academia.

In recent years, Stanford’s program has sparked identical programs throughout the world; at TEDMED 2015, Mochly-Rosen described this globalization. I recently spoke with her about the SPARK Global program, which she co-directs with Kevin Grimes, MD, MBA.

How has SPARK inspired similar programs throughout the world?

We’ve found our solution for translational research to be particularly powerful. Of the 73 completed projects at Stanford, 60 percent entered clinical trials and/or were licensed by a company. That’s a very high accumulative success rate. So I think it has showed other groups that we have a formula that really works – a true partnership with academia and industry. It’s the combination of industry people coming every week to advise us and share lessons learned and our out-of-the-box, risk-taking academic ideas that makes SPARK so successful.

We feel that what we’ve learned is applicable to others. Kevin and I also feel very strongly that universities need to take responsibility to make sure inventions are benefitting patients. So we’re trying to do our part.

How do you and Dr. Grimes help develop the global programs?

When a university asks about our program, we invite them to come visit us for a couple of days so they can talk to SPARKees (SPARK participants), meet SPARK advisors and watch our weekly meeting. Sometimes they also ask Kevin and I to come to their country to help set up a big event or assist in other ways. If they begin a translational research program at their institution, we offer for them to be affiliated with SPARK Global. Everyone is invited.

There are now SPARK programs throughout the world, including the United States, Taiwan, Japan, Singapore, South Korea, Australia, Germany and Brazil. We are also working with other countries, including Norway, Israel, Netherlands, Poland and Finland, to help them start a program.

Do researchers in other countries face the same challenges as those in the U.S. when developing new drugs?

There are many common challenges. And there are also some advantages and challenges that are different in other places. So it’s a mix, both within and outside the U.S.

There are several key components to the success of translation research. It’s important to have a good idea. It’s even more important to have good advisors from industry to help develop the idea. And it’s very important that the people involved are open-minded and not inhibited by hierarchical structures. In some places, there is a big problem with hierarchy – particularly in parts of Europe and East Asia. In some cultures, it’s also difficult to get experts to volunteer and academics can’t afford to pay multiple advisors. Also, some universities don’t have a good office of technology to help with patent licensing, which can be a major challenge.

Continue Reading »

Clinical Trials, Research, Science Policy, Stanford News

At the heart of reproducibility lies the problem of transparency

At the heart of reproducibility lies the problem of transparency

spare ribsImagine recreating a recipe — say, your uncle Darryl’s BBQ sauce. Without a detailed recipe — including not only the list of ingredients but how long he cooked the sauce and when he added which ingredients — you’re not likely to be able to exactly reproduce his delicious sauce.

The same is true of research.

One of the frustrating recent discoveries about biomedical research is that, all too often, initially exciting results can’t be reproduced. And how do we know if an effect is real if we can’t make it happen again?

Researchers say that billions of dollars are wasted on research that has never been reproduced.

Lately, research funders and others have become obsessed with reproducible research. One problem is that most researchers aren’t motivated, financially or otherwise, to copy someone else’s study exactly. Better for your reputation and funding to do something original. The result is still another irreproducible study.

A second problem at the heart of irreproducible studies is transparency. Without a good understanding of a scientific paper’s methods, exact protocol and full results (which researchers rarely include in their paper), it’s very challenging for other researchers to reproduce the work.

Yesterday, Stanford’s John Ioannidis, MD, PhD, and his team at Stanford published one of two inaugural papers for the launch of PLoS Biology’s new Meta-Research Section. The paper by Ioannidis and colleagues provides a baseline that shows just how far we have to go to create a fully transparent biomedical literature.

Ioannidis, a professor of health research and policy, and colleagues took a random sample of 441 journal articles from biomedical journals from between 2000 and 2014. From that sample, they found that no team of authors made all their data available, only one team provided a full protocol, and the majority did not disclose funding or conflicts of interest.

With such low levels of transparency, it wasn’t surprising that replication studies were likewise rare. We can hope funders can find ways to motivate researchers to offer better transparency and reproducibility.

Previously: On communicating science and uncertaintyA conversation with John Ioannidis, “the superhero poised to save” medical research
Photo by jeffreyw/Flickr

Clinical Trials, Ethics, Patient Care, Research

When medical knowledge is at a crossroads, how research can take patient preferences into account

When medical knowledge is at a crossroads, how research can take patient preferences into account

4000195795_6841659fc6_z (1)Let’s say you have high blood pressure that can be treated with one of two medications.

Neither drug is experimental; both are within the standard of care. Your doctor doesn’t have any medical reason to recommend one or the other. But she’d like to help the medical community figure out which one works best, and she’s wondering if you would, too. If so, you can enroll in a randomized study, effective immediately.

The question is, what steps are necessary to ensure you understand and consent to the research?

One possibility is that your doctor informs you about the purpose of the research, its risks and benefits, and your alternatives to participating; she then documents the conversation and your decision in your medical record. A patient-friendly consent process is essential to the success of this type of research on clinical practices, say researchers at the Stanford Center for Biomedical Ethics (SCBE), and most patients are comfortable skipping a written consent form when the form might prove so cumbersome that the research couldn’t go forward. Patients also prefer to talk about participating in these studies with their own doctors, not with researchers.

But draft guidance from the federal Office for Human Research Protections (OHRP), if finalized, would require formal written consent in any study that is designed to assess a risk, even if the same risk exists in ordinary clinical care. In other words, whether you get Hypertension Medication A vs. Hypertension Medication B is characterized as a research risk, even though the risk is inherent in the doctor visit whether you participate in the study or not.

“They make it seem really risky,” said Stephanie Alessi Kraft, an SCBE clinical ethics fellow and the lead author of a paper in the American Medical Association Journal of Ethics that argues for reconsideration of the draft guidance. “We’re talking about cases of genuine uncertainty and equipoise. In our research, we use the example of a gumball machine. You know you’re going to get a gumball. You know you’re going to get a medication that works. You just don’t know what color.”

Continue Reading »

Big data, Clinical Trials, Events, Research

At TEDMED 2015: Benign drugs? Not under the lens of big data

At TEDMED 2015: Benign drugs? Not under the lens of big data

This year’s TEDMED was held Nov. 18-20 in Palm Springs, Calif. Stanford Medicine is a medical research institution partner of TEDMED, and a group of MD and PhD students who represented Stanford at the conference will be sharing their experiences here.

xCUEHR0MrJlqiC9phSMFFEjCxjrDDo54Bv0Hc18sYdkPicture this: you go to the doctor and find out that your cholesterol is high. Your doctor prescribes you a medication taken by millions of Americans for lowering cholesterol – Pravastatin. A few months later, you see your doctor again because of persistent depression, and again, you are given a commonly prescribed medication – Paxil.

Russ Altman, MD, PhD, opened his 2015 TEDMED talk with this seemingly innocuous scenario. But through the course of his talk, Altman demonstrated how his lab leveraged big data to reveal the adverse side effects of supposedly benign pharmacological interventions.

When choosing medications for my patients during my clinical rotations, I would often cite evidence from randomized controlled trials about the clinical benefits versus the risks of that particular drug. However, this evidence-based medicine has one major limitation: In clinical studies, patients are usually only on one drug.

My patients, on the other hand, would often come in with bags full of prescription bottles in order to show me which drugs they took, since there were too many medication names to memorize. Often, I found myself wondering quietly, “Is there any way to know if combining these drugs could lead to an adverse event?”

Continue Reading »

Chronic Disease, Clinical Trials, Mental Health, Research, Stanford News

Treating insulin resistance may speed recovery from major depression

Treating insulin resistance may speed recovery from major depression

depressionIn a randomized, placebo-controlled clinical trial detailed in this study in Psychiatry Research, pioglitazone – a generically available drug that’s approved for type 2 diabetes – helped to relieve symptoms of major depression in patients whose blues had withstood an assault by standard therapeutic regimens for six months or longer.

But this beneficial effect was seen only in depressed patients who were also insulin-resistant.

Depression is remarkably common. Stanford psychiatric researcher Natalie Rasgon, MD, PhD, the study’s senior author, told me that close to one in five Americans are diagnosed with depressive illness at some point in their lives.

Insulin resistance, a stepping stone on the path to type 2 diabetes (not to mention cardiovascular disease and probably Alzheimer’s), is even more common: About one in three otherwise healthy Americans – and an even greater share of people with depression – are insulin-resistant. Especially prevalent among overweight people, insulin resistance also occurs more often than one might expect even among thinner folks, a lot of whom don’t have the faintest idea that’s the case.

Insulin, released by the pancreas in response to food intake, alerts cells throughout the body to the presence of glucose, the body’s primary energy source, in the blood. Insulin-resistant people’s cells fail to take up glucose adequately, leaving high residual blood levels of the sugar to wreak havoc on the body’s tissues. Because the brain is a glucose glutton – it soaks up about 20 percent of all glucose consumption in a healthy, active person – it’s easy to imagine that lousy glucose uptake in the brain would have all kinds of deleterious effects, including effects on mood. Food for thought, anyway.

Here’s how my news release described the study:

[R]esearchers were blinded as to which patients were receiving pioglitazone versus a placebo. The patients didn’t know which they were getting, either. … All the patients had been experiencing episodes of depression lasting, on average, more than one year. Their symptoms had failed to remit under standard treatment regimens. They remained on these regimens for the duration of the Stanford study and, in addition, were given either pioglitazone or a placebo. … The patients were tested for depression severity and insulin resistance at the study’s outset and then roughly every two weeks from the beginning of the trial to the end.

A total of 37 patients – 29 women and eight men – completed the 12-week study. The insulin-sensitive subjects did about as well on the drug as they did on placebo. But among the insulin-resistant group, those given pioglitazone showed a much greater improvement than those who got a placebo. They also showed more improvement than insulin-sensitive patients did.

The more insulin-resistant a participant was at the beginning of the study, the better the drug’s antidepressant effect. Possible, but not proven, explanation: It could be that for some patients standard antidepressant therapies can kick into gear only once these patients’ insulin resistance is reduced. Hungry brains gotta eat.

Previously: Survey shows nearly a quarter of U.S. workers have been diagnosed with depression in their lifetime, Revealed: the brain’s molecular mechanism behind why we get the blues, and International led by Stanford researchers identifies gene linked to insulin resistance
Photo by S.Hart Photography

Clinical Trials, Ethics, Health Policy, Public Health, Stanford News

Using social media in clinical research: Case studies address ethical gray areas

Using social media in clinical research: Case studies address ethical gray areas

decisions

If a public-health researcher is reviewing Facebook profiles of 14-year-old males for firearm references and discovers photos or words referencing a potentially threatening situation, should the researcher intervene? What levels of privacy should these children expect in the online world?

These are the kinds of difficult questions that ethics consultants are faced with as they attempt to provide moral and legal guidance to researchers gathering health-related data from the Internet.

To help researchers with these nascent ethics issues, the Clinical Research Ethics Consultation Collaborative, a group of almost 50 bioethicists who provide free or low-cost ethics consultations across the United States, has begun publishing case studies on its most ethically challenging cases. Thus far they’ve posted 40 case studies in the categories of behavioral/social science research, clinical trials, genetics, pediatrics, research misconduct and surrogate decision making. The site also includes information on how to participate in educational webinars and collaborative case discussions.

This effort is being led by Benjamin Wilfond, MD, at Seattle Children’s Research Institute and University of Washington, and Mildred Cho, PhD, at the Stanford Center for Biomedical Ethics.

“Our bioethics consortium has learned a great deal from the complex ethics consultations that we’ve been providing since 2005,” said Cho. “Now we have a strategy for sharing these best practices with others, to provide moral and legal guidance to researchers across the country and to better inform policymakers on evolving ethical gray areas.”

More information on the collaborative or to request a consult can be found on this website.

Previously: The challenge – and opportunity – of regulating new ideas in science and technologySocial media brings up questions, ethical unknowns for doctorsBuild it (an easy way to join research studies) and the volunteers will come
Photo by NLshop/Shutterstock

Clinical Trials, Pain, Research, Stanford News

Pain-in-the-neck, begone! Better way to relieve chronic neck and shoulder pain?

Pain-in-the-neck, begone! Better way to relieve chronic neck and shoulder pain?

shoulderHundreds of millions of people worldwide (115 million in the United States alone) suffer from chronic pain. Stanford diagnostic radiologist Sandip Biswal, MD, calls this group “one of the largest populations in the world for medical need of any kind.” But current treatments either aren’t all that great or – in the case of opioids, which are highly effective – put patients at risk for addiction.

A pair of randomized, double-blinded clinical trials, described in a study co-authored by Biswal, former Stanford visiting scholar Charlie Koo, PhD, and several colleagues and published in Nature Scientific Reports, may point to a potential path toward more pain-free lives. In the trials, patients with chronic neck or shoulder pain were treated with three to six 90-minute sessions of either standard physical therapy – so-called transcutaneous electrical nerve stimulation,  or TENS, along with exercise and both manual and heat treatments – or a protocol designed by Koo, who now runs a facility called the Pain Cure Center in Palo Alto, California.

The new method, which Koo calls Noxipoint therapy, also employs electrical stimulation of painful areas, but in a carefully defined way: electrodes are placed precisely at both of the two attachment points for each muscle in pain, and the electrical-current jolt is brief and just enough to cause local soreness and dull, but not sharp, pain. Patients receiving the novel therapy are also told to take it easy for several days after each treatment.

In both trials, Noxipoint therapy proved superior to conventional physical therapy using TENS by close to an order of magnitude. Four weeks after their last treatment, patients given Noxipoint therapy reported substantial pain reduction, restoration of function (for example, regained range of motion) and improved quality of life, without significant side effects. Those given standard treatment reported no significant lasting improvement.

These trials are preliminary and call for confirmation in larger studies, Biswal told me. Given the pressing need for safe, lasting relief from chronic pain and the apparent success of this new method, it would be nice to see those expanded trials take place.

Previously: “People are looking for better answers”: A conversation about chronic painNational survey reveals extent of Americans living with pain and Stanford researchers address the complexities of chronic pain
Photo by Jason Trbovich

Big data, Clinical Trials, Health Policy, Precision health, Research

Push-button personalized treatment guidance for patients not covered by clinical-trial results

green buttonA pediatrician, a cardiologist and a biomedical informaticist walk into a pharmacy. They all look as if they could use some strong medicine. “We want a Green Button,” they tell the pharmacist in unison.

“Green Button? Hmmm. I can’t say I know how to compound that prescription,” the puzzled pharmacist replies. “But if all three of you are ordering it, maybe I should. Can you tell me what, specifically, goes into a Green Button?”

“A lot of patients,” reply the three thirsty health experts.

“OK, I’ll play along,” says the pharmacist, beginning to lose his patience. “What comes out?”

“If we knew the answer to that, we wouldn’t need a Green Button.”

Actually, that punch line is no joke. The “Green Button” signifies a profound, potentially pervasive approach that could revolutionize medical practice. In a just-published feature in Inside Stanford Medicine, I report on a futuristic (but not too futuristic) vision of a “learning health-care system” outlined in a 2014 Health Affairs paper by three Stanford experts: pediatric specialist Chris Longhurst, MD, cardiologist Bob Harrington, MD, and biomedical informaticist Nigam Shah, MBBS, PhD.

As I noted in that feature:

The randomized clinical trial is considered the gold standard of medical research. In a randomized clinical trial… participants are randomly assigned to one of two – or sometimes more – groups. One group gets the drug or the procedure being tested; the other is given a placebo or undergoes a sham procedure. … Once the trial’s active phase ends, rigorous statistical analysis determines whether the hypothesis, spelled out in advance of the trial, was fulfilled.

There’s one problem: Clinical trials select only a small, artificial subset of the real population. The rest of us are kind of out of luck.

“Clinical trials are designed to prove one thing,” Shah told me. “And you’re testing it on people with just one thing: type 2 diabetes, eczema, whatever. But most real-life people don’t have just one thing. They have three or four or five things.”

Enter the Green Button. Suppose you’re a clinician facing a patient for whom no clear clinical guidelines exist. Instead, according to the scheme depicted by Longhurst, Harrington and Shah, you press a virtual “green button” on a computer screen displaying your patient’s electronic medical record. This triggers a real-time search of millions, or tens or millions, of other electronic records. In a matter of minutes, up pops a succinct composite summary of the outcomes of 25 or 100 or perhaps 1,000 patients very similar to the one in front of you – same race, same height, same age, same symptoms, similar medical histories, lookalike lab-test results – who were given various medications or procedures for the condition you’re hoping to treat. Those “lookalikes,” it turns out, respond much better to one treatment than to the others – something you’d have been hard put to guess on your own.

That’s all very nice, you say. Now I get your “artisanal faux-joke” lead. But, you ask, why does the button have to be green? And I answer: It doesn’t. But the other good colors were already taken.

Previously: Widely prescribed heartburn drugs may heighten heart-attack risk, New research scrutinizes off-label drug use and A new view of patient data: Using electronic medical records to guide treatment
Photo by Green Mamba :)–<

Clinical Trials, Mental Health, Parenting, Pediatrics, Research, Stanford News

Parents can help their teens recover from bulimia, say Stanford researchers

Parents can help their teens recover from bulimia, say Stanford researchers

Mom&teenTeenagers with bulimia nervosa benefit from their parents’ help in stopping their eating disorder. In fact, a therapy that involves parents works better for teens than one that does not, according to the first large head-to-head comparison in adolescents of two well-known bulimia treatments.

The findings are described in a study of 130 young people with bulimia that was published last week in the Journal of the American Academy of Child and Adolescent Psychiatry.

The research, which was jointly led by Stanford’s James Lock, MD, PhD, and a longtime collaborator, Daniel Le Grange, PhD, compared an approach tailored to teens with one commonly used in adults. In family-based therapy, the bulimia patient and a parent work together to stop the disordered eating behavior. In contrast, in cognitive behavioral therapy, which is widely recognized as the best approach for bulimic adults, there is more focus on changing abnormal thoughts about food and less emphasis on behavior change.

At the end of six months of treatment, 39 percent of patients in family-based therapy had abstained from the binge-and-purge cycle of bulimia for at least four weeks. Only 20 percent of those in the cognitive behavioral therapy group had done the same. The gap persisted six months after treatment ended, though it seemed to have closed by a year after the end of treatment.

Lock, who directs the Comprehensive Eating Disorders Program at Lucile Packard Children’s Hospital Stanford, said the findings are not surprising, given that teens are at a different stage of the illness and have different cognitive capabilities than adults with bulimia. But they are very important, since they suggest that the family-based approach is a faster way for young patients to recover from bulimia. From our press release about the study:

“The strategy for cognitive behavioral therapy requires a fair amount of abstract reasoning, motivation and persistence that often has not reached full capacity in teens,” [Lock] said, adding that doctors may need to decide on a case-by-case basis whether a teen would benefit from one treatment versus the other. “The cognitive and developmental context is very different for teens than for adult patients,” he said.

And it’s normal for teenagers to need their parents’ assistance in navigating difficult situations, he added. “The big take-home message is that families can really help their kids with bulimia nervosa.”

Previously: Family therapy an effective way to treat anorexic teens, Incorporating the family to help teens overcome eating disorders and Families can help their teens recover from anorexia, new study shows
Photo by J.K. Califf

Clinical Trials, Health Disparities, Mental Health, Research, Stanford News

How people with mental illness get left out of medical research studies

How people with mental illness get left out of medical research studies

One of the enduring challenges of evidence-based medicine is that the characteristics of people who participate in clinical trials can differ markedly from those of patients who ultimately access the treatment which the trial evaluates. One of the many reasons this occurs is that researchers often exclude patients with certain characteristics from participating in clinical trials.  In a new study in Journal of Psychiatric Research, my colleagues Laura Roberts, MD; Janet Blodgett, and I examine a particular population to whom this occurs: People with mental health and/or substance use disorders.

If scientists are to live up to their laudable commitment to sharing the benefits of health research with all citizens, they’ll have to more consistently include people with psychiatric problems in studies

In a sample of 400 highly-cited randomized trials across 20 common chronic disorders, we found that half had eligibility rules that prevented people with psychiatric problems from enrolling.   Those disease research areas with high rates of reported psychiatric exclusion criteria in clinical trials included low back pain (75 percent), osteoarthritis (57 percent), COPD (55 percent), and diabetes (55 percent).  People with conditions such as depression, anxiety disorders, alcohol problems and schizophrenia thus may face some added risk when they seek health care: People like them were often left out of the research that tells doctors what medical treatments work.

The study also raises questions about whether some clinical trials make much of a contribution to knowledge. For example, now that psychiatric and other substance use problems are virtually normative among smokers, what is the point of smoking cessation studies that continue to exclude the very populations that do most of the smoking?

Including people with psychiatric problems in medical research may require extra resources for researchers (e.g., people with serious mental illness may be harder to follow up) or pose other challenges in completing clinical trials. But if scientists are to live up to their laudable commitment to sharing the benefits of health research with all citizens, they’ll have to meet these challenges and more consistently include people with psychiatric problems in medical research studies.

Addiction expert Keith Humphreys, PhD, is a professor of psychiatry and behavioral sciences at Stanford and a career research scientist at the Palo Alto VA. He has served in the past as a senior advisor in the Office of National Drug Control Policy in Washington, DC. He can be followed on Twitter at @KeithNHumphreys.

Stanford Medicine Resources: