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Clinical Trials, FDA, Health Policy, Stanford News

New ideas to help FDA discover drug risks

The U.S. Food and Drug Administration sometimes finds out that a drug it has approved for the market has dire and unanticipated side effects. A report released today by the Institute of Medicine suggests steps to help the agency catch such problems earlier in the process.

A key point is for the FDA to use more vigorously its authority to order additional studies after a drug is on the market. “Right now many studies are commissioned mainly when there’s a fire,” said Stanford Professor Steven Goodman, MD, PhD, a co-chairman of the Institute of Medicine (IOM) committee that produced the report, in an interview with me last week. “We think it’s better to initiate them when there’s just smoke.” Goodman is the medical school’s associate dean for clinical and translational research and a professor of medicine and of health research and policy.

The report comes as Congress is considering legislation reauthorizing the user fees that help to fund the FDA and is weighing ways to improve the agency’s drug-approval and tracking systems. Recent situations with the antidiabetes drug Avandia, the pain-reliever Vioxx and the cholesterol-reducing drug Crestor underscore the need to adopt new safety measures. The report proposes some factors that could indicate the need for a post-approval study. According to a release from the IOM:

[The report] identified some circumstances in which a product’s benefits or risks are particularly uncertain, including “first in class” drugs that have been approved based on surrogate endpoints used previously for other drug classes, and drugs for which several endpoints provide conflicting evidence about risk, such as an anti-hypertensive drug that lowers blood pressure but increases weight. In such cases, the committee recommended that FDA require safety research after approval or provide a public rationale for why it is not necessary. Early initiation of such studies could limit the harm done by drugs with risks that are later found to be unacceptable and avoid crises in which the agency is faced with few good options, the committee said.

Autism, Global Health, Research

Autism in Africa?

Autism has sometimes been described as a disease of industrialized high-technology societies. If that’s truly the case, it could have serious implications for our understanding of the disease. So I was troubled to read a post today on the blog Left Brain/Right Brain that shows a major gap in what we know about global incidence of Autism Spectrum Disorder, not to mention the possible lack of support for those with ASD in the developing world.

Apparently, no epidemiological studies have been done on autism in Africa. That’s a key finding in a review that was published in the July issue of the African Journal of Psychiatry by Muideen Bakare, MBBS, FMCPsych, of the Federal Neuro-Psychiatric Hospital in Nigeria and Kerim Munir, MD, of Boston’s Children’s Hospital. The two psychiatrists conducted searches of the Pubmed database for the period from January 2000 through December 2009. They found 12 papers addressing aspects of autism in Africa, but only two involved any epidemiological analysis that could give some sense of the scope of ASD on the continent. And one of those two papers was on Somalis in Sweden, while the other was a broader study of autism in the Middle East that included Tunisia and Egypt. After reviewing all 12 of the papers, the authors concluded:

Studies are required, specifically epidemiological studies, to define the magnitude of the problem of ASD as well as the characteristics of children with ASD in Africa, especially sub-Saharan Africa. These might also help answer the bothering question regarding the etiology of ASD and may also shed light on the reasons for possible differences in prevalence between geographical regions, if any exist. Africa also needs more policy making attention directed at child and adolescent mental health service provision, especially regarding the issues of childhood developmental disorders and intellectual disability.

Autism, Parenting, Pediatrics

Autism therapies: It still comes down to parents

Autism therapies: It still comes down to parents

There has been a recent flurry of new discoveries about the nature and cause of autism (revised estimates about the role of the environment vs. genetics, new data about the likelihood of a younger sibling having autism it the older one has it, research advancing the idea of different biological types of autism). But as important as this research may be, it doesn’t change the day-to-day reality for parents currently raising children with autism.

A column posted today by Lisa Jo Rudy, who writes about autism for About.com, offers a useful reminder about the challenges these parents face: They must sort through a wide array of time-consuming and costly therapies for these kids who have very different needs from each other despite all being on the autism spectrum. While there may be some experts who can offer guidance, they are few and far between and often have long waiting lists. What that means is that parents often shoulder the burden for how to proceed. In writing about her own experience raising a son with autism, Rudy notes, “I was constantly rocked by waves of guilt over whether I was doing ENOUGH, TOO MUCH, or the WRONG THING to help him.”

She also discusses various approaches that are widely accepted and observes:

Over the years, I dipped (with Tom [her son]) into auditory processing therapy, vision therapy, dietary therapies, dance therapy, RDI, Floortime, music therapy, social skills therapy… But being a bit of a skeptic, it occurred to me early on that there was NO WAY to know which of these would help the most, or even to be sure which were making a difference when his skills improved. After all, he wasn’t going to quit OT, PT, speech or school in order to try out vision therapy exclusively!

What was worse, since all these therapies are essentially “alternative” in the sense that a typical pediatrician knows little about them, there’s no one to help guide a parent through the maze. Yes, there are coaches out there, but none know more than the well-versed autism parent about whether X Y or Z therapy is going to be the best option for their individual child with autism.

The column does not offer a neat solution. But it offers useful advice on how to evaluate and make choices. And it does explain why parents of children with autism can become so frustrated. For many seeking help, they have no one to turn to but themselves.

Previously: What’s a parent to do: Risk of autism appears to run higher in siblings and Surprise: Environment’s big role in autism risk

Autism, Health Policy

Who pays for autism therapy?

The battle to get health insurers to cover a particular therapy for children with autism – Applied Behavior Analysis, or ABA – is heating up, and an article posted today on AISHealth gives a quick update on four Blue Shield/Blue Cross plans that are resisting pressure to pay for such services:

At least four Blues plans are in legal or regulatory hot water over their refusal to cover the cost of applied behavior analytics (ABA) – a common form of treatment for children with autism spectrum disorder – in their standard policies. The controversy could reach a climax in 2014 when the health reform law will require health plans to cover behavioral therapies on par with other medical treatments in all policies.

At issue is what ABA actually is and who’s eligible to provide it. On the one hand, mental health professionals, including the National Institute of Mental Health, government programs including Medicaid, the U.S. Surgeon General, the American Academy of Pediatrics, the American Psychological Association, the American Society of Pediatrics and more than half of all states consider ABA to be, as the California Department of Insurance (CDI) puts it, “a common and proven approach toward improving the lives of children with autism” and a “proven transformative therapy.”

ABA therapy is based on behavioral conditioning techniques, CDI points out, “and reinforcement of positive behaviors to shape behaviors and teach new skills.” It adds, “Decades of research show it to be a successful and well-established treatment for autism and not an experimental or investigational treatment.”

But many health plans, including Blues plans, question that. Some call the therapy experimental, and others say it’s an educational service, not medical treatment. And many plans say they just can’t cover services provided by non-licensed professionals. For example, Empire Blue Cross and Blue Shield, which is owned by WellPoint, Inc., “takes into account the terms of the member’s policy,” says spokesperson Sally Kweskin. “Many policies only provide benefits for services rendered by licensed clinicians, and many benefit contracts exclude coverage for services that are educational in nature.”

Mind you, the Blues aren’t the only insurers under pressure. A news release issued yesterday from a law firm in Philadelphia announced that its suit against CIGNA Insurance for denying coverage for ABA therapy for autism had been granted class action status in federal court.

The stakes in these cases are pretty high as the cost for covering all requests for ABA would be a substantial sum. There is, of course, no cure for autism, and until there is, many families will be demanding these services.

Autism, In the News, Pediatrics, Research

What’s a parent to do: Risk of autism appears to run higher in siblings

You may have heard about a new UC Davis study showing that parents of a child with autism are substantially more likely to have another child with autism. While it’s already been established that an infant who has an older sibling with autism has a greater chance of developing the disorder, this new research ups the odds to about 19 percent, from the previous estimate of 3 to 10 percent. A release about the findings, which are to appear in the September issue of the journal Pediatrics, was posted online yesterday.

This research is the latest twist in the effort to untangle what is behind autism, a neurological disorder estimated to affect one of every 110 children born this year. Although some of the past culprits — vaccines and uncaring mothers — have been ruled out as causes, there remains much confusion about how much the disorder results from environmental factors, genetics or increased awareness and diagnoses of the disorders. Last month, for instance, a Stanford release about a new paper reported that “non-genetic factors play an unexpectedly large role in determining autism risk, turning upside down recent assumptions about the cause of this common, disabling developmental disorder.” Now we have this new study saying genetics matter more than you might think.

This sort of back and forth is, of course, the way that science advances, but that doesn’t necessarily help clarify things for parents of a child with autism deciding whether or not to have another baby. A post on a New York Times blog tries to put it in perspective:

The findings prompted child development researchers to urge greater awareness for families who have a child with autism and may be considering more children. Although 1 in 5 is a greater risk than previously expected, it still means that 4 out of 5 children with an autism spectrum disorder will not develop the condition, said Alycia Halladay, the director of environmental research for Autism Speaks, an autism research group that supported the study along with the National Institutes of Health.

“Family history is a very strong risk factor, but there are other risk factors as well,” she said. “There are strong environmental risk factors. We don’t know what those are yet, but this is not the only factor that goes into an autism diagnosis.”

Previously: Stanford expert discusses environmental and genetic factors in autism risk and Surprise: Environment’s big role in autism risk

Clinical Trials, FDA

FDA begins to revamp approval process for medical devices

Medical device makers complain of a regulatory obstacle course at the U. S. Food and Drug Administration, which delays them from getting their new products to market. In turn, some consumer advocates, policy makers and physicians — most notably a recent panel from the Institute of Medicine — contend that the current system does not provide adequate safeguards for patients, let alone test the efficacy of these devices.

The FDA today took a step toward righting the system, issuing for the first time ever draft guidelines on how it will conduct benefit-risk determinations during pre-market review of certain medical devices.

In a release, Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, said:

Clinical data is the foundation for determining the safety and effectiveness of medical devices requiring FDA pre-market approval, As medical devices grow increasingly complex, many factors impact our benefit-risk determinations, especially for PMA devices. This guidance aims to provide more clarity to manufacturers about what factors we consider when making an approval decision.

Of course, the devil is in the details, so the agency has posted the guidance proposal on its website and is accepting comments. It remains to be seen whether the medical device industry will see the criteria as a step forward, but they are likely to met with a cool reception by many of the experts on the IOM panel who authored the July 29 report. As was reported in a New York Times editorial, that group “found the current regulatory approach so flawed that it called for it to be scrapped and replaced with a system better designed to protect the public’s health.”

Previously: Comfort from FDA with one question

Bioengineering, Stanford News

$20 million Coulter endowment to boost bioengineering start-ups

“This is more like business.”

That’s what Russ Altman, MD, PhD, chair of bioengineering, said about a new endowment that was announced today. The Wallace H. Coulter Foundation gave $10 million – with Stanford then matching the gift – to create an endowment that would help translate ideas that address unmet medical needs into treatments and devices that improve human health. The program will provide seed funding for bioengineering research projects, with the goal of launching start-ups or finding corporate partners to produce and distribute the fruits of their research.

Altman explained how it differs from a grant from the National Institutes of Health:

“The projects have quarterly milestones and can be killed by the oversight committee if the milestones are not met. This is not how academic grants usually go. There is a very strong emphasis on keeping focused on what is needed for successful transfer to professional management via a start-up or a license to an existing company. Funding for this sort of work is hard to get from the NIH, so the existence of a fund in perpetuity to support this kind of work is incredibly valuable . . .”

A previous five-year grant of $5 million to Stanford’s Department of Bioengineering from the Coulter Foundation made possible the development of a blood test that could be an alternative to amniocentesis, a new type of surgical dressing that aims to prevent scarring, a drug that may improve cognition for people with Down syndrome and an ultra-cheap ventilator for hospitals in developing nations that can’t afford the current models. The foundation has recently established similar $20 million endowments at Duke University, the University of Virginia, the University of Michigan and Drexel University.

Events, Research, Science, Stanford News

New class of physician-scientists showcase research

New class of physician-scientists showcase research

symposium4.jpg

How can we better study frostbite? Why do so many patients skip their ophthalmology appointments? Does it make a difference where on the spine neural stem cells are injected when trying to treat paralysis?

Those are some of the questions that were addressed in the 28th annual Stanford Medical Student Research Symposium, as discussed in a story in today’s Inside Stanford Medicine. The event showcases some great projects, and it also underscores Stanford’s effort to address what some fear could be the declining role of physician/scientists.

Last year, Andrew Schaefer, MD, the editor of a new book, The Vanishing Physician-Scientist?, noted that while there are no precise statistics on the number of physician-scientists, there are some troubling trends indicating that a greater proportion of research is being done by PhDs. (He discussed the book in a podcast that is part of the medical school’s “1:2:1″ interview series.)

The student symposium offers compelling examples of how research can be rooted in clinical practice and how physicians have a perspective on research that must not be lost. “What we really love is seeing people doing things that make a difference,” said Laurence Baker, PhD, director of medical student scholarship and professor of health research and policy, speaking of the projects being presented at the event earlier this month.

Photo by Norbert von der Groeben: Yuri Kim (left) listens to Shah Ali’s explanation of his research project on postnatal cardiomyocyte generation in murine models of aging and cardiac injury.

CDC, Infectious Disease, Public Health

Failure to vaccinate linked to pertussis deaths

Failure to vaccinate linked to pertussis deaths

The U.S. Centers for Disease Control and Prevention today released disappointing numbers about adults who had received the tetanus, diphtheria, and pertussis (Tdap) vaccine. (It’s the third item in its Oct. 14 Morbidity and Mortality Weekly Report.)

“Suboptimal” is how the agency described the 5.9 percent of adults who had reportedly received the vaccine by 2008, three years after the CDC first recommended the shot. The low numbers undoubtedly contributed to the recent spike in pertussis cases across the United States, including the death of nine infants in California because of the disease. The shot serves as a one-time substitution for the traditional 10-year booster dose of tetanus, diphtheria (Td) vaccine.

Medical Education

Publish or perish: Grad students facing tougher barriers

Being the first author on a paper in an esteemed journal is the objective for graduate students nationwide. Such an achievement opens the door to joining the faculty of elite institutions and has been viewed as a necessary rite of passage for academic scientists. This worthy ambition, however, has become less attainable, and that dilemma is the subject addressed by Stanford biochemistry professor Suzanne Pfeffer, PhD, the president of the American Society of Biochemistry and Molecular Biology, in her latest column in the society’s magazine.

Pfeffer lays out how multidisciplinary research increasingly is leading to papers with multiple authors and how journals, in turn, are being more demanding of the manuscripts they receive. She writes:

Why don’t more of our students publish sooner? Part of the problem is that reviewers and journals are demanding more. In the late 1970s and early 1980s, the sequence of an important gene was sufficient for publication in the flashiest of journals. I envied those manuscript reviews – what could the referees criticize when a sequence was a sequence? Now, journals quibble over whether to publish entire genomes. A referee can always ask for more experiments, another mutant, another control, and, because most journals want to maintain the highest standards, the editors agree. Such an approach may make for great papers, but it actually can be harmful to younger workers in our field because it sets the bar for publication further from their grasp.

Pfeffer doesn’t offer a simple solution, but makes several suggestions about how to ease the pain.

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