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FDA, Medicine and Society, Men's Health, Research, Science, Women's Health

Sex matters: Why we shouldn’t conduct basic research without taking it into account

Sex matters: Why we shouldn't conduct basic research without taking it into account

2593063816_9a4eaba16e_zIn a PNAS opinion piece (.pdf) published last week, two Stanford faculty are among the authors arguing that sex shouldn’t be overlooked in basic research studies. Londa Schiebinger, PhD, director of the Gendered Innovations in Science, Health & Medicine, Engineering, and Environment program, and Marcia L. Stefanick, MD, director of the Stanford Center for Health Research on Women and Sex Differences in Medicine, take issue with the fact that much of the research that leads to drugs, devices, and our conclusions about biology comes from studies conducted on non-human animals and cell cultures without considering their sex.

Evolutionarily speaking, sex is one of the most well-conserved biological differences, of fundamental importance to 100 percent of the population. Paying more attention to it, the authors claim, would help biomedical research disaggregate data and explain heterogenous outcomes. While some think it would create unnecessary duplication to account for sex earlier in the research process, before drugs and treatments are tested on humans, the authors argue that such practices would save money and be more efficient in the long run. Early tests are far less expensive than removing something from the market because it has adverse effects on half the population. Moreover, preventing such adverse outcomes would keep people of both sexes safer and healthier.

The article states that the FDA is beginning to reconsider whether unisex dosing is accurate and safe for many drugs, and cites that “about 80% of rodent drug studies are conducted only on males, and 8 of 10 drugs withdrawn from the US market from 1997 to 2000 posed greater health risks for women than for men.”

Previously: Stanford professor encourages researchers to take gender into account, A look at NIH’s new rules for gender balance in biomedical studies and Why it’s critical to study the impact of gender differences on diseases and treatments
Photo by Rick Eh?

FDA, In the News, otolaryngology, Public Health, Science Policy

With e-cigarettes, tobacco isn’t the only danger

With e-cigarettes, tobacco isn't the only danger

16546091210_99279fd110_zE-cigarettes are far from safe, Robert Jackler, MD, writes in a strongly worded op-ed that appeared over the weekend in the San Jose Mercury News.

Most at risk are teens and tweens, enticed by flavors ranging from cotton candy, gummy bear and root beer to peanut butter cookie. (An aside: Can you imagine a hardened, pack-a-day smoker deciding to curb his or her harmful habit by switching to cotton candy-flavored e-cigarettes?)

Interestingly, these flavors, which are thought to be safe in foods may be upping the harmfulness of the e-cigs; after all, the lungs process chemicals much differently than the stomach does. (Remember popcorn lung? In the early 2000’s, a group of workers at a microwave popcorn plant fell ill after inhaling too much of the flavoring agent, diacetyl, used to give popcorn its buttery taste.)

From Jackler’s piece:

In 2009, to reduce youth smoking, the FDA banned flavors (other than menthol) from traditional cigarettes. Fearing regulatory action, the e-cigarette industry response has echoed the playbook of the tobacco industry. One brand went so far as to commission a study which, not surprisingly, arrived at the improbable finding that flavors do not appeal to the young. The industry argues that flavored e-cigarettes should be allowed because they have not been proven unsafe.

Jackler goes on to warn of the progressive nature of lung damage — e-cigarette smokers may be accumulating harm well before they notice a problem.

Previously: Raising the age for tobacco access would benefit health, says new Institute of Medicine report, How e-cigarettes are sparking a new wave of tobacco marketing, E-cigarettes and the FDA: A conversation with a tobacco-marketing researcher and E-Cigarettes: The explosion of vaping is about to be regulated
Photo by Jonny Williams

Applied Biotechnology, Clinical Trials, FDA, Research, Stanford News

An inside look at drug development

An inside look at drug development

B0008664 Assorted pills, tablets and capsules

How are drugs born? If you’re really curious about this, you’d be fascinated by the weekly meetings of industry experts and academic researchers taking part in Stanford’s drug-development training program known as SPARK.

A recently published book, A Practical Guide to Drug Development in Academia, crystallizes the sessions. Even if you’re not a scientist dreaming of curing cancer with your latest discovery, you might find it interesting.

In his recent review of the book for Nature Chemical Biology, industrial medicinal chemist Derek Lowe, PhD, writes:

I would actually welcome it if this book’s intended audience were broadened even more. Younger scientists starting out in the drug industry would benefit from reading it and getting some early exposure to parts of the process that they’ll eventually have to understand. Journalists covering the industry (especially the small startup companies) will find this book a good reality check for many an over-hopeful press release. Even advanced investors who might want to know what really happens in the labs will find information here that might otherwise be difficult to track down in such a concentrated form.

Lowe also wrote about the book last week on his blog, In the Pipeline, where an interesting discussion has begun.

Previously: SPARK program helps researchers cross the “valley of death” between drug discovery and development and Accelerating the translation of biomedical research into clinical applications.
Photograph from Wellcome Images

Addiction, FDA, Health Policy, Pediatrics, Public Health

Raising the age for tobacco access would benefit health, says new Institute of Medicine report

Raising the age for tobacco access would benefit health, says new Institute of Medicine report

cigarette packToday, the Institute of Medicine released a new report evaluating the public health effects of reducing teenagers’ access to cigarettes and other tobacco products. Right now, in most places in the United States, you must be 18 years old to buy cigarettes and other tobacco products. But a few states and cities have higher minimums, and in 2013, the IOM convened a committee, at the request of the U.S. Food and Drug Administration, to examine the potential effects of a higher minimum legal age for tobacco access across the country.

The committee, which was led by Richard Bonnie of the University of Virginia and included Stanford adolescent medicine expert Bonnie Halpern-Felsher, PhD, reviewed the existing scientific literature on tobacco use in teens. They also devised mathematical models to predict what would happen if the federal minimum legal age were 19, 21 or 25.

The report brief (.pdf) says, in part:

Based on its review of the literature, the committee concludes that overall, increasing the MLA [minimum legal age] for tobacco products will likely prevent or delay  initiation of tobacco use by adolescents and young adults. The age group most impacted will be those age 15 to 17 years. The committee also concludes that the impact of raising the MLA to 21 will likely be substantially higher than raising it to 19. However, the added effect of raising the MLA from 21  to 25 will likely be considerably less.

The parts of the brain most responsible for decision making, impulse control, sensation seeking, and susceptibility to peer pressure  continue to develop and change through young adulthood, and adolescent brains are uniquely vulnerable to the effects of nicotine. In  addition, the majority of underage users rely on social sources—like family and friends—to get tobacco. Raising the MLA to 19 will therefore not have much of an effect on reducing the social sources of those in high school. Raising the MLA to 21 will mean that those who can legally obtain tobacco are less likely to be in the same social networks as high school students.

Although it can take time to fully realize the benefits of reduced smoking, since heart disease, lung cancer and other diseases linked to smoking take decades to develop, the payoff would ultimately be significant, the report adds:

…if the MLA were raised now to 21 nationwide, there would be approximately 223,000 fewer premature deaths, 50,000 fewer deaths from lung  cancer, and 4.2 million fewer years of life lost for those born between 2000 and 2019.

Previously: How e-cigarettes are sparking a new wave of tobacco marketing, To protect teens’ health, marijuana should not be legalized, says American Academy of Pediatrics and UN’s top health official: Anti-tobacco efforts can lead to better health “in every corner of the world”
Photo by Thomas Lieser

Addiction, FDA, Health Policy, Medicine and Society, Public Health, Public Safety

To keep edibles away from kids, marijuana policies must be “fully baked”

To keep edibles away from kids, marijuana policies must be "fully baked"

sanfran031606_fig1_highresDepending on your position, legal marijuana might raise images of stoners on every street corner or of users enjoying a private puff in their backyards. However you probably don’t picture a child munching on a pot-laden brownie she found in her kitchen cupboard.

But as Stanford legal experts Robert MacCoun, PhD, and Michelle Mello, JD, PhD, point out in a commentary published today in the New England Journal of Medicine, the loose state regulation of marijuana edibles creates some unnecessarily and potentially serious public health risks that should concern everyone.

Packaged in brightly colored wrappers, edibles often mimic popular sweets, but they contain a powerful dollop of tetrahydrocannabinol (THC), the chemical responsible for marijuana’s psychoactive effects. Some edibles contain multiple “servings” of THC per package.

Both Colorado and Washington — the two states with legal recreational marijuana — require “child-resistant” packaging and a warning to “keep out of the reach of children.” But edibles remain quite attractive to children, who may confuse them with regular candies and snacks, and potentially deceptive to adults, who may assume one bar is a just one serving. “I look at these packages and I get hungry just looking at them,” MacCoun said.

The edibles are not regulated as either a food or a drug by the U.S. Food and Drug Administration, because the federal government considers marijuana illegal. Legalizing states have been slow to fill the gap, and have done so incompletely, Mello said. “This is sort of a weird space that’s betwixt and between federal and state oversight,” she said.

It’s time for the medical community to get involved, MacCoun said. “Most people don’t understand the brain metabolizes chemicals ingested by mouth differently than those smoked.”

Ingested marijuana offers a delayed high, so people keep eating thinking they are fine. The intoxication lasts longer and is associated with more hallucinations and perceptual distortions, he said. “It’s almost like a different drug.”

For now, the issue is most pressing in Colorado and Washington, but many other states are considering legalizing recreational marijuana, including California, MacCoun said.

“We’re not taking some strong position these products should be banned. Sensible and fairly modest regulations would reduce the risk without greatly restricting people’s freedom to consume these products,” MacCoun said.

Previously: Discussing the American Academy of Pediatrics’ call to put the brakes on marijuana legalization, To protect teens’ health, marijuana should not be legalized, says American Academy of Pediatrics and Medical marijuana not safe for kids, Packard Children’s doc says
Photo by DEA

Big data, Clinical Trials, FDA, NIH, Research, Science

Transparency in clinical trials: The importance of getting the whole picture

Transparency in clinical trials: The importance of getting the whole picture

New rules for clinical trials Scope blog 2015.02.02Last week, the Journal of the American Medical Association ran a Viewpoint article from Francis Collins, MD, PhD, director of the National Institutes of Health and Kathy Hudson, PhD, deputy director of NIH, about the U.S. Health and Human Services’s plans to beef up transparency of clinical trials of FDA-regulated drugs and devices.

As they write, the rate of results-sharing for clinical trials is fairly dismal. Some of the reasons for this go beyond researchers; for example, it’s extremely difficult to get negative results published in scientific journals. Collins and Hudson point out that another avenue exists for sharing summary results: NIH’s ClinicalTrials.gov website. But even there, less than one-third of researchers had shared results within four years of the end of their studies. Collins and Hudson are critical of this lapse in data sharing:

Without access to complete information about a particular scientific question, including negative or inconclusive data, duplicative studies may be initiated that unnecessarily put patients at risk or expose them to interventions that are known to be ineffective for specific uses. If multiple related studies are conducted but only positive results are reported, publication bias can distort the evidence base. Incomplete knowledge can then be incorporated into clinical guidelines and patient care. However, one of the greatest harms from nondisclosure of results may be the erosion of the trust accorded to researchers by trial participants and, when public funds are used, by taxpayers.

The new rules make the expectations to report some summary details about clinical trials, including adverse events, explicit. Although NIH has always encouraged sharing of summary results, the rules haven’t always been explicit. Now that there will be detailed guidance, the penalty for not complying will be harsher:

Thus, with the implementation of clearer requirements, augmented support materials and resources, and facilitated reporting, the NIH expects that investigators and sponsoring organizations will have the necessary tools to provide accurate, complete, and timely trial results submissions. However, for grantees who are subject to the amendments act and fail to comply after sufficient notification, the law is clear that NIH and other federal funders of clinical trials must then withhold further funding for the grant and any future grant to the grantee. In addition, the timely reporting of clinical trials will be taken into consideration during review of subsequent applications for funding.

The proposed changes to the regulations are currently in the public comment period, which will end in a few weeks, on February 19. After a review of the comments (and possible revisions), a final rule will likely be issued in a few months time. Once the rule goes into effect, it will be interesting to watch how this changes the research process for new NIH and FDA-regulated studies.

Previously: Shake up research rewards to improve accuracy, says Stanford’s John IoannidisRe-analyses of clinical trial results rare, but necessary, say Stanford researchersHow important is it to publish negative results?Researchers call for “democratization” of clinical trials data and A critical look at the difficulty of publishing “negative” results
Photo by U.S. Department of Defense

Ethics, FDA, Health Policy, In the News, Stanford News

Stanford experts weigh in on spate of "right to try" laws for the terminally ill

Stanford experts weigh in on spate of "right to try" laws for the terminally ill

4286759185_f958aedc10_zTerminally ill patients should be able to access medication that could help them, regardless of how far along that drug might be in the FDA‘s in-depth approval process, right? Yes, some states such as Colorado, Missouri and Lousiana have said. They’ve adopted so-called “right-to-try” laws that gives dying patients access to drugs that have passed only the first stage of the FDA approval process.

Yet these laws — which are modeled on a policy from the libertarian Goldwater Institute — are ultimately useless given that federal law trumps state law, according to Stanford scholars Patricia Zettler, JD, and Henry Greely, JD, in an opinion piece published recently in JAMA Internal Medicine. In addition, the laws are redundant, they write:

Since the late 1980s, patients with serious and terminal conditions have been treated with unapproved medical products. Following sharp criticism from AIDS access about blocking access to potentially effective, but unproved, treatments, as well as congressional intent, the FDA issued regulations that are intended to provide patients with faster access to novel drugs for life-threatening conditions… Although satisfying the agency’s requirements may, at first glance, seem onerous, in practice the FDA very rarely rejects requests for expanded access.

Zettler, who formerly worked for the FDA, pointed out a link that is telling: During fiscal year 2012-2013, the FDA received 977 requests for “expanded access” (these requests may include more than one patient, Zettler said). It approved 974 of them.

None of the state or federal laws require a drug company to provide experimental drugs, and Zettler said she knows of only one – NeuralStem, Inc., a Maryland-based company that is developing therapies for central nervous system disorders –  that intends to provide drugs under these laws. By skipping the FDA’s process, the companies risk angering the FDA, whose favor they need for their drug approval, Zettler told me.

Why then these laws, which are currently also being considered in Michigan, Nevada and Arizona?

Well, Zettler told me, they’re political no-brainers. Imagine the political rants: “So-and-so made my mom die faster,” or “Joe Baloozabum opposes dying patients” – nope, that doesn’t fly inside any Beltway. Many state politicians are also motivated by a “good faith desire to help people,” Zettler said.

But she doubts that states have the expert staff needed to evaluate drug applications. And they don’t have the legal green-light either, she said, pointing out a recent ruling blocking Massachusetts’ attempt to ban a long-acting opiod.

Zettler said the state-based debates simply add a new wrinkle to a discussion that’s been percolating for decades.

Previously: No one wants to talk about dying, but we all need to and Asking the hardest questions: Talking with doctors while terminally ill
Photo by Melanie Tata

Cancer, FDA, Genetics, Research, Science, Stanford News

Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

6825694281_dfb79615d6_zIf you’re a regular reader of this blog, or follow cancer literature, you’ll have heard of a signaling pathway called Hedgehog that is activated in many cancers, including brain, skin and even bladder. It’s a cute name for cellular cascade that can kill when inappropriately activated.

Neurologist Yoon-Jae Cho, MD, treats children with brain tumors called medulloblastomas. He and postdoctoral fellow in his lab, Yujie Tang, PhD, published a study yesterday in Nature Medicine that could one day help some patients whose Hedgehog-driven tumors have become resistant to available therapies.

As Cho explained in an e-mail to me:

Medulloblastomas are the most common malignant brain tumors in children. They are comprised of various subgroups, including one with activation of a strong oncogenic signal called the Hedgehog pathway. Notably, the Hedgehog pathway is also activated in several other cancers including basal cell carcinoma, the most common cancer worldwide. Therefore, pharmaceutical companies and several research groups have developed drugs to target this pathway.

The most common of these drugs targets a downstream protein component of the pathway called Smoothened, including one currently marketed by Genentechcalled vismodegib (trade name Erivedge) and an investigational drug produced by Novartis called LDE225. Blocking the activity of Smoothened stops the chain reaction leading to division of the cancer cells. You can think of it (in simplified terms) as a line of dominoes standing on end, waiting for an eager finger to begin the chain reaction. Removing one domino (nixing Smoothened activity) can sometimes stop the rest of the row from falling and block the cancerous cell from dividing. But, as Cho explained:

Unfortunately, many cancers activate the Hedgehog pathway downstream of Smoothened and are inherently resistant to these therapies. Other cancers that are initially responsive to these drugs develop resistance through activation of downstream Hedgehog pathway components.

Cho and his colleagues have now described a new, novel way to interfere with the Hedgehog pathway. They’ve found that compounds that inhibit a protein called BRD4 can stop the growth of human Hedgehog-driven cancers – even when they’re resistant to drugs blocking Smoothened activity. This is particularly interesting because the BRD family of proteins recognizes and binds to particular chemical tags on chromatin that control whether (and when) a gene is made into a protein. It’s the first time such an epigenetic regulator has been implicated as a target in the Hedgehog pathway. Additionally, it’s a new avenue to explore for patients with Hedgehog-driven medulloblastomas – as many as half of whom will be resistant to Smoothened inhibition, according to a previous study co-authored by Cho and members of the International Cancer Genome Consortium’s Pediatric Brain Tumor Project. Cho concludes, “Our study offers a promising new treatment strategy for patients with Hedgehog-driven cancers that are resistant to the currently used Smoothened antagonists.”

Previously: New skin cancer target identified by Stanford researchers, Humble anti-fungal pill appears to have noble side-effect: treating skin cancer and Studies show new drug may treat and prevent basal cell carcinoma
Photo by Phillip Taylor

Addiction, FDA, Health Policy, otolaryngology, Public Health

How e-cigarettes are sparking a new wave of tobacco marketing

e-cig tip - smallFollowing the FDA’s announcement earlier this spring that it would regulate the sale – but not marketing – of electronic cigarettes, debate has continued on the safety of using e-cigarettes and the ethics of advertising them.

In case you missed it, today’s New York Times delves into the issue and highlights how Big Tobacco is now rolling into the world of e-cigarettes, which writer Matt Richtel calls an “overnight sensation.” A subsidiary of Reynolds American plans to begin distributing its Vuse e-cigarette line nationwide on June 23 with a campaign that includes television ads (forbidden for cigarettes) in major markets, and other tobacco companies have similar entries in the works. Questions about the potentially far-reaching effects advertising of e-cigarettes, including promoting smoking tobacco and reaching child audiences, concern public-health advocates and other critics – and a U.S. Senate hearing is planned for Wednesday.

From the article:

Matthew L. Myers, [JD,] president of the Campaign for Tobacco-Free Kids, who is scheduled to testify at the Senate hearing, said the fact that the F.D.A. did not limit marketing allowed tobacco companies to return to the airwaves with ads that make e-cigarettes sexy, rebellious, glamorous — “exactly the same themes we saw work with kids in the U.S. for decades with cigarettes.”

In the absence of marketing regulation, “they will set the agenda,” Mr. Myers said of the tobacco companies. “They will drive the evolution of the product in a way that serves their interests and not public health, and that’s exactly what’s happening.”

Robert Jackler, MD, chair of otolaryngology at Stanford Medicine, is an expert on tobacco marketing who studies it through his center, the Stanford Research Into the Impact of Tobacco Advertising. Like Myers, he has vocalized his concerns about e-cigarettes and tobacco companies’ aggressive marketing tactics – especially those targeted toward teens – and you can hear more about his views and research in this recent podcast.

Previously: E-cigarettes and the FDA: A conversation with a tobacco-marketing researcherE-Cigarettes: The explosion of vaping is about to be regulatedStanford chair of otolaryngology discusses federal court’s ruling on graphic cigarette labels and What’s being done about the way tobacco companies market and manufacture products
Photo by Li Tsin Soon

Big data, Events, FDA, Public Health, Stanford News, Technology

Rising to the challenge of harnessing big data to benefit patients

Rising to the challenge of harnessing big data to benefit patients

FDA guyMuch has been written on Scope about the annual Big Data in Biomedicine conference, held here last week. My colleague Bruce Goldman was on the scene all three days, and he offers more highlights from the event in an online story.

Noting how Lloyd Minor, MD, dean of the School of Medicine,  encouraged the audience “to rise to the challenge of harnessing computer technology, biomedical informatics and social media – collectively known as big data  – to benefit clinical practice,” Goldman goes on to describe the FDA’s work in this area:

“If you eat a salad, you’re pretty much a global citizen,” said [Taha Kass-Hout, MD, chief health informatics officer at the Food and Drug Administration], noting that the ingredients of a typical salad may travel halfway around the world to get to our table. Unfortunately, the well-traveled salad can pick up a host of microbial free-riders en route. Over the last year the FDA has assembled a publicly accessible database holding the genomic sequences of more than 5,000 food-poisoning culprits such as Salmonella and listeria, he said.

In a new initiative, the FDA has been monitoring social media to enhance its surveillance capabilities. “Maybe we’ll find that we can detect outbreaks earlier that way,” he said. It may also be possible, using these methods, to draw inferences about beneficial or adverse effects of drugs prescribed for indications other than the ones for which they’ve been specifically approved. This could expedite new uses for existing drugs.

Previously: Discussing access and transparency of big data in government, U.S. Chief Technology Officer kicks off Big Data in Biomedicine, Euan Ashley discusses harnessing big data to drive innovation for a healthier world and Big laughs at Stanford’s Big Data in Biomedicine Conference
Photo of Kass-Hout by Saul Bromberger

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