The Food and Drug Administration has approved changes to the label for mifepristone, also known as "the abortion pill," the agency said this week. The new label says that the drug (sold under the brand name Mifeprex) can be taken later in pregnancy and at a lower dose than what was recommended on the old label. Many doctors already follow the new regimen in what's known as "off-label" use, because recent studies have shown that this regimen is safer and more effective than the protocol on the old label. But a few states, including Ohio, Texas and North Dakota, had laws that required doctors to follow the regimen on the label exactly. "These laws compelled health care providers to use an outdated, inferior and less effective regimen," Planned Parenthood said in a statement, weighing in on the FDA's new rule. "The FDA's approval of the new Mifeprex label means that medication abortion [using drugs to end a pregnancy] can once again be provided everywhere in the U.S. in accordance with what research shows is safest and most effective," the statement said. [11 Big Fat Pregnancy Myths] Here are the facts about mifepristone: Mifepristone is a medication used to induce abortion. It's taken in combination with another drug, called misoprostol, to end a pregnancy early on. The drug combination is an alternative to the surgical abortion procedure performed in a clinic, called an aspiration abortion.. How does it work? Mifepristone blocks the action of the hormone progesterone, which is important to maintain a pregnancy. Blocking progesterone causes the lining of the uterus to break down, and ends the pregnancy, according to Planned Parenthood. What changes did the FDA make to the mifepristone label? The old label said that mifepristone could be taken up to 49 days after a woman's last menstrual period, but the new label says that the drug can also be taken later in pregnancy: up to 70 days after a woman's last period. The new label also lowers the dose of the medication, from 600 milligrams to 200 mg. This regimen reduces the side effects, and also the cost, of a medication abortion, according to the American College of Obstetricians and Gynecologists. Finally, the new label reduces the number of appointments that a woman needs for a medication abortion from three to two. The old label said that in addition to the initial appointment needed to get a prescription for the medication, women needed to return to the doctor three days after taking mifepristone, and again 14 days after taking the drug. But the new label eliminates the appointment after three days, and says that a woman should return for follow-up with her health care provider seven to 14 days after taking the medication. Is mifepristone the same as the morning-after pill? No, the morning-after pill, also called emergency contraception, is taken to prevent pregnancy from occurring a short time after unprotected sex; it does not affect an established pregnancy. What are the risks? Common side effects of a medication abortion include nausea, weakness, fever/chills, vomiting, headache, diarrhea and dizziness, according to the FDA. Serious side effects are rare, but can include infection and hemorrhage; these occur in less than 0.5 percent of people who take the medication, the FDA said. Copyright 2016 LiveScience, a Purch company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
Pharmaceutical Statistics | Year: 2010
Bayesian methods are often used to reduce the sample sizes and/or increase the power of clinical trials. The right choice of the prior distribution is a critical step in Bayesian modeling. If the prior not completely specified, historical data may be used to estimate it. In the empirical Bayesian analysis, the resulting prior can be used to produce the posterior distribution. In this paper, we describe a Bayesian Poisson model with a conjugate Gamma prior. The parameters of Gamma distribution are estimated in the empirical Bayesian framework under two estimation schemes. The straightforward numerical search for the maximum likelihood (ML) solution using the marginal negative binomial distribution is unfeasible occasionally. We propose a simplification to the maximization procedure. The Markov Chain Monte Carlo method is used to create a set of Poisson parameters from the historical count data. These Poisson parameters are used to uniquely define the Gamma likelihood function. Easily computable approximation formulae may be used to find the ML estimations for the parameters of gamma distribution. For the sample size calculations, the ML solution is replaced by its upper confidence limit to reflect an incomplete exchangeability of historical trials as opposed to current studies. The exchangeability is measured by the confidence interval for the historical rate of the events. With this prior, the formula for the sample size calculation is completely defined. Source
Just about every topic, from eminent domain to “hand” size, has scuttled onto the debate stage this election cycle. But the presidential candidates have uttered little about science policy “It’s been conspicuous by its absence,” says Dr. Peter J. Hotez, Dean of the National School of Tropical Medicine at Baylor College of Medicine. Nonetheless, the Republican frontrunner, Donald Trump, has made public remarks that give voters a glimpse into what some of his scientific policies might be. We asked some science and policy experts to discuss Trump’s stances, and what that could mean for Americans in the future. Go slow on climate action: Trump has tweeted that climate change is a Chinese-driven hoax, though he later called the Tweet a joke. In an interview with Fox and Friends, he called climate change “just a very, very expensive form of tax” and “very hard on business.” Sizing up the science: “There’s been a misperception that either you get a good economy or you protect the environment,” says Peter LaPuma, an associate professor in the Milken Institute School of Public Health at George Washington University. LaPuma, who worked as a sustainable energy consultant for Booz Allen Hamilton before joining George Washington, says many companies have found that sustainable practices actually boost their bottom lines. For example, IT companies like Apple have begun using renewable energy to power their data centers, a switch that often saves money because the cost of energy sources like solar has dropped so much. Immediate action to combat climate change has immediate benefits, according to LaPuma. “Climate change is not just polar bears 100 years from now,” he says. Replacing a coal-fired power plant with a solar farm can benefit health immediately, as well as clearing the air for better views of the country’s natural landscape. Cut the EPA: Trump has said he would cut funding for the Environmental Protection Agency and return environmental protection responsibilities to the states. He claims the agency hurts business, and in an interview with The Wall Street Journal, called the EPA “the laughingstock of the world.” Sizing up the science: “There would be serious repercussions” by 2020 if the EPA were severely downsized or abolished, according to Rice University’s Baker Institute for Public Policy professor Neal F. Lane, who directed the National Science Foundation and later the White House Office of Science and Technology Policy under President Clinton. Lane says the EPA plays a critical role in protecting clean air and drinking water, and that its regulations have helped rehabilitate polluted water bodies like Lake Erie, which was pronounced “dead” in the 1960s. “This is not just a bunch of regulators hugging trees,” he adds. Though states do have a part to play in regulation, the country needs a federal regulating body, according to Lane, because contaminated water and air can cross state borders. That’s not to say citizens shouldn’t weigh in on the agency’s proposed rules. “There will always be a healthy debate between the private sector and the federal government on these regulations,” says Lane. For this reason, he said, the EPA solicits public comment before making new rules. If Congress supported Trump in slashing funds for the EPA or changing the law to remove the agency’s power to regulate, Lane predicts there would be an outcry from overwhelmed governors and “reasonable people who care about their families, their children and their life style.” Alter vaccination schedules to avoid autism: Trump says he favors vaccines, but giving children smaller doses over a longer period of time. He has blamed vaccines for causing autism in children. Sizing up the science: “I remember wanting to throw something at the TV when I heard it,” Hotez says of Trump’s debate statement linking vaccinations and autism. Hotez, who develops vaccinations and also has a daughter with autism, says studies have found no link between autism and vaccination. “The anti-vaxxers keep moving the goalposts,” he says. After scientific studies debunked accusations against specific vaccinations, Hotez says those against vaccinations started a different fad: arguing to change the vaccination schedule to protect children. But infants’ immune systems face up to hundreds of new antigens every day, according to Hotez. Adding a few more in the form of a vaccination does not harm infants. He says changing the FDA’s approved vaccination schedule without clinical testing about immune response could decrease vaccines’ efficacy. To imagine what a future with fewer or less effective vaccines might look like, Hotez suggests voters think of California’s recent outbreak of measles, a true threat to children’s health. “It’s one of the great killers of children in the world,” he says. “One hundred thousand children die every year of measles.” Defund Planned Parenthood: Although Trump says Planned Parenthood does a lot of good for women’s health, he says he would defund its clinics because of their abortion services. Sizing up the science: “The good thing is that he doesn’t think [Planned Parenthood] is evil,” says Amy Tsui, a professor at Johns Hopkins Bloomberg School of Public Health. But, she says, no federal funding has gone to abortion since the Hyde Amendment of 1976 (though Medicaid can fund abortion in the case of rape, incest, or endangerment of the mother’s life). If Trump defunds all Planned Parenthood clinics, even those that don’t perform abortions, then he’ll be “throwing the baby out with the bathwater,” according to Tsui. She says Planned Parenthood’s low-cost care and urban clinic locations, helps low-income women in particular. In fact, Leighton Ku, Director of the Center for Health Policy Research at George Washington University, says that decreased access to Planned Parenthood’s contraception services could increase the rate of unwanted pregnancies and possibly cause a spike in abortions. Abolish and replace the Affordable Care Act: Trump recently released his healthcare plan to replace the Affordable Care Act. Highlights include promises to lower American healthcare cost by allowing insurer bids across state lines, make health insurance tax deductible, and remove barriers to prescription drugs entering from outside the country. Sizing up the science: George Washington’s Ku says the number of Americans without health insurance is at its lowest in recent recorded history, and has reached that point without ballooning healthcare costs. He says he’s concerned that repealing the Affordable Care Act might leave 13 million people insured under the plan without coverage. Allowing insurers to compete across state lines could potentially lower cost, but Ku points out that state insurance standards differ, and Trump has not clarified which state’s rules would apply in interstate deals. Ku also views tax deductibility as a red herring: Low-income Americans, who struggle the most to get insured, already pay little to no taxes on care. Lowering barriers to imported medicine could decrease prices, but Ku warns that pharmaceutical manufacturers will likely try to raise prices outside the U.S. if imports grow more common. This might cut into some of Americans’ savings. Restrictions on some countries, like China, should continue, he says, because of issues with counterfeited pharmaceuticals. Even so, the FDA would need more resources to monitor imports. Regardless, Ku doubts a Republican Congress would go along with Trump’s proposal. In summary, Trump’s proposals have not won over the scientists we consulted. Hotez expressed hope that Trump will bring experts onboard to make more informed proposals if he becomes the Republican nominee. But Lane says he’s skeptical even of that. “Who would he recruit to his science team?” asks Lane. “How capable would they be of providing advice? Of course, I don’t have the answer to that. But it’s a question voters should have in their minds.”
News Article | September 2, 2016
For children with autism and a class of genetic disorders, exposure to diagnostic ultrasound in the first trimester of pregnancy is linked to increased autism severity, according to a study by researchers at UW Medicine, UW Bothell and Seattle Children's Research Institute. The study published Sept. 1 in Autism Research studied the variability of symptoms among kids with autism, not what causes autism. What they found is that exposure to diagnostic ultrasound in the first trimester is linked to increased autism symptom severity. The greatest link is among kids with certain genetic variations associated with autism; 7 percent of the children in the study had those variations. FDA guidelines currently recommend that diagnostic ultrasound only be used for medical necessity. "I believe the implications of our results are to bolster the FDA guidelines," said corresponding author Pierre Mourad, a UW professor of neurological surgery in Seattle and of engineering & mathematics in Bothell who specializes in translational research on ultrasound and the brain. Mourad said their results are about the first trimester of pregnancy. Data looking at the effect of ultrasound on the second and third trimester showed no link, he said. The researchers used data from the Simons Simplex Collection autism genetic repository funded by the Simons Foundation Autism Research Initiative. The data was derived from 2,644 families among 12 research sites across the United States. "There has been a real struggle in why there are so many kids with autism," said lead author Sara Webb, UW Medicine researcher in psychiatry and behavioral sciences. "Where does this disorder develop from? How do kids get autism? And the second question is why are kids with autism so different from each other? This study really looks at the second question. Within kids with autism, what are some of the factors that may result in a child having a good outcome or higher IQ or better language or less severity versus a child who maybe takes more of a hit and continues to struggle throughout their lifespan?" Webb said the research team approached their work based on a three-part model explaining variability in kids with autism. The first is a genetic vulnerability to the disorder. Second, is an outside stressor. And the third implies that the outside stressor has to impinge on a kid at a certain time. Webb said a number of outside stressors have been proposed and investigated in autism. This study looked at only one of them -- ultrasound. As a mother of two, Webb said given what she knows now, she would not have ultrasound in the first trimester unless there is a medical necessity and that includes knowing how far along the pregnancy is. "If we can figure out this information in any other way, I would go with that," she said. "It's always worth considering that when we do medical procedures, there are great benefits but also risk." In an earlier study, Mourad and co-authors Webb, Abbi McClintic (UW Medicine researcher in neurological surgery) and Bryan King, now a professor of psychiatry at the University of California, San Francisco, published a paper in Autism Research in 2014 that showed ultrasound exposure in-utero caused mice to exhibit autistic-like symptoms. Mourad said he and King wanted to study the issue further. They brought together a team with a wide range of autism experience. King, formerly with UW Medicine, had conducted several clinical trials with children with autism. Webb works in developing biomarkers in kids with autism. Raphael Bernier, UW Medicine researcher in psychiatry and behavioral sciences, works with the Simon sample. Michelle Garrison, UW Medicine researcher with Seattle Children's Research Institute specializes in statistics and epidemiology. Mourad said he and his colleagues now intend to look more closely into links between ultrasound and autism severity, as well as the possibility - thus far not shown - that ultrasound exposure could contribute to autism incidence.\ The study was supported by the NIH and the Simons Simplex Collection.
In cancer research, no success is more revered than the huge reduction in deaths from childhood leukaemia. From the 1960s to the 2000s, researchers boosted the number of children who survived acute lymphoblastic leukaemia from roughly 1 in 10 to around 9 in 10. What is sometimes overlooked, however, is that these dramatic gains against the most common form of childhood cancer were made not through the invention of new drugs or technologies, but rather through a reassessment of the tools in hand: a dogged analysis of the relative gains from different medicines and careful strategizing over how best to apply them side by side as combination therapies. “It wasn't just about pounding drugs together,” says Jedd Wolchok, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City. “It was about understanding the mechanism and figuring out what should be given when.” That lesson has particular relevance in cancer research today. A new class of immunotherapies — which turn the body's immune system against cancerous cells — is elevating hopes about combination therapies again. The drugs, called checkpoint inhibitors, have already generated great excitement in medicine when applied on their own. Now there are scores of trials mixing these immune-boosting drugs with one another, with radiation, with chemotherapies, with cancer-fighting viruses, with cell treatments and more. “The field is exploding,” says Crystal Mackall, who leads the paediatric cancer immunotherapy programme at Stanford University in California. Fast-moving trends in cancer biology often fail to meet expectations, and little is yet known about how these drugs work together. Some observers warn that the combinations being tested are simply marriages of convenience — making use of readily available compounds or capitalizing on business alliances. “In many cases, we're moving forward without a rationale,” says Alfred Zippelius, an oncologist at the University of Basel in Switzerland. “I suspect we'll see some disappointment in the next few years with respect to immunotherapy.” But many clinicians argue that delay is not an option as their patients queue up for the next available clinical trial. “Right now I have more patients that could benefit from combinations than there are combinations being tested,” says Antoni Ribas, an oncologist at the University of California, Los Angeles. “We're always waiting on the next slot.” Immunotherapies have been more than a century in the making, starting when physicians first noticed mysterious remissions in a few people with cancer who contracted a bacterial infection. The observations led to a hypothesis: perhaps the immune system is able to kill tumours when made hypervigilant by an infection. The concept has vast appeal. What better way to beat a fast-evolving biological system such as a tumour than with a fast-evolving biological immune system? But it took decades for researchers to turn that observation into something useful. Part of the trouble, they eventually learned, is that tumours suppress the immune response. T cells, the immune system's weapon of choice against cancer, would sometimes gather at the edge of a tumour and then just stop. It turned out that a class of molecules called inhibitory checkpoint proteins was holding those T cells at bay. These proteins normally protect the human body from unwarranted attack and autoimmunity, but they were also limiting the immune system's ability to detect and fight tumours. In 1996, immunologist James Allison, now at the University of Texas MD Anderson Cancer Center in Houston, showed that switching off a checkpoint protein called CTLA-4 helped mice to fend off tumours1. The discovery suggested that there was a way to re-mobilize T cells and beat cancer. In 2011, the US Food and Drug Administration (FDA) approved the first checkpoint inhibitor — a drug, called ipilimumab, that inhibits CTLA-4 — to treat advanced melanoma. The improvements were modest: about 20% of patients benefited from ipilimumab, and the survival gain was less than four months on average2. But a handful of recipients are still alive a decade after starting the therapy — a stark contrast with most new cancer drugs, which often benefit more patients in the short term, but don't have a durable response (see 'Desperately seeking survival'). Ipilimumab was at the leading edge of a flood of checkpoint inhibitors to enter clinical trials. The drug's developer, Bristol-Myers Squibb of New York, followed up with the approval of nivolumab, which inhibits the protein PD-1. And a host of other companies have jumped into the immunotherapy fray, as have academics such as Edward Garon at the University of California, Los Angeles. “Our group gladly shifted into this,” says Garon, who began focusing on checkpoint inhibitors in 2012. “It was very clear this was going to have a major impact.” But even as the family of checkpoint inhibitors was rapidly expanding, the drugs were running up against the same frustrating wall: only a minority of patients experienced long-lasting remission. And some cancers — such as prostate and pancreatic — responded poorly, if at all, to the drugs. Further research revealed a possible explanation: many people who were not responding well to the drugs were starting the treatment without that phalanx of T cells waiting at the margins of their tumours. (In the lingo of the field, their tumours were not inflamed.) Researchers reasoned that if they could raise this T-cell response first, and recruit the cells to the edges of the tumour, they might get a better result with the checkpoint inhibitors. That realization fuelled a rush to test combinations of drugs (see 'Combinatorial explosion'). Radiation and some chemotherapies kill enough tumour cells to release proteins that the immune system might then recognize as foreign and attack. Vaccines containing these proteins, called antigens, could have a similar effect. “On some level, one can make an argument for almost any drug combining well with an immunotherapy,” says Garon. “And obviously we know not all of them will.” One of the first combinations to be tested was made up of two immunotherapies — ipilimumab and nivolumab — at once. Although the targets of these drugs both do the same job, silencing T cells, they do so in different ways: CTLA-4 prevents the activation of T cells; PD-1 blocks the cells once they have infiltrated the tumour and its environment. And treating mice with compounds that block both proteins yielded a more-inflamed tumour as well3. “There was reason to think that if you block both, the T cells will be even more ready to kill the tumours,” says Michael Postow, an oncologist at Memorial Sloan Kettering. Together, ipilimumab and nivolumab boost response rates in people with advanced melanoma from 19% with just ipilimumab to 58% with the combination4. The combination also produces more-dangerous side effects than using either drug alone, but physicians are learning how to treat immunotherapy reactions, says Postow. Ipilimumab generally doesn't help people with lung cancer when given on its own, but researchers are now testing it with nivolumab. Normally, they would not have bothered to investigate a combination involving a drug that had failed on its own, Garon says. The new approach is grounded in immunology, but some researchers worry that the effort could be wasted, he adds. Researchers are also testing inhibitors of other checkpoint proteins, including TIM-3 and LAG-3, in combination with those that block PD-1. The combination approach is breathing life into drugs that had been shelved. For example, a protein called CD40 stimulates immune responses and has shown promise against cancer in animals. But in the wake of disappointing early clinical trials, some companies put their CD40 drugs to the side. Years later, mouse studies showed that combining CD40 drugs with a checkpoint inhibitor could boost their effect. Now, at least seven companies are developing them. Cancer immunologists have listed the protein as one of the targets they are most interested in studying, says Mac Cheever, a cancer immunologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington. Cancer vaccines — long pursued by researchers but burdened by repeated failures in clinical trials — may also see a renaissance. There are now more than two dozen trials of cancer vaccines that make use of a checkpoint inhibitor. Some promising combinations have been uncovered by serendipitous clinical observations. Researchers at Johns Hopkins University in Baltimore, Maryland, were conducting trials of epigenetic drugs, which alter the chemical tags on chromosomes. They shifted a handful of people with lung cancer who had not responded to the drugs to a clinical trial of nivolumab. Five of them responded — a much higher proportion than expected. The discovery became the seed for an ongoing clinical trial launched in 2013 to study combinations of epigenetic drugs and immunotherapies. Preclinical work has now provided evidence that epigenetic drugs can affect aspects of the immune response. These chance observations could lead to real advances, says Wolchok. “We're riding the wave of enthusiasm.” But extracting the most from these combinations will require more well-designed preclinical studies to support the human ones. Just as attention to combinations of chemotherapies fuelled advances in treating paediatric leukaemias, the current combinatorial craze will require careful planning to work out the right pairings and timing of therapies. Another class of drug, known as targeted therapies, could also receive a significant boost from immunotherapy. These drugs, which target proteins bearing specific mutations, generate a high response rate when given to patients with those mutations, but the tumours often develop resistance to the drugs and come roaring back. Coupling targeted therapies with a checkpoint inhibitor, researchers reason, could yield both high response rates and durable remissions. One of the first targeted therapies for melanoma was an inhibitor that is specific to certain mutations in BRAF proteins that can drive tumour growth. However, an early attempt to combine this drug with ipilimumab was aborted when trial participants showed signs of possible liver damage5. No one was injured, but for some it was an important reminder that combinations can yield unanticipated side effects. “It was a good lesson for us to learn,” says Wolchok. “It will not be as simple as we imagined.” Paying careful attention to sample collection during clinical trials would help researchers to catch toxicity problems early, says Jennifer Wargo, a cancer researcher at MD Anderson. “We're making mistakes by looking just at clinical endpoints,” she adds. “We need to be smarter about how we run these trials.” In one of his latest trials, Wolchok wants to combine immunotherapy with a drug that targets a cellular pathway that some cancer cells use to maintain their rapid division. Cancers with mutations in this pathway, which is regulated by the protein MEK, can be extraordinarily difficult to treat. But the pathway is also important for T-cell development, so Wolchok is working to determine the right timing for the treatment. One approach could be to use a MEK inhibitor to quiet tumours in mice and to release tumour antigens. He would then wait for the T-cell response to rejuvenate before adding the immunotherapy. “You want to make sure you're not trying to activate the immune system at the same time you're turning off that signalling,” he says. Garon is watching such trials with optimism, but he's aware that there may be a limit to how well combinations will perform. He sees a cautionary tale in a drug from an earlier era that works mainly in people with a mutation in the protein EGFR. Researchers spent a decade trying to find drugs that could turn a non-responding patient into a responder. “It is now clear that there probably is no such agent,” he says. “I'm hopeful we won't be repeating that same response, but we have to watch our data cautiously.” Researchers are so ravenous for those data that the results are being unveiled at major meetings at an earlier stage than in the past, he adds. “People are getting up and presenting response rates when the number treated is five,” Garon says. “We generally have had a higher threshold than that.” He worries that presenting such early data could prompt community physicians in the audience to start making decisions on treatments before they are appropriately studied. The excitement is also fuelling a frenzy of clinical trials that are often based on speed rather than rationale. “Right now I'm kidding myself if I say I'm picking a combination because I have a scientific reason to pick it,” says Mackall. “It's likely to just be what was available.” The strategy may still produce some wins. “There is plenty of opportunity for serendipity now,” says Robert Vonderheide, who studies CD40 at the University of Pennsylvania in Philadelphia. But as the field matures, he says, this could give way to a more-systematic approach, similar to the careful planning and testing of variables used for paediatric leukaemias. Despite his concerns, Garon is excited to be a part of the immunotherapy wave. Last autumn, he and his colleagues held a banquet for the patients who had been enrolled in his first immunotherapy trials three years earlier. These were the lucky survivors — the few who had shown a dramatic response. As he looked around the table at the guests of honour, he marvelled at their recovery. All had been diagnosed with advanced lung cancer, and many had been too weak to work. Now they were talking about their families, re-embarking on careers and taking up old hobbies such as golf and running. “We've never been able to hold a banquet like that before,” he says. “I would love to hold many more.”