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Brain Cells Made from Urine
Human excreta could be a powerful source of cells to study disease, bypassing some of the problems of using stem cells, such as the risk of developing tumors and difficulties in obtaining blood samples from children
By Monya Baker and Nature magazine | Monday, December 10, 2012 | 1
Getting neurons from cells discarded in urine, may one day help develop therapies for neurodegenerative diseases like Parkinson's disease.
Image: Lihui Wang
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Some of the waste that humans flush away every day could become a powerful source of brain cells to study disease, and may even one day be used in therapies for neurodegenerative diseases. Scientists have found a relatively straightforward way to persuade the cells discarded in human urine to turn into valuable neurons.
The technique, described online in a study in Nature Methods this week, does not involve embryonic stem cells. These come with serious drawbacks when transplanted, such as the risk of developing tumors. Instead, the method uses ordinary cells present in urine, and transforms them into neural progenitor cells — the precursors of brain cells. These precursor cells could help researchers to produce cells tailored to individuals more quickly and from more patients than current methods.
Researchers routinely reprogram cultured skin and blood cells into induced pluripotent stem (iPS) cells, which can go on to form any cell in the body. But urine is a much more accessible source.
Stem-cell biologist Duanqing Pei and his colleagues at China's Guangzhou Institutes of Biomedicine and Health, part of the Chinese Academy of Sciences, had previously shown that kidney epithelial cells in urine could be reprogrammed into iPS cells.
However, in that study the team used retroviruses to insert pluripotency genes into cells — a common technique in cell reprogramming. This alters the genetic make-up of cells and can make them less predictable, so in this study, Pei and his colleagues introduced the genes using vectors which did not integrate in the cellular genome.
One of their experiments produced round colonies of reprogrammed cells from urine that resembled pluripotent stem cells after only 12 days — about half the time usually required to produce iPS cells. When cultured further, the colonies took on the rosette shape common to neural stem cells.
Tumor-free
Pei and his colleagues transferred the cells to a growth medium used for neurons, and found that these reprogrammed cells went on to form functional neurons in the lab.
When the team repeated the experiment and transplanted the cells into newborn rat brains, the cells did not form tumors. Instead, when the brains were examined four weeks later, the cells had taken on the shape and molecular markers of neurons.
Neural progenitors proliferate in culture, so researchers can produce plenty of cells for their experiments. Getting enough cells has previously been a problem for such 'direct reprogramming' techniques, which produce neurons more quickly than producing and differentiating iPS cells.
“This could definitely speed things up,” says James Ellis, a medical geneticist at Toronto's Hospital for Sick Children in Ontario, Canada, who makes patient-specific iPS cells to study autism spectrum disorders.
The benefit of sourcing cells in this way is that urine can be collected from nearly any patient, says geneticist Marc Lalande, who creates iPS cells to study neurogenetic diseases at the University of Connecticut Health Center in Farmington, and is particularly intrigued by the possibility of making iPS cells and neural progenitors from the same patient.
“We work on childhood disorders,” he says. “And it's easier to get a child to give a urine sample than to prick them for blood.”
This article is reproduced with permission from the magazine Nature. The article was first published on December 9, 2012.
I am not one of those who in expressing opinions confine themselves to facts.
-- Mark Twain
What? Off-label communication is protected free speech?
Cry havoc and let slip the dogs of war!
Not so fast.
As Steve Usdin of BioCentury so aptly opines, the ruling is “far less consequential than media coverage suggests.”
According to Usdin:
… companies and individuals who take the decision as a signal that the rules of the road have changed and they are now free to promote off-label indications put themselves in great legal and economic peril, attorneys who helped persuade the court to overturn Caronia's conviction told BioCentury.
At the same time, the decision by one of the country's most influential and respected courts to overturn a criminal conviction on First Amendment grounds is persuasive evidence that, in the long term, FDA will have to change some of the assumptions underpinning its regulation of medical products.
FDA, which now has lost a string of First Amendment cases, cannot forever hold on to the notion that it is empowered to prohibit drug companies and their employees from saying things that anyone else is free to say. Sooner or later, according to legal experts, the agency will have to reconcile itself with the idea that industry has the right to truthful, non-misleading speech.
While change is inevitable, the pace of change is uncertain. It is also not clear who will shape that change - FDA employees, judges, or members of Congress.
In short the Caronia ruling didn’t really answer any questions so much as it opened up the conversation. And that alone is worth the price of admission.
What will it mean on the ground? In the short term, not much. But it’s not about instant gratification for aggressive marketers.
This ruling isn’t the beginning of the end of FDA warning letters on off-label communication -- but it very well may be the end of the beginning of such speech being off-limits to prudent corporate compliance officers.
Equally important, what will it mean for off-label conversations with patients and caregivers? What will it mean for regulated speech on social media?
As William Safire once said, “Is sloppiness in speech caused by ignorance or apathy? I don’t know and I don’t care.”
Usdin’s complete story, Free speech, in theory, can be found here.
TransCelerate Appoints Dalvir Gill as CEO
TransCelerate has named Dalvir Gill, PhD, as its Chief Executive Officer, effective January 1, 2013. Dr. Gill will lead the independent non-profit entity, which was formed by ten healthcare and pharmaceutical companies in September to improve the quality of clinical studies and bring new medicines to patients faster by facilitating the collaboration required to solve common challenges encountered during the clinical trial process. Dr. Gill will succeed Garry Neil, MD, who has served as interim CEO. Dr. Neil will remain as Chairman of the Board of Directors.
Dr. Gill has more than 25 years of drug development experience. Prior to his appointment as CEO of TransCelerate, he was the President of Phase II-IV Drug Development at PharmaNet-i3, an organization specializing in drug development services. In this role, Dr. Gill was responsible for a global business spanning nearly 40 countries.
Nature Biotechnology reports:
Having Hamburg, who is a “tough cookie,” remain at the FDA provides something of a “public health bulwark against political intrusions,” says Pitts.
The full article, Cuts loom over research and industry following Obama re-election, can be found here.
Yesterday I participated on the Pennsylvania BIO-sponsored panel, “Election Aftermath: The Fiscal Cliff and the Future of Healthcare Reform.”
You might have heard of these issues.
My fellow panelists were Senator Bob Casey (D, PA), Congressman Jim Gerlach (R, PA) and Gary Karr (Executive VP, AdvaMed). The panel was expertly moderated by Chris Satullo (Executive Director of News and Civic Dialogue at WHYY).
Much of the evening’s focus was on the collision of healthcare innovation and national healthcare policy – and not in a good way.
Specific items of discussion were IPAB – Uncle Sam dictating (for tens of millions of Americans) what treatments will be available for physicians and patients; PCORI – the government instructing physicians as to how to practice medicine, FDA reform (specifically surrounding the issue of predictability), waste in Medicare and Medicaid, the medical device tax (both Casey and Gerlach are for repeal of the tax), the President’s call to roll back biologics exclusivity from 12 to 7 years (both Casey and Gerlach are for preserving 12) and, of course, the issues surrounding state exchanges.
Since states are the laboratories of innovation, governors should be given wide authority to design programs that best fit the needs of their particular situations. Ultimately states will learn from each other. HHS waivers should be broad. We’ll see.
The worst scenario is a one-size-fits-all top-down approach that fits everyone poorly. Alas – that’s a pathway preferred by many inside the Beltway. A key issue here is that of essential health benefits, what are they and who makes the call.
Congressman Gerlach was especially effusive (and appropriately so) of the free-market design of Medicare Part D. Lower than expected costs, high utilization and user satisfaction. And he strongly agreed this is a model that can work in the design and implementation of state exchanges.
Jim Dandy.
Senator Casey mentioned his strong support of NIH funding. I suggested to the Senator (politely) that perhaps more than a small slice of that largesse should be redirected to the FDA.
Does White Oak have a friend in Pennsylvania?
Nature reports:
FDA under pressure to relax drug rules
Industry says antibiotic pipeline is being blocked by overly stringent clinical-trial requirements for new treatments.
The latest skirmish in the battle between human and microbe played out on 29 November in a hotel conference room in Silver Spring, Maryland. There, an assembly of scientists and clinicians debated the merits of an experimental antibiotic. For some, the coveted prize was not just an endorsement of the drug itself, but a sign that the US Food and Drug Administration (FDA) is finally ready to rethink its clinical-trial requirements for antibiotics — requirements that the drug industry says are unrealistic.
The number of FDA approvals of new antibiotics has dropped even as multi-drug-resistant strains of bacteria have proliferated. FDA advisers at last week’s meeting did recommend approval of telavancin (Vibativ) — a derivative of vancomycin — for the treatment of hospital-acquired pneumonia when alternative drugs are not suitable. But that vote came nearly two years after the FDA had rejected the drug for a second time because clinical data did not measure up to the agency’s guidelines.
“The agency has painted itself into a statistical corner,” says Scott Hopkins, chief medical officer of Rib-X, a drug company in New Haven, Connecticut, focused on antibiotics. “While the infectious-disease community was crying out for new antibiotics, the FDA seemed to be going in the opposite direction.”
Many trace the agency’s tougher stance to the scandal surrounding telithromycin (Ketek), an antibiotic approved by the FDA in 2004 and later linked to liver failure. In 2007, the US Congress launched an investigation into whether the FDA had ignored staff concerns about Ketek’s safety. The following year, the agency convened its advisers to discuss antibiotics then under review. “Four drugs representing over a billion dollars of investment went into that week and only one came out alive,” recalls Mark Leuchtenberger, president of Rib-X.
Telavancin was caught in the changing tides. When Theravance, the company in South San Francisco, California, that developed the drug, designed the large phase III clinical trials needed for approval, the FDA simply required a demonstration that the drug eliminated symptoms of infection as reliably as the approved antibiotic vancomycin. But, after Theravance submitted its second application on 30 June 2010, the FDA decided instead that applicants needed to show that patients were no more likely to die — of any cause — within 28 days of treatment with a new drug.
Theravance scrambled to gather the data, hunting down medical records for 1,419 out of the 1,503 patients scattered across dozens of countries that were enrolled in the telavancin trials. But the FDA determined that the study lacked statistical power and asked for new clinical studies. Theravance refused, and a stalemate followed.
Strict clinical guidelines for antibiotics have dogged the industry ever since, with pneumonia providing a good illustration. Patients who contract pneumonia in hospital are already ill, making it hard to know if the treatment under review played a part in their death. That means trials have to be larger to capture enough deaths to have any statistical meaning. This, combined with the relative rarity of infections that warrant the use of new antibiotics and the further FDA requirement that patients not receive other antibiotics before they get the experimental drug, has set the goal out of reach, argues David Shlaes, who runs Anti-Infectives Consulting in Stonington, Connecticut. Not a single new antibiotic for hospital-acquired pneumonia has been submitted for approval since the new guidelines were put in place. “The trial simply cannot be done,” says Shlaes. “Whoever was writing these guidance documents doesn’t live on the same planet that I do.”
However, since the Ketek scandal, the political winds have reversed. This summer, Congress passed a set of measures to encourage antibiotic development. In May, Janet Woodcock, head of the FDA’s Center for Drug Evaluation and Research, pledged to “reboot” the antibiotic-approval process. And in September, the FDA told Theravance that its advisers would take another look at telavancin, resulting in last week’s vote.
Investors have also noticed these changes, says Leuchtenberger. Last week, Rib-X announced that it had raised US$18.7 million to help the company start phase III trials of an antibiotic that could target skin infections. “Without some of these positive developments this year, you’re looking at a number of companies that might not be around any more,” he says.
Shlaes, however, emerged from the telavancin meeting still doubtful, noting a continued focus on all-cause mortality. He says that, for now, he will continue to advise his clients to apply for approval in Europe first, where regulators have not been as demanding as the FDA. “I’ve been very optimistic about the whole thing,” he says. “But the FDA has to do something to show that it is actually rebooting.”
I was pleased to chair the Fifth Annual Risk Management and Drug Safety Summit.
REMS is a tactic. Safe Use is a strategy and Safe Use is the new normal.
Some take-aways:
According to Greg Fiore, MD (Chief Medical Officer and Acting Head of Global Pharmacovigilance at The Medicines Company), we are now in a “new world order” where pharmacovigilance teams finally have a seat at the table. But, per Fiore, we are still spending too much time, talent, and treasure of process – and not nearly enough on insights development and use.
Good points. Could this be because ever-more process is a good excuse for actually doing something? Such action would require not just more dollars and FTEs for PV teams – but would also mean changing the cognitive mapping of the way many companies do business. It might actually mean that patient safety takes priority over marketing and sales.
Fiore also mentioned the need to consider what benefits a more aggressive use of social media might mean for pharmacovigilance.
Is it time to “friend” Gerald Del Pan?
Josephine Torrente, JD (a Director at Hyman, Phelps & McNamara), made the point that REMS is labeling (a view held by most at the conference) and that the implications for shared REMS must be taken into account – especially when it comes to biosimilars. Josephine also addressed the issue of possible FDA waivers from shared REMS programs. She doesn’t see it as likely.
Is this another possible point of political intrusion? As with Plan B, will the HHS Secretary decide to grant such a waiver if the FDA declines to do so? Ms. Torrente feels petitioning the Humphrey Building for such divine intervention would have little chance of success. Glad to hear that.
The class-wide Opioid REMS was much on everyone’s mind, and Stuart Kim, JD (Senior Regulatory Counsel, Covidien), made a strong case for a more active role by state-level stakeholders. The context for this was the crucial need to differentiate the desire to address abuse versus misuse. The failure to recognize the different nature of these issues will lead to negative and unintended consequences. He also asked, per the CME requirements, why we are not looking to a more thoughtful level of measurement. Just “ticking the box” on CME won’t solve any problems. Rather, Stuart pointed to a goal of a Moore’s Scale Level 7 achievement of actually improving patient outcomes.
For more on Moore’s Scale, see here.
Addressing abuse is one thing – but smartly dealing with misuse (while not as sexy or politically potent) is at least of equal import.
After Stuart’s presentation, I offered the following prediction:
FDA will not approve generic opioids minus the innovator-developed abuse-resistant technologies – unless they are forced to. IP issues? You bet. Watch this space for more on this issue as it rises to the top of the FDA agenda. (And don’t be thrown off-guard by what’s going on north of the border.)
Eleanor Segal, MD (Consultant, Segal PV Systems), discussed pharmacovigilance trends in the EU, with specific focus on how the EU is actually becomes less harmonized both between it’s own members – and with the FDA. And the new EU directive on Phase IV studies didn’t give anyone a warm and fuzzy feeling.
James Frame, MD (Medical Director, David Lee Cancer Center, Chair of ASCO REMS Working Group, and President, West Virginia Oncology Society) spoke about the “onerous” burdens that many REMS plans are placing on physicians. Not news, but he made the good point that such burdens impact patient access issues such as time spent with physician, availability of support staff to address patient needs – both of which could actually lead to less optimal care. Unintended consequences – but certainly not unpredictable when both sponsor and agency fail to take the weight of “practice burden” into account.
It’s the risk of risk mitigation.
Maybe its time for the FDA (and sponsors) to engage a “physician representative” when it comes to REMS design.
Day One ended with a thoughtful presentation by former FDAer Lynn Mehler, JD (Partner, Hogan Lovells). Lynn predicted that the FDA would be looking forward to more class-wide REMS.
We shall see.
Richard Hermann, MD (Safety Science Physician, Patient Safety, Global Regulatory Affairs, AstraZeneca) brought the issue of risk/benefit analysis via a validated grid into the conversation. His baby, the BRAT, is only one methodology under discussion – but it is an important one in the “date versus information” debate. He urged the audience not be prisoners of process and to fight cultures that are resistant to change be they in industry or at the FDA. He acknowledged that many firms are operating in a “change-weary environment.”
Well, if the Pope can start tweeting and off-label promotion is protected free speech, there is hope for us all.
What will tomorrow bring.
Fasten your seatbelts.
Court: off-label promotion protected
The U.S. Court of Appeals for the Second Circuit said in a 2-1 ruling in United States v. Caronia on Monday that the "government cannot prosecute pharmaceutical manufacturers and their representatives under the [Food, Drug and Cosmetic Act (FDCA)] for speech promoting the lawful, off-label use of an FDA-approved drug." In the ruling, Judge Denny Chin wrote that so long as the off-label use of the FDA-approved drug is legal, the government's interpretation of FDCA's misbranding provisions to prohibit and criminalize the promotion of off-label use "unconstitutionally restrict[s] speech." FDCA prohibits misbranding, but does not expressly prohibit the promotion or marketing of drugs for off-label use. Chin noted that off-label promotion that is false or misleading is not protected by the First Amendment. In a dissenting opinion,
Judge Debra Ann Livingston said the ruling "calls into question the very foundations of our century-old system of drug regulation," adding that if drug companies "were allowed to promote FDA-approved drugs for nonapproved uses, they would have little incentive to seek FDA approval for those uses."
The case concerns Alfred Caronia, a former specialty sales consultant at Orphan Medical, which was acquired by Jazz Pharmaceuticals plc. He was convicted in 2008 of conspiracy to introduce a misbranded drug into interstate commerce based on audio recordings in which he promoted the off-label use of narcolepsy drug Xyrem sodium oxybate. Caronia, who was sentenced to one-year probation and 100 hours of community service, appealed, arguing that his conviction was based solely on his speech and therefore violated his First Amendment rights.
The appeals court vacated and remanded to the lower court the decision convicting Caronia.
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
