Three researchers at UC San Diego were awarded about $5.6 million in grants aimed at funding efforts to remove technological barriers to moving stem-cell research projects into clinical trials.
The California Institute for Regenerative Medicine awarded nearly $33 million in grants Thursday to 19 researchers across the state. CIRM was established in November 2004 as the state's stem cell agency, thanks to voters' passage of Proposition 71.
"These awards are a crucial component of CIRM's commitment to accelerate the development of stem cell-based therapies for people of the world,'' CIRM President Alan Trounson said. "CIRM funds all stages of therapy development, from basic research to translational awards, but any of these could be stalled by technological bottlenecks. In funding these innovative tools and technologies, CIRM is removing those barriers before they can delay cures.''
Among the grant recipients announced today were UC San Diego researchers Lawrence Goldstein, Karl Willert and Shu Chien. Goldstein and Chen each received about $1.8 million, while Goldstein was awarded about $2 million.
Stem cells created from mature cells, called induced pluripotent stem cells, retain a distinct 'memory' of their former purpose that might limit their potential for therapeutic use.
Stem cells made from mature cells and rewound to an embryonic-like state retain a distinct "memory" of their past that might limit their potential for therapeutic use, scientists reported Wednesday in the journal Nature.
In a side-by-side comparison of these induced pluripotent stem cells and embryonic stem cells, researchers from the Salk Institute in San Diego found a consistent pattern of reprogramming errors — places where the iPS cells did not revert completely to an embryonic state.
"This study definitively demonstrates that there are differences between the two cell types," said Joseph Wu, a stem cell biologist at the Stanford University School of Medicine who was not involved in the research.
Knowing exactly what those differences are is a key step in developing ways to use iPS cells to treat diseases, experts said. Most researchers still consider embryonic stem cells to be the gold standard for regenerative medicine because they can grow into any type of cell in the body. But many scientists and policymakers would like to see treatments based on iPS cells because they can be made without destroying embryos. In addition, iPS cells can be custom-made for patients, ensuring a perfect genetic match.
To catalog the differences between the two cell types, the Salk team, led by molecular biologist Joseph Ecker, studied the epigenomes — chemical markers attached to DNA that regulate the way genes dial on and off — of 11 different cell lines.
They looked at 1.2 billion places in each genome where such chemical markers exist. The analysis was unusually rigorous — and therefore unusually revealing, Ecker said. Earlier studies examined representative regions in the genome, rather than the whole thing.
"Up to this point, people were looking through a keyhole," he said. "We're opening up the door."
For the most part, the contents of Ecker's metaphorical rooms looked alike. But when they zoomed in, inconsistencies emerged.
Large regions of the iPS epigenomes hadn't reverted to the embryonic state, but instead held on to the epigenetic memory of their tissue of origin. When the researchers used the iPS cells to create mature cells in the lab, this memory persisted.
The regions were clustered near telomeres and centromeres, structures that help direct how chromosomes divide.
"There is something about these regions that makes it harder to modulate the epigenome," Ecker said.
In some ways the iPS cells were different from one another, suggesting the reprogramming process itself might contribute to aberrations, he added.
That does not mean iPS cells can't be used in medicine, experts said. Improvements in technology could one day erase their epigenetic memory.
In addition, Wu said, scientists might find ways to harness that epigenetic memory to help treat disease. For example, if heart cells generated from iPS cells retain some of their cardiac characteristics, he suggested, they might be useful in therapies to treat heart disease.
"We need to do more research to see what exactly this means," he said.
Early work on bone marrow cells to heal fragile hearts showed only modest effects. But new research looks at different types of stem cells. 'We're trying to tear pages out of nature's playbook,' says a Chicago cardiologist.
Hoping for a more direct approach that could generate new tissue, Marbán started studying stem cells that come from the heart instead of from bone marrow.
These so-called cardiac progenitor cells naturally repair heart muscle — but they do so far too slowly "to cope with a catastrophic injury" like a heart attack, Marbán says.
The cells are also rare, accounting for about 1 in every 40,000 working heart cells, he estimates. But in larger concentrations, they might be able to speed up the healing process.
To find out, Marbán is leading a trial involving patients who have suffered heart attacks within the past month. First a cardiologist threads a catheter through a patient's neck and into his heart to collect "little snippets of tissue," Marbán says. Those are then cultured in the lab for about a month, until the initial population of cardiac progenitor cells grows to tens of millions. Finally, they're infused back into the patient's heart through another catheter.
The hope is that the cardiac stem cells will take root and reverse the scar. Results should be out later this year. "Let's just say we're extremely encouraged," Marbán says. "It looks like it's working, and cleanly."
Multipurpose cells
In other labs, researchers are focused on more powerful, pluripotent stem cells that have the potential to grow into any type of tissue in the body. Some labs are using embryonic stem cells, and others are studying induced pluripotent stem cells derived from adult tissues and rewound to an embryonic-like state.
"The only cell type that becomes a heart cell is a pluripotent stem cell," says Dr. Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease at UC San Francisco. If bone marrow stem cells or cardiac progenitor cells do manage to create new heart muscle, he says, "it will be a tiny amount."
But research involving pluripotent stem cells is still preliminary. At the Harvard Stem Cell Institute in Boston, Dr. Kenneth Chien has grown mouse embryonic stem cells into a strip of mature cardiac tissue. But Chien's "heart patch," described in a 2009 edition of the journal Science, was only six to seven cell layers thick — too thin to work as a graft or grow blood vessels. He says he is now developing a three-dimensional cardiac muscle patch "akin to a heart Band-Aid."
Any therapy derived from pluripotent stem cells is a long way from being ready to test in humans. Among other technical hurdles, replacement tissues grown from embryonic stem cells run the risk of rejection, just as with organ transplants. In addition, the same forces that make both types of stem cells so flexible also mean they have the potential to generate tumors. When pluripotent stem cells are used to grow heart cells, researchers have encountered difficulty getting them to beat in sync with surrounding heart tissue.
So some of the most promising work with pluripotent stem cells isn't about making replacement heart tissue but finding other ways to ramp up the heart's own healing abilities. For example, Srivastava's lab has identified three genes that convert connective cells in the heart called fibroblasts directly into cardiomyocytes. Murry calls the research, which was published last year in the journal Cell, a potential "game changer."
Northwestern's Losordo has been studying stem cell treatments for about 14 years. He agrees that the best approach might be to apply what scientists have learned about creating stem cells to turn back the clock within a person's own body. "If you can make a patient's own cell behave as if it's younger, problem solved."
Early work on bone marrow cells to heal fragile hearts showed only modest effects. But new research looks at different types of stem cells. 'We're trying to tear pages out of nature's playbook,' says a Chicago cardiologist.
It's one of the most vexing problems in medical science: How can you mend a broken heart?
A decade ago, researchers and cardiologists thought they had found an answer in stem cells. These powerful cells lurk throughout the body, repairing and maintaining tissues as needed. In the laboratory, scientists can transform them into heart cells. When implanted in animals, they grow into new heart tissue too.
So it was with high hopes that researchers transfused stem cells into patients suffering from heart failure — people whose hearts, weakened by heart attacks or other conditions, no longer pumped enough blood through their bodies. But in clinical trials, the effects have been modest. Stem cells appeared to help, but not as much as doctors had hoped — and not in the ways they had expected.
Now those early results are pointing researchers toward other types of stem cells that may be better suited to help repair cardiac muscle. With 5 million Americans currently suffering from heart failure — and their ranks sure to grow as 76 million baby boomers march into old age — cardiologists are counting on breakthroughs in stem cell therapy.
"We're trying to tear pages out of nature's playbook," says Dr. Douglas W. Losordo, director of the program in Cardiovascular Regenerative Medicine at Northwestern Memorial Hospital in Chicago.
As the era of regenerative medicine dawned, stem cells seemed a perfect candidate to rebuild damaged hearts.
The stem cells in bone marrow were particularly tantalizing. Long used to rebuild the immune systems of cancer patients, scientists discovered that they also have the capacity to grow into heart muscle, blood vessels and other tissues — at least under certain laboratory conditions. Bone marrow is easy to extract from patients, and the therapeutic cells derived from it are a perfect genetic match for patients, greatly reducing the risk of tissue rejection.
Researchers and clinicians imagined using stem cells to undo the damage caused by a heart attack. In just a few minutes, a blockage in an artery can cut off oxygen to the heart, killing as many as a billion cells. The cells, for the most part, don't grow back. Instead, what remains is scar tissue and a weakened circulatory system.
Heart attacks aren't nearly as deadly as they used to be — more than 4 out of 5 heart attack victims are still alive after one year, according to a study last month in the American Journal of Medicine.
But the damage caused by a heart attack can result in heart failure — and patients diagnosed with heart failure have an average life expectancy of less than five years, according to Dr. Chuck Murry, director of the Center for Cardiovascular Biology at the University of Washington in Seattle.
That helps explain the enthusiasm for clinical trials involving stem cells from bone marrow. From 2002 to 2006 alone, there were at least 18 randomized controlled studies involving nearly 1,000 patients.
"Everyone started putting bone marrow in the heart," says Christine Mummery, a researcher at Leiden University Medical Center in the Netherlands, who has studied how to turn stem cells into heart muscle cells called cardiomyocytes.
But the results, she says, were a mixed bag. The treatment appeared to be safe, but patients had only transient improvement.
"People went from being very sick to a little less sick," Mummery says.
There is a silver lining: Even stem cells that don't grow into new heart cells seem to help patients in other ways. As the bone marrow transplant trials continue, researchers are trying to sort it all out.
"It's a little bit mysterious," says Dr. Eduardo Marbán, director of the Cedars-Sinai Heart Institute in Los Angeles.
Marbán, like many, believes the improvements came about because transplanted cells secreted chemicals that boosted heart function — not because any new heart tissue grew. The "stem cells are working mostly by raising an alarm to resident cardiac stem cells. They seem to work indirectly."
An Australian medical journal has "stopped all drug advertising forthwith" over concerns it could unduly influence doctors, and has called on similar publications to do the same.
The journal of Emergency Medicine Australasia, which publishes the latest research and unique patient cases in the field of emergency medicine, has announced it will no longer carry advertisements paid for by pharmaceutical companies.
Such advertising could "change the prescribing practices of doctors", said professors George Jelinek and Anthony Brown in a joint statement on Thursday.
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"It is time to show leadership and make a stand, and medical journals have a critical role to play in this," they said.
"At Emergency Medicine Australasia we have, therefore, drawn a line in the sand, and have stopped all drug advertising forthwith.
"We invite other journals to show their support and follow suit by declaring their hand and doing the same."
Prof Jelinek is medical director and professorial fellow in the Emergency Practice Innovation Centre at St Vincent's Hospital and the Faculty of Medicine at the University of Melbourne.
Prof Brown is from the Department of Emergency Medicine at Royal Brisbane and Women's Hospital, and the School of Medicine at the University of Queensland.
They said the ban followed discussions with fellow emergency medicine specialists, who had aired concerns such as:
- Advertised drugs were supported by evidence that was neither "of reasonable quality, nor independent".
- There were cases of "dubious and unethical" research practices by the industry, including "ghost authorship" where scientific papers do not disclose all of their authors.
- Academics could also face industry pressure to withhold negative research, and together this could "inflate views of the efficacy" of heavily promoted drugs.
The professors also said drug ads were counter to a medical journal's mission to provide objective data that enabled doctors to make judgments based on the best available evidence.
"Meanwhile doctors - and indeed journal editors - generally deny they are influenced (by the ads), yet clearly they are," they said.
"Drug companies value drug advertising in medical journals because it works ... generating at least US$2 - US$5 in revenues for every dollar spent."
Australian law restricts pharmaceutical companies to advertising their products only in medical journals, and about a dozen specialist and subscription-based magazines and newspapers that target the nation's health professionals.
Peak pharmaceutical body Medicines Australia (MA) said the professors' stated concerns were a "gross misrepresentation" of the industry's interaction with doctors.
"The fact is the industry has a strict code of conduct that requires companies to meet a high ethical standard," said MA chief executive Dr Brendan Shaw.
"Advertising in medical journals must be accurate, balanced and fully supported by government-approved product information.
"It is a legitimate means of keeping doctors abreast of the choice of new medicines that are available to them."
He said there was a global policy requiring drug companies to publish the results of clinical trials whether they had a positive or negative outcome, and all contributing researchers should be named.
Emergency Medicine Australasia is the journal of the Australasian College for Emergency Medicine.
Are older adults not properly represented in clinical trials? That's the conclusion of a study published this week in the Journal of General Internal Medicine.
Led by researchers from the Robert Wood Johnson Foundation, the team surveyed 109 clinical trials, finding that 20.2% of them excluded patients above a specified age, and 45.6% of the rest excluded people with conditions that could relate to the elderly (for example, a physical disability or other functional limitation).
This is an issue, the authors point out, because as the population ages, medical professionals will need guidance on what to prescribe and how to treat the elderly. But many of these studies seem in one way or another to be avoiding the issue altogether.
"Unfortunately, funding remains inadequate to sufficiently expand geriatrics research," the authors wrote, pointing to a 2004 journal review that found only 5% of studies focused on older adults.
Perhaps age and age-related issues are seen as factors that would confound an experiment's results. But, the study authors point out, those very factors are what need to be tested, because a young person's reaction to a drug may be very different – even dangerously different – from an older person's response.
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Avastin may be linked to fatal side effects, study says
By Mary Forgione, Tribune Health
Avastin, a popular cancer drug that slows the growth of some types of tumors, may also be linked to an increased risk of death, new research suggests.
A study published Tuesday in the Journal of the American Medical Assn. reviewed randomized controlled clinical trials from 1966 to 2010 with a total of 10,217 patients.
FOR THE RECORD: An earlier version of this post said the FDA withdrew approval of Avastin for breast cancer patients in December. In fact, the FDA moved to begin the process of withdrawing approval. Genentech has requested a hearing appealing this proposed withdrawal, a spokeswoman for the company said in an e-mail.
The rate of death, or "fatal adverse event" in researcher-speak, hit 2.5% for patients who took Avastin, known generically as bevacizumab, and a chemotherapy drug. That compared to 1.5% for those who took chemotherapy drugs alone. The most common causes of death were hemorrhage, neutropenia and gastorintestinal tract perforation. Here's the study abstract.
And by definition, "fatal adverse event" means the death was probably caused by a drug.
Avastin made news in December when the Food and Drug Administration moved to begin the process of withdrawing approval of Avastin as a treatment for breast cancer because the federal agency found no evidence that it extended the lives of women who had the disease. Drug maker Genentech requested a hearing appealing this proposed withdrawal. In that action, the drug was still approved for kidney, brain and lung cancers.
The researchers write in conclusion: "It is important for physicians and patients to recognize the risks as well as the benefits associated with bevacizumab treatment and to monitor closely to identify and treat serious adverse effects."
It's likely we'll be hearing more about this apparent connection in the months and years to come.
Most industries globalise to reduce costs: Cost is not, however, the primary driver for the globalisation of clinical research: Low site fees currently are offset by high communication and logistics costs. The primary attraction is generally subject availability. As a side benefit, data quality is better in many developing countries than in developed countries. The multiplicity of legal and regulatory regimes offsets these advantages, and can be serious problems in multinational trials. Clinical trial agreements are a small area of the legal and regulatory impact that will grow in importance as globalisation of the industry continues. In the United States, it takes clinical trial sponsors an average of 35 days to negotiate clinical trial agreements (CTAs) with community-based sites and site management organisations, and 96 days with academic centers.1 Investigative sites have ranked ÔLegal ReviewÕ and ÔContracts & BudgetsÕ higher than ÔSubject Recruitment Õ as a source of delay for clinical trials.2 New drugs can generate revenue of over USD1 million per day, so the cost of these delays adds up quickly. In addition, most new drugs enjoy patent exclusivity for only a few years at best, so time is of the essence.
In the United States, some of the delays occur when the sponsor is in one state and the site is in another. The difficulties are
magnified when the sponsor or site is outside the United States. It is magnified further when sites are in multiple countries.
It is magnified further when sites and sponsors on multiple trials are in multiple countries. It is magnified still further when
sites and sponsors are in multiple states and provinces within multiple countries. With the steady globalisation of clinical
research, these difficulties will become ever more burdensome.
Abstract: As clinical research increasingly becomes a global enterprise, investigators and sponsors must deal with multiple legal jurisdictions, with differing laws, regulations and other rules. A mutual understanding of the legal environment will streamline the clinical trial agreement negotiation process and avoid contracts that are legally unenforceable. A sampling of laws and other rules that impact clinical trial agreements is provided. The objective of this paper is to elicit contributions to a comprehensive and detailed compilation of rules that impact clinical study agreements.
The Legal Environment
As clinical research increasingly becomes a global enterprise, investigators and sponsors must deal with multiple legal jurisdictions, with differing laws, regulations and other rules. (The term "law," as used in this paper, includes both laws and regulations.) These rules establish expectations based on each party's locale. Public and non-profit entities also have various legal constraints. These rules limit the flexibility of investigators (i.e., research sites) when negotiating clinical trial agreements (CTAs). The objective of this paper is to elicit contributions to a comprehensive and detailed compilation of rules that impact clinical study agreements.
Because the rules may be numerous, obscure or subject to change and differing interpretations, it is often difficult even for contract specialists in the affected organizations to understand their application in specific circumstances and to intricate language drafted by sponsors. A mutual understanding of these regional and institutional differences by both sponsors and investigators will streamline the clinical trial agreement negotiation process.
Investigators are subject to rules on multiple
levels:
International
Multinational
National
State or Province
Ethics Committee
Institutional
Societal
International.
Various international bodies that define rules for clinical research such as the Nuremberg Code, Declaration of Helinski, and the International Conference on Harmonization ICH E6 Guideline for Good Clinical Practice. However, they do not enforce their rules; they leave that to governments. (There may, someday, be an exception to this generalization: The World Trade Organization theoretically could adjudicate accusations of unfair clinical research trade practices.) In addition, some industry associations publish ethical codes that require member compliance with international rules.
Multinational
. Multinational laws may apply. The European Union (EU) and Mercosur (Uruguay, Paraguay, Argentina and Brazil) have published extensive laws for their member states. Member states may or may not be required to enforce these laws as their own. Adoption of the EU Clinical Trials
Directive by member states is required, and an arduous process of "approximation" is now in progress. Of the Mercosur members, only Uruguay legally enforces Mercosur laws as its own.
National.
Nations in the developed world, and many in the developing world, have laws that govern the conduct of clinical research within their borders, and sometimes outside their borders. These laws are generally variations on a theme, although the variations can be quite significant, and rules that some countries consider important may be absent in other countries. In practice, levels of reporting, auditing and enforcement vary widely, with none at all apparent in some countries.
State and Province.
States and provinces may have their own laws that specifically or incidentally govern clinical research. This generality applies to every state in the United States, but with different specifics. The author is unaware of any county, city or parish laws specific to clinical research, although they may exist, perhaps in countries without states or provinces.
Ethics Committees
. Ethics committees may have rules that do not have legal force but, for practical purposes, are strictly required. Ethics committees may review CTAs as part of their normal review process; anything that potentially impinges on subject welfare (or anything else they consider within their jurisdiction) may receive their attention.
Institutional.
Institutional laws place requirements on specific types of entities such as federal, state, non-profit, or those that receive funding from those sources. Non-negotiable rules of the entity that are not legal requirements are not addressed in this paper. Such rules may originate from the entity's idiosyncratic interpretation of the laws, which have been known to be ambiguous.
Societal
. The customs of a society may prohibit contract terms that are otherwise legal. Concepts of personal privacy, for example, may be problematic in societies where the individual is subordinate to the extended family.
A study may be subject to conflicting laws, even if the sponsor and investigator are in the same legal jurisdictions. These conflicts are normally resolved by priority of law, e.g., national laws override state laws, but it may not always be straightforward to untangle (or remember) overlapping conditional requirements, authorizations and prohibitions. For example, if HIPAA requires a disclosure and a state law prohibits it, which prevails? Some laws may apply to one party to an agreement, but not to the other party, e.g., if they are in different jurisdictions or are different types of entities. The parties to the agreement may be unaware of the conflicts of law, unaware of a law at all, or may interpret differently the laws or to whom they apply.
When the sponsor and investigator have knowledge of the entire legal environment, time need not be wasted attempting to negotiate terms that are clearly illegal. Negotiation of the law's interpretation and implementation will provide adequate stimulation for the parties. Of course, there may be circumstances when the conflict between laws, regulations, and legally or self-imposed institutional restrictions make an agreement impossible,
