Sponsored by Sens. Sherrod Brown (D-Ohio), Sam Brownback (R-Kan.) and Al Franken (D-Minn.), the Creating Hope Act aims to solve a nagging problem inherent to the market-driven world of pharmaceutical manufacturing: how to encourage the creation of expensive-to-develop drugs that few patients need?

The lawmakers hope to do so by offering expedited FDA approval of potentially popular drugs to pharmaceutical companies that develop treatments for rare pediatric diseases. The idea is that the financial incentive associated with bringing “blockbuster” drugs to the market sooner will encourage companies to work harder researching the lesser needed treatments.

The proposal expands on a 2007 law that offers “priority review vouchers” to companies that develop new drugs for neglected tropical diseases. Drugs yielding vouchers, under the bill, must meet the definition of “rare” established by the Orphan Drug Act, and must not have previous approval from the FDA.

The bill would also prohibit companies from getting vouchers under the 2007 law for drugs already on the market abroad. Closing that loophole would force the companies to create new treatments, rather than simply bringing old ones to market in the U.S.

The National Institutes of Health estimates that there are more than 6,000 diseases qualifying as rare under the Orphan Drug Act, a vast majority of which get little or no drug company research money because the return on investment would be so small.

“We are falling woefully and inadequately short in our efforts to cure and treat rare and neglected pediatric diseases and conditions,” Brown said in a statement announcing the bill. 

Kids’ healthcare advocates agree. 

“This legislation aligns government and private sector interests and will be a major step forward in addressing the unmet needs of children with devastating illnesses, including life-threatening cancer,” said Nancy Goodman, executive director of Kids v Cancer

The project, named Human Heredity and Health in Africa or “H3Africa,” will use genetic techniques developed in the West to explore the roots of human life among populations that carry the world’s oldest and most diverse sets of genes.

Founders of the plan say that 10 years after the first full human genome was mapped, what scientists can learn about genetic variation and disease in Africa will have global relevance.

“Africa is the cradle of humanity, so things that we learn in Africa will undoubtedly have broad implications for peoples in all other parts of the planet,” said Francis Collins, director of the U.S. National Institutes of Health (NIH).

But the idea is also to free Africa from what some describe as “scientific colonialism,” and to try to halt a brain drain of researchers who have tended to leave the continent to study the ups and downs of its health from afar.

Bongani Mayosi, head of the department of medicine at the University of Cape Town, said the project represents “a very, very important shift in the way science is done in Africa.”

“Up until now, we have been operating almost in a colonial mode of doing science, where people from outside Africa have been coming to collect samples, and then processing them and publishing their papers outside Africa,” Mayosi said at a briefing in London to explain the project.

“What is different about this initiative is that it seeks to do science in Africa, by Africans and for Africans.”

HUGE NEED, BUT LITTLE CAPACITY

With $25 million from the NIH and $12 million from the London-based global charity the Wellcome Trust, H3Africa plans to build expertise in countries where it is much needed but sorely lacking, so that African scientists can in future conduct large, robust scientific studies on their own people.

Researchers will help set up ‘biobanks’ to collect DNA and medical information from hundreds of thousands of African people so that scientists can study links between genes and disease.

They also hope to set up or build on local research centers and use genome-wide scanning and sequencing technologies to find genetic change that may contribute to specific illnesses.

Some studies will focus on the role genes play in Africa’s biggest killer diseases — malaria, tuberculosis and HIV/AIDS — while others will look at conditions like high blood pressure, heart disease and stroke, all of which are becoming widespread in African populations.

Despite the huge burden of infectious disease that it carries, Africa lags the rest of the world in health research: a report from Thomson Reuters in April found its contribution to the global body of scientific research is very small and does little to benefit its own populations.

It said Africa suffers from a “hemorrhage of talent,” with many of its best brains leaving to study abroad.

LARGELY IGNORED, UNTIL NOW

Speaking in a week when scientists are marking the 10th anniversary of the publication of the first draft of the human genome, Charles Rotimi, president of the African Society of Human Genetics, said his continent had been largely ignored by the genetic revolution.

In the U.S., Europe and Asia, ever faster gene sequencing tools have enabled scientists to begin to untangle the genetic roots of many major diseases and explore their links and interactions with environment and lifestyle factors like diet.

Genome-wide association studies, which scan gene maps, are an important tool in this work. But of the hundreds of such studies conducted in the past decade, only one, on malaria, was based on African populations — a state of affairs that Rotimi described as “really tragic.”

“It is clear that so far we have not equally applied the tools of genomics,” he said.

“Africa is the trunk and root of human evolutionary history, so what we get from there is going to be equally important to other parts of the world.”

(Editing by Mark Trevelyan)

Members of the tiny, isolated tribe had given DNA samples to university researchers starting in 1990, in the hope that they might provide genetic clues to the tribe’s devastating rate of diabetes. But they learned that their blood samples had been used to study many other things, including mental illness and theories of the tribe’s geographical origins that contradict their traditional stories.

The geneticist responsible for the research has said that she had obtained permission for wider-ranging genetic studies.

Acknowledging a desire to “remedy the wrong that was done,” the university’s Board of Regents on Tuesday agreed to pay $700,000 to 41 of the tribe’s members, return the blood samples and provide other forms of assistance to the impoverished Havasupai — a settlement that legal experts said was significant because it implied that the rights of research subjects can be violated when they are not fully informed about how their DNA might be used.

The case raised the question of whether scientists had taken advantage of a vulnerable population, and it created an image problem for a university eager to cast itself as a center for American Indian studies.

But genetics experts and civil rights advocates say it may also fuel a growing debate over researchers’ responsibility to communicate the range of personal information that can be gleaned from DNA at a time when it is being collected on an ever-greater scale for research and routine medical care.

“I’m not against scientific research,” said Carletta Tilousi, 39, a member of the Havasupai tribal council. “I just want it to be done right. They used our blood for all these studies, people got degrees and grants, and they never asked our permission.”

Researchers and institutions that receive federal funds are required to receive “informed consent” from subjects, ensuring that they understand the risks and benefits before they participate. But such protections were designed primarily for research that carried physical risks, like experimental drug trials or surgery. When it comes to mining DNA, the rules — and the risks — are murkier.

Is it necessary, for instance, to ask someone who has donated DNA for research on heart disease if that DNA can be used for Alzheimer’s or addiction research?

Many scientists say no, arguing that the potential benefit from unencumbered biomedical research trumps the value of individual control.

“Everyone wants to be open and transparent,” said Dr. David Karp, an associate professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas, who has studied informed consent for DNA research. “The question is, how far do you have to go? Do you have to create some massive database of people’s wishes for their DNA specimens?”

The Havasupai settlement appears to be the first payment to individuals who said their DNA was misused, several legal experts said, and came after the university spent $1.7 million fighting lawsuits by tribe members.

Even as the Havasupai prepared to reclaim the 151 remaining blood samples from a university freezer this week, Therese Markow, the geneticist, defended her actions as ethical. Those judging her otherwise, she suggested, failed to understand the fundamental nature of genetic research, where progress often occurs from studies that do not appear to bear directly on a particular disease.

“I was doing good science,” Dr. Markow, now a professor at the University of California, San Diego, said in a telephone interview.

Edmond Tilousi, 56, a cousin of Carletta Tilousi and the tribe’s vice chairman, can climb the eight miles from his village on the floor of the western Grand Canyon to the rim in three hours, when he is in a rush. Horse or helicopter are the other ways out, and Mr. Tilousi is increasingly rare among the tribe’s members in his ability to make the hike. Beginning in the 1960s, an extraordinarily high incidence of Type 2 diabetes led to amputations, even among the younger members, and forced many to leave the canyon for dialysis.

In late 1989, Mr. Tilousi’s uncle Rex Tilousi approached John Martin, an Arizona State University anthropologist who had gained the tribe’s trust, to ask if he knew a doctor who could help. “I asked him, ‘How can we prevent this from spreading?’ ” the elder Mr. Tilousi recalled.

Professor Martin approached Dr. Markow. A link had recently been reported between a genetic variant and the high rate of diabetes among Pima Indians. If a similar link was found among the Havasupai, it might point to an important risk factor.

The two professors received money from the university to study diabetes in the tribe. Dr. Markow was interested in schizophrenia research as well, and in the summer of 1990, with a grant from the National Alliance for Research on Schizophrenia and Depression, she and her graduate students began collecting blood samples in Supai. Women here remember being happy to see her in those days, an athletic figure who talked to them about how to be more healthy. Working out of the health clinic in the center of the village, Dr. Markow recruited tribe members to ask others to give blood.

“I went and told people, if they have their blood taken, it would help them,” said Floranda Uqualla, 46, whose parents and grandparents suffered from diabetes. “And we might get a cure so that our people won’t have to leave our canyon.” Roughly 100 tribe members who gave blood from 1990 to 1994 signed a broad consent that said the research was to “study the causes of behavioral/medical disorders.”

The consent form was purposely simple, Dr. Markow said, given that English was a second language for many Havasupai, and few of the tribe’s 650 members had graduated from high school. They were always given the opportunity to ask questions, she said, and students were also instructed to explain the project and get written and verbal consent from donors.

Dr. Markow examined several genes that were thought to have medical relevance, including for schizophrenia, metabolic disorders and alcoholism, she said, but found little to pursue. The Havasupai did not, it turned out, share the gene variant linked to diabetes in the Pima.

But a few years later, a graduate student using new technology came up with a way to discern variations in the Havasupai DNA, which was stored in a university freezer, and he wrote a dissertation based on his research.

Carletta Tilousi, one of the few Havasupai to attend college, stopped by Professor Martin’s office one day in 2003, and he invited her to the student’s doctoral presentation.

Ms. Tilousi understood little of the technical aspect, but what she heard bore no resemblance to the diabetes research she had pictured when she had given her own blood sample years earlier.

“Did you have permission,” she asked during the question period, “to use Havasupai blood for your research?”

The presentation was halted. Dr. Markow and the other members of the doctoral committee asked the student to redact that chapter from his dissertation.

But months later, tribe members learned more about the research when a university investigation discovered two dozen published articles based on the blood samples that Dr. Markow had collected. One reported a high degree of inbreeding, a measure that can correspond with a higher susceptibility to disease.

Ms. Tilousi found that offensive. “We say if you do that, a close relative of yours will die,” she said.

Another article, suggesting that the tribe’s ancestors had crossed the frozen Bering Sea to arrive in North America, flew in the face of the tribe’s traditional stories that it had originated in the canyon and was assigned to be its guardian.

Listening to the investigators, Ms. Tilousi felt a surge of anger, she recalled. But in Supai, the initial reaction was more of hurt. Though some Havasupai knew already that their ancestors most likely came from Asia, “when people tell us, ‘No, this is not where you are from,’ and your own blood says so — it is confusing to us,” Rex Tilousi said. “It hurts the elders who have been telling these stories to our grandchildren.”

Others questioned whether they could have unwittingly contributed to research that could threaten the tribe’s rights to its land. “Our coming from the canyon, that is the basis of our sovereign rights,” said Edmond Tilousi, the tribe’s vice chairman.

Many members are still suffering from diabetes and say they were never told if researchers had learned anything that could help them. The classes on nutrition that Dr. Markow had sponsored with grant money have since petered out.

Ms. Uqualla, who had recruited blood donors, said she felt shamed by the news that it had been used for research that could potentially damage the tribe. “I let my people down,” she said.

The money from the settlement will be divided among the 41 tribe members. Ms. Uqualla, for one, hopes to buy a horse trailer.

But Stephen F. Hanlon, a lawyer who has represented the tribe members without charge, said the resources the university agreed to provide, including scholarships and assistance in obtaining federal funds for projects like a new health clinic, had the potential to transform the tribal village at the bottom of one of the world’s most famous natural wonders.

On Tuesday, Ms. Tilousi cried as a university official unlocked the freezer in the nondescript storage room in the Tempe campus where the blood samples had long been stored. Wearing protective glasses, gloves and a lab coat, she and a delegation of tribal members sang in Havasupai as they saw the blood that had been taken from them and from their relatives, now dead.

On the box inside the freezer was scrawled the name, “Markow.”

[Newsweek] The unsettling story of Henrietta Lacks begins with an everyday occurrence: a trip to the doctor’s office. The 30-year-old African-American’s 1951 diagnosis of cervical cancer would change her life, and the damaged cells taken from her body without permission would alter the course of medical history. At a time when health-care reform is a key concern for the White House and millions of Americans, Lacks’s story is a potent reminder of the injustices that were perpetrated by the health-care industry on the poor and uneducated not long ago. 

Raised by her grandfather on a tobacco farm in Virginia, Henrietta Lacks was the granddaughter of slaves. She gave birth to her first child at 14 and later married the father of the baby, who happened to be her first cousin—not uncommon at the time. Shortly after Henrietta turned 30, she felt a knot in her lower stomach that she knew meant something was wrong. But with a husband and a house full of kids to take care of, Lacks could ill afford to worry for long; her family also had little money for a doctor’s visit, and at the time, many hospitals offered African-American patients substandard treatment.

Months later, after the birth of her fifth child, the knot was still there, so Lacks finally asked her husband to drive her to Johns Hopkins hospital, the only medical facility nearby that saw “colored people” for free. There, the doctors diagnosed Lacks with stage I epidermoid carcinoma of the cervix, which would require her to have radiation treatments a few times a month. During her first two-night stay in the hospital, doctors sliced several pieces of tissue from her cancerous tumor and placed them in a dish in the hopes of growing and studying them. Neither Lacks nor her family gave permission for her cells to be taken.

George Gey, then the head of tissue-culture research at Johns Hopkins, had been trying to grow malignant cells outside the body for nearly three decades, hoping to determine what caused cancer and ultimately how to cure it. Most cells died quickly in the lab, and the few that did survive failed to grow. But Gey was determined to grow the first immortal human cells—a continuously dividing line of cells that all descended from one original sample, cells that would replenish themselves and never die. Lacks’s damaged cells turned out to be the answer to his prayers. Her cancer cells grew unlike any the doctor had seen before, doubling in number every 24 hours. Excited by the findings, Gey began to alert his peers that he was sure he’d found the first immortal cells. And then he began sending Lacks’s cell culture, named “HeLa” to avoid using Lacks’s name, to any scientist who was interested in using it for cancer research. He sent the cells to Texas, India, New York, Amsterdam—anywhere researchers might find them useful.

But neither Gey’s excitement nor research helped Henrietta Lacks. Six months after being diagnosed with cancer, she was dead. She was taken back to her hometown of Clover, Va., and buried in a plain wooden box in an unmarked grave. It would be years before her family would realize that her living cells, which survive to this day, had birthed a multimillion-dollar industry selling human biological materials and had contributed to the study of cancer, had helped in developing the polio vaccine, and had allowed scientists to determine the effects of the atom bomb. They also led to important advances in in vitro fertilization, cloning, and gene mapping. HeLa has been bought and sold by millions of researchers in the decades since, likely earning hundreds of millions of dollars for the medical industry. Johns Hopkins maintains it never benefited financially from the sale of the cells.

Neither did the Lacks family. Most of Henrietta’s children died with only limited knowledge of what had actually been done with their mother’s cells, and today few of her grandchildren or other relatives can even afford to have insurance of their own, according to a new book by Rebecca Skloot, The Immortal Life of Henrietta Lacks.

Some 60 years after doctors committed what today would be an unconscionable violation of medical ethics, there’s still only limited information on how often the practice of taking samples without consent was done to patients of poor backgrounds and limited education. But Henrietta Lacks certainly wasn’t the only African-American mistreated by the American medical establishment. Books such as Harriet Washington’s Medical Apartheid  have documented many cases of blatant misuse of medical practices on unknowing and unsuspecting black patients in the name of furthering science and discovering cures.

It might seem as though this kind of disturbing and unethical practice would be limited to another, less-enlightened time, such as the ’30s and ’40s, which is when the granddaddy of all medical injustices, the infamous Tuskegee syphilis study, began. But some evidence uncovered by Washington’s book suggests that black orphan children were used as test subjects as recently as the ’80s in New York: tests to determine the effectiveness of some AIDS treatments were given to the children without adult consent.

In a just world, Henrietta Lacks’s descendants would have health care given to them free for the rest of their lives, like the victims of the Tuskegee study. But instead her case stands as yet another example of the medical establishment’s mistreatment of poor and minority Americans, the aftereffects of which linger to this day.

Find this article at http://www.newsweek.com/id/233671

So how might the new Bioethics Commission operate? Fortunately, we have some idea because its new chair, Amy Gutmann, outlined her views on how bioethics commissions should be run in an article, “Deliberating About Bioethics” in the Hastings Center Report back in 1997. Most of the 13 member panel hasn’t been appointed yet, but Gutmann is well-known for her scholarly work on deliberative democracy, which she defines “as a form of government in which free and equal citizens (and their representatives), justify decisions in process in which they give one another reasons that are mutually acceptable and generally accessible, with the aim of reaching conclusions that are binding in the present on all citizens but open to challenge in the future.”  

In her article (co-authored with political philosopher Dennis Thompson), Gutmann distinguishes deliberative democracy from proceduralism and constitutionalism. In proceduralism, once basic rules of the game have been hammered out, moral disagreements are resolved through political bargaining or by moving them out of politics into the private sphere. Constitutionalism tries to avoid moral disagreement by creating a sphere of protected rights that are shielded from ordinary politics.

In Gutmann’s conception, deliberative democracy is an ongoing, transparent, society-wide discussion of fundamental values. Deliberative democracy is supposed to serve four important social purposes by addressing four ineradicable sources of moral disagreement. She identifies the four sources of moral disagreement as arising from (1) the scarcity of resources; (2) limited generosity; (3) incompatible moral values; and (4) the incomplete understanding that characterizes almost all moral conflicts. The four social purposes that deliberative democracy is supposed to address are (1) the promotion of the legitimacy of collective decisions; (2) the encouragement of public-spirited perspectives on public issues; (3) the promotion of mutually respectful decisionmaking: and (4) the correction of inevitable collective action mistakes.

Gutmann offers some concrete examples of how she thinks deliberative democracy might work. Let’s take scarcity. She notes that far more people need organs than there are organs available for transplant. How do we decide who gets them? She suggests that “deliberation can help those who do not get what they want or even what they need come to accept the legitimacy of a collective decision.” As it happens in 1984, the U.S. Congress passed the National Organ Transplant Act which made organ sales illegal. Since then donated organs have been allocated by the United Network of Organ Sharing based on various medical criteria depending on the specific organ. Although some voices (including mine) have been arguing for compensating donors as a way to increase supplies, it is true that there has not been much public pressure to change the current system. However, one hopes that the deliberative process will someday correct this particular collective action mistake. On the other hand, we can expect a lot more bioethical deliberation if the U.S. adopts a more centralized and increasingly government-controlled health care system. In another article Gutmann favorably cites the United Kingdom’s National Institute for Health and Clinical Excellence (NICE) as an example of how democratic deliberation works in making decisions about what medicines and treatments will be made available to patients in that country’s National Health Service.

The next issue is limited generosity. Gutmann acknowledges, “Deliberation will not turn self-centered individualists suddenly into public-spirited citizens.” She argues that members of bioethics commissions should not be chosen just to represent specific interest groups; that would simply result in old-fashioned interest group bargaining. Gutmann asserts that the number and diversity of voices on a bioethics commission is not necessarily the most important factor in making deliberation work. Instead bioethics commissioners “must come to the forum open to changing their own minds as well as to changing the minds of their opponents.” Bioethics commissioners will be more amenable to changing their minds on such limited questions as when is it appropriate to include minors in medical research rather than issues like abortion and assisted suicide.

Which brings us to Gutmann’s third source of moral disagreement—incompatible moral values. Here she recommends that bioethics commissions isolate irresolvable conflicts and focus on areas where agreement might be possible, e.g., minors in medical research. As an example of how deliberation can “economize” on moral disagreements, she cites the fetal tissue research guidelines issued in 1975 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The commission held extensive public hearings and consulted legal experts, scientists, ethicists, and philosophers before promulgating its regulations allowing fetal tissue research. Those regulations included the requirement that researchers seeking to harvest tissue not have any part in the timing, method, or procedures used to terminate a pregnancy; no inducements to terminate a pregnancy could be made; both parents must consent; and artificial life support for nonviable fetuses was prohibited. But this deliberative outcome did not hold. In 1988, arguing that the fetal tissue research could encourage abortion, the Reagan administration imposed and later the Bush administration maintained a federal funding moratorium on fetal tissue transplant research. The moratorium was lifted by President Bill Clinton in 1993.

The history of the bioethical deliberation over fetal tissue research might be seen as an example of Gutmann’s fourth purpose of deliberation, the correction of mistakes. In the fetal tissue case, later experts did argue that political appointees under Reagan and Bush were mistaken in their belief that federal funding of fetal tissue research would lead to more abortions. On the other hand, given that a National Institutes of Health advisory panel in 1988 recommended after considerable deliberation that the moratorium be lifted, one suspects that the encourages-more-abortions argument for banning federal funding was a stand-in for a deeper philosophical repugnance toward all abortion. In any case, the fetal tissue case and President Obama’s decision last year to overturn President George W. Bush’s limits on federal funding of human embryonic stem cell research shows that bioethics decisions in the U.S. are already provisional and open to challenge.

I generally agree with the proceduralists and constitutionalists. In order to keep the social peace and allow various visions of the human to flourish along side of one another, certain big questions about birth, death, and the meaning of life must be isolated from politics, making them private concerns to be protected from majoritarian tyranny. But for her part, Gutmann concludes hopefully, “By making democracy more deliberative, we stand a better chance of resolving some of our moral disagreements, and living with those that will inevitably persist, on terms that all can accept.” Given the current stark polarization that characterizes our national political institutions (if not public opinion), Gutmann, as head of the new Presidential Commission for the Study of Bioethical Issues, has her work cut out. Good luck to her.

Ronald Bailey is Reason’s science correspondent. His book Liberation Biology: The Scientific and Moral Case for the Biotech Revolution is available from Prometheus Books.

But it wasn’t always so. In the 1970s and ’80s, companies raced to get out of the vaccine business because of the high manufacturing costs, the high chance of failure, and the threat of lawsuits if patients suffered adverse side effects. But then the federal government passed the Childhood Vaccine Injury Act in 1986, which created a pool of money for patients who experienced adverse effects and shielded companies from lawsuits. Advances in technology have driven manufacturing costs down. “And companies have seen that if a vaccine is on a government program, one doesn’t have to spend money to promote it,” Bogorad said.

The market is dominated by a handful of global players, including U.K.-based GlaxoSmithKline, France’s Sanofi Pasteur, Wyeth, which has now merged with New York-based Pfizer Inc., Switzerland’s Novartis AG and Merck and Co. Inc. of New Jersey. This makes it difficult for smaller players to break in.

But this cadre of vaccine giants relies on an ecosystem of smaller companies to fill its pipeline with preventive therapies. And that pipeline could grow now that the Bill and Melinda Gates Foundation has pledged $10 billion to fund vaccine research.

Bogorad said New England provides a ripe landscape for mergers and acquisitions. Case in point is Acambis. The Cambridge company, which has potential vaccines targeting herpes, influenza, dengue fever and West Nile virus, was bought last year by Sanofi Pasteur for $548 million.

One local vaccine company that has been growing independently is Xcellerex Inc. The Marlborough company was founded in 2004, has 120 employees and is cash-flow positive. Xcellerex provides outsourced manufacturing services and equipment, using a disposable system that eliminates the need for steam sterilization of bioreactors used to make vaccines and other biologics. CEO Joe Zakrzewski said the method cuts down on the chances for contamination of vaccines or other products.

Zakrzewski claims that the process can speed up getting a product to market and that clinical trials using the technology can cost one fourth that of clinical trials using traditional biologics manufacturing methods. Xcellerex’s clients include Cambridge-based Acceleron Pharma Inc., whose lead product is a biotherapeutic designed to increase red blood cell and bone formation and is in Phase 2 clinical trials.

Xcellerex also develops its own therapeutics and has launched a Phase 1 clinical trial for a potential vaccine targeting yellow fever. Bogorad and other analysts say that the travel vaccine market is a small segment of the market, but Zakzrewski said there is still money to be made. “Right now, it’s a $100 million market. But 90 percent of the people who need the yellow-fever vaccine don’t get it, because the risks of the current vaccine are too high. So we love it when people say the market is small. We think it could be $1 billion.”

Xcellerex officials say that their vaccine candidate is fundamentally different from current vaccines because it uses a dead virus rather than a live one. Xcellerex has partnered with other companies on manufacturing four or five vaccines in the past. In October, the company announced it would partner with Rockville, Md.-based Novavax to ramp up large-scale manufacturing for its H1N1 vaccine.

The perils of this high-stakes business can be seen across New England. Protein Sciences Corp., in Meridien, Conn., received a blow when the U.S. Food and Drug Administration rejected its potential flu vaccine this fall, because the agency wanted more safety data. Analysts and public health officials had been watching the progress of the potential vaccine because it would represent a novel breakthrough. While current vaccines for influenza are made from fertilized chicken eggs, which is slow and expensive, the Protein Sciences target aims to produce flu cells in caterpillars.

Antigenics Inc., in Lexington, also faced a regulatory setback this fall when European authorities rejected its potential cancer vaccine, called Oncophage. Cancer vaccines have been an elusive target so far, but officials in area companies say that is going to change.

“We (in the industry) are starting to learn from our mistakes. It’s not a matter of if, but when,” said Eric Von Hofe, CEO of Antigen Express Inc. The Worcester-based vaccine developer is working on targets using synthetic peptides, which are protein fragments, that Von Hofe says can be manufactured more quickly than the traditional chicken-egg method. Von Hofe is reporting positive interim results for a Phase 2 vaccine study targeting breast cancer. But so far, no synthetic vaccines have been approved by the FDA. 

According to the report, when a company-funded study’s primary finding wasn’t favorable, that result was usually buried and something else positive was highlighted, without disclosing the switch.

The documents used in the review were obtained by lawyers suing Pfizer for refunds on prescriptions paid for by insurers and consumers. The lawyers, who are seeking class action status for the cases, claim Pfizer concealed evidence the epilepsy drug Neurontin didn’t work for those unapproved uses, including nerve pain, migraines and bipolar disorder.

One of the report’s authors is an expert witness for the plaintiffs; another has received fees from the lawyers.

Pfizer disputes the report’s conclusions, saying the company never “attempted to mislead the medical community about the effectiveness” of the drug for certain uses. “We believe the review suffers from significant bias, insufficient data, poor methodology, and cannot pass the threshold of credible scientific research,” Pfizer said in a statement.

The report, by researchers at the University of California at San Francisco and the Johns Hopkins Bloomberg School of Public Health, comes two months after Pfizer was fined a record $2.3 billion — including an unprecedented $1.2 billion criminal fine — for illegally marketing other blockbuster drugs.

The report appears in Thursday’s New England Journal of Medicine.

Dr. Sidney Wolfe, head of health research at consumer group Public Citizen, called it the first comprehensive look “at studies in which a company and people working for it so maliciously manipulated the data to make a drug look more effective than it actually was.”

“In every instance, the published article made the drug look better than it would have,” said Wolfe, a member of the Food and Drug Administration’s drug safety advisory committee. “This results in harm.”

Neurontin was approved by the FDA a decade ago for treating seizures and later for pain caused by shingles — but not for other conditions. Its potential side effects include suicidal tendencies and depression.

While doctors can prescribe drugs for unapproved, or off-label uses, drug companies are legally barred from promoting their products for such uses. Drugmakers often test drugs for additional conditions and publicize the results. But they don’t always seek approval for those new uses, particularly if the new findings aren’t convincing.

Experts believe most Neurontin sales were for off-label uses — the ones in the reviewed studies. Sales peaked at $2.7 billion in 2004, when Pfizer paid $430 million in government fines to settle allegations it improperly marketed the epilepsy drug for unapproved uses. By last year, Neurontin sales fell to $387 million due to cheaper generic versions sold as gabapentin.

For the new review, the researchers examined 20 patient studies funded by New York-based Pfizer and its Parke-Davis unit on use of Neurontin for preventing migraines or treating nerve pain or bipolar disorder. The studies were published in medical journals or presented at conferences, mostly over the last decade.

In eight of the 12 published studies, the main outcome listed in internal documents differs from the one later given in the published report. In half the cases, a new primary outcome was substituted and in others, the original main outcome was instead reported as a secondary measure or wasn’t disclosed at all.

The authors cited some limitations to their review, including not knowing who made the changes.

“We cannot be certain that selective reporting was a decision made by employees of Pfizer and Parke-Davis, since the authors of the published reports included nonemployees,” the researchers wrote.

Arthur Caplan, director of the University of Pennsylvania’s Center for Bioethics, called the report “one of the most ethically disturbing papers I’ve read in some time” and “an indication that people have been playing fast and loose with studies,” particularly industry ones.

Caplan said the FDA should have the power to audit industry drug studies. Wolfe said there should be bigger fines and jail terms for manipulating study data, plus tougher rules for studies being published in journals.

Medical journals in recent years have required that studies be listed on a federal Web site, www.clinicaltrials.gov, to be eligible for publication. That move was made partly to make it harder for industry to hide studies on products that don’t pan out and only publish those with good results. The study descriptions also list their primary and secondary outcomes.

Pfizer said it now has 1,245 company-sponsored studies listed on the Web site.

[San Diego Union Tribune] Scientists in San Diego and in other parts of California are working on numerous projects related to stem cell research, and some of that research is showing promise, at least in the early stages. At a time when the state’s finances are bordering on distress, this research gives at least some reassurance to voters that the $3 billion investment approved through Proposition 71 in 2004 may someday pay off.

Just last week, a team at the Scripps Research Institute in La Jolla led by assistant professor Kristin Baldwin reported that it had bred live mice from mouse skin cells. Many hope that this line of research will offer an alternative to the controversial use of embryonic stem cells, which requires the destruction of human embryos and which led President George W. Bush to place federal funding restrictions on that kind of research.

In June, in yet another line of stem cell research, scientists at the Salk Institute for Biological Studies announced that they had cured a cell taken from a patient with Fanconi anemia, a disease that can cause bone marrow failure. “We haven’t cured a human being, but we have cured a cell,” Salk professor Juan-Carlos Izpisua Belmonte told this newspaper at the time the research was published in the journal Nature.

Although stem cell research is being done in many nations from Singapore to Britain to Israel, in this country, San Diego has become a center for research thanks greatly to Proposition 71. The San Diego Consortium for Regenerative Medicine, which includes the University of California San Diego, Burnham Institute for Medical Research, Salk and Scripps Research have received tens of millions of dollars in grants to further their efforts in stem cell research. In a recent funding round, consortium institutes received six grants totaling more than $16 million. To continue their work, the Salk scientists conducting the research involving Fanconi anemia received a $6.6 million grant from the California Institute for Regenerative Medicine, established under Proposition 71.

The research at Scripps and other institutions involving the skin cells has drawn considerable attention because of the ethical issues that likely will arise. While both supporters and opponents have welcomed the news from the research, in which skin cells from adult mice were coaxed into the equivalent of embryonic stem cells, there is also an enhanced potential for human cloning, a dangerous and frightening prospect.

The guidelines issued after President Barack Obama rescinded the Bush administration funding restrictions will act to restrain some research that may push the limits, but those guidelines don’t affect researchers outside the United States.

It is important that the politicians and other government officials at the state, federal and international level continue to listen to and work with researchers to strike the proper balance between continued support for the promising lines of research and proper regulations, so that ethical and moral lines cannot be crossed.

[American Medical News] The board that administers New York’s stem cell research funding program recently approved using state money to pay women who donate fresh oocytes for an experimental technique called somatic cell nuclear transfer, also known as therapeutic cloning.

The policy makes New York the first American government body, state or federal, to use taxpayer dollars to do more than reimburse egg donors for direct expenses incurred in donating. Opponents of the move said it would encourage women to undertake a painful, sometimes risky procedure for speculative research.

The board, however, “felt it was a good thing to step forward and move in that direction and perhaps be viewed as a leader,” said David C. Hohn, MD, vice chair of the Empire State Stem Cell Board’s ethics and funding committees.

“We looked seriously at the fact that there are places where direct expenses are reimbursed, and the number of people who are coming forward as donors is extremely small,” said Dr. Hohn, executive director of health policy at the Roswell Park Cancer Institute in New York. “The clear lack of funding seemed to be presenting a barrier to donation for those kinds of activities.”

The board, responsible for handing out $600 million in research grants over 10 years, said the payments should not exceed compensation standards set by the American Society for Reproductive Medicine for women who donate eggs to help infertile couples conceive.

ASRM says $5,000 is OK, payments between $5,000 and $10,000 require specific justification, and anything more than $10,000 is inappropriate. The New York board requires an institutional review board to examine any proposed egg-donor payment policy, and all applications for stem cell grants are evaluated by scientists from outside the state. The national average payment to egg donors is $4,217, according to a 2007 survey published in Fertility and Sterility, the journal of the American Society for Reproductive Medicine.

The New York board said in its resolution that “there is no significant difference in the risks associated with oocyte donation solely for research purposes and oocyte donation for reproductive purposes.”

The biggest risk from egg donation is ovarian hyperstimulation syndrome, according to a 2007 National Academy of Sciences report. Symptoms include nausea and vomiting, bloating, hemoconcentration, breathing difficulties, hospitalization and kidney failure in rare cases. In 2005, the academy adopted ethical guidelines limiting egg-donor compensation to direct expenses, which usually fall far short of $5,000.

New National Institutes of Health rules that took effect July 7 bar spending federal dollars on somatic cell nuclear transfer. In SCNT, the donor egg is fused with the nucleus of a diseased cell to create a genetically identical blastocyst. Stem cell lines can be derived from the embryo and studied for clues about how the disease develops and how to treat it.

Researchers experimenting with SCNT in California and Massachusetts have complained that restrictions limiting egg-donor compensation are impeding their scientific endeavors.

Speculative research?

The New York stem cell board’s decision, announced in June, was not unanimous. One member of its ethics committee, the Rev. Thomas Berg, PhD, voted against the egg-donor payment policy.

The board “has unconscionably, and on behalf of the taxpayers, set in place a plan that will put women at risk and lets the state pay them off with lots of money,” said Berg, a senior fellow at the Westchester Institute for Ethics & the Human Person, in a statement. “Ovarian stimulation is a dangerous and sometimes fatal procedure. This plan is a gross exploitation of women for speculative research.”

Marcy Darnovsky, PhD, associate executive director of the Center for Genetics and Society in California, also objected to the New York compensation plan. She said there is a difference between paying women to donate eggs for in vitro fertilization and doing the same for stem cell research.

“In the case of providing eggs for someone else’s fertility treatments, we know at this point there’s a pretty reliable chance that a baby will result,” she said. “But in the case of somatic cell nuclear transfer, it’s completely speculative research, and more and more scientists have determined it’s not worth pursuing at this point.”

Several breakthroughs in the reprogramming of adult skin cells to behave like embryonic stem cells have led some scientists to put therapeutic cloning research on the back burner. But Dr. Hohn said the New York board wanted to encourage all promising avenues of research.

“Do we know what the value of this research is going to be? No,” Dr. Hohn said. “But there are theoretical reasons why it could be profoundly helpful for a variety of diseases on the radar screen. … The logic for the use of these cells is compelling, and we shouldn’t stand in the way.”

-Kevin O’Reilly

The data from the study suggest that embryonic stem cells and the reprogrammed cells, known as induced pluripotent stem (iPS) cells, have overlapping but still distinct gene expression signatures. The differing signatures were evident regardless of where the cell lines were generated, the methods by which they were derived or the species from which they were isolated, said Bill Lowry, a researcher with the Broad Stem Cell Research Center and a study author.

“We need to keep in mind that iPS cells are not perfectly similar to embryonic stem cells,” said Lowry, an assistant professor of molecular, cell and developmental biology. “We’re not sure what this means with regard to the biology of pluripotent stem cells. At this point our analyses comprise just an observation. It could be biologically irrelevant, or it could be manifested as an advantage or a disadvantage.”

The study appears in the July 2, 2009 issue of the journal Cell Stem Cell.

The iPS cells, like embryonic stem cells, have the potential to become all of the tissues in the body. However, iPS cells don’t require the destruction of an embryo.

The study was a collaboration between the labs of Lowry and UCLA researcher Kathrin Plath, who were among the first scientists and the first in California to reprogram human skin cells into iPS cells. The researchers performed microarray gene expression profiles on embryonic stem cells and iPS cells to measure the expression of thousands of genes at once, creating a global picture of cellular function.

Lowry and Plath noted that, when the molecular signatures were compared, it was clear that certain genes were expressed differently in embryonic stem cells than they were in iPS cells. They then compared their data to that stored on a National Institutes of Health data base, submitted by laboratories worldwide. They analyzed that data to see if the genetic profiling conducted in other labs validated their findings, and again they found overlapping but distinct differences in gene expression, Lowry said.

“This suggested to us that there could be something biologically relevant causing the distinct differences to arise in multiple labs in different experiments,” Lowry said. “That answered our first question: Would the same observation be made with cell lines created and maintained in other laboratories?”

Next, UCLA researchers wanted to confirm their findings in iPS cell lines created using the latest derivation methods. The cells from the UCLA labs were derived using an older method that used integrative viruses to insert four genes into the genome of the skin cells, including some genes known to cause cancer. They analyzed cell lines derived with newer methods that do not require integration of the reprogramming factors. Their analysis again showed different molecular signatures between iPS cells and their embryo-derived counterparts, and these signatures showed a significant degree of overlap with those generated with integrative methods.

To determine if this was a phenomenon limited to human embryonic stem cells, Lowry and Plath analyzed mouse embryonic stem cells and iPS lines derived from mouse skin cells and again validated their findings. They also analyzed iPS cell lines made from mouse blood cells with the same result

“We can’t explain this, but it appears something is different about iPS cells and embryonic stem cells,” Lowry said. “And the differences are there, no matter whose lab the cells come from, whether they’re human or mouse cells or the method used to derive the iPS cells. Perhaps most importantly, many of these differences are shared amongst lines made in various ways.”

Going forward, UCLA researchers will conduct more sophisticated analyses on the genes being expressed differently in the two cell types and try to understand what is causing that differential expression. They also plan to differentiate the iPS cells into various lineages to determine if the molecular signature is carried through to the mature cells. In their current study, Lowry and Plath did not look at differentiated cells, only the iPS and embryonic stem cells themselves.

Further study is crucial, said Mark Chin, a postdoctoral fellow and first author of the study.

“It will be important to further examine these cells lines in a careful and systematic manner, as has been done with other stem cell lines, if we are to understand the role they can play in clinical therapies and what effect the observed differences have on these cells,” he said.

The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 150 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA’s Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. To learn more about the center, visit our web site at http://www.stemcell.ucla.edu.