Neurologists asked her questions and issued commands as they pinpointed the exact spot in her brain for electrical stimulation. At one point, “I suddenly felt hopeful and optimistic about the future,” recalls Ms. Battiloro, who had battled severe depression for more than a decade. That’s when the doctors knew they had found Brodmann 25, an area deep in the cerebral cortex associated with negative mood. They secured the electrodes in place, then sedated Ms. Battiloro while they ran an extension wire under the skin, down the side of her head and into her chest, where they implanted a battery pack to supply her brain with a mild electrical current.

Within two months, Ms. Battiloro says, her depression had lifted considerably. Now, nearly four years later, it hasn’t returned. “My friends and family are amazed,” say Ms. Battiloro, 41, of Boynton Beach, Fla. “I’m a new and improved Lisa.”

Deep brain stimulation, sometimes called a pacemaker for the brain, has helped halt tremors in more than 100,000 patients with Parkinson’s disease and other movement disorders since 1997. Now, researchers are reporting encouraging results using the procedure for psychiatric conditions as well. Ms. Battiloro was one of 17 patients in a study published this month in the Archives of General Psychiatry. After two years of DBS, 92% reported significant relief from their major depression or bipolar disorder and more than half were in remission, with no manic side effects.

“We are seeing dramatic effects in the small numbers of subjects, and they are not just getting well, they are getting well without side effects and without relapsing,” says neurologist Helen Mayberg, who led the study at Emory University in Atlanta.

Other clinical trials are studying DBS as a treatment for epilepsy and obsessive-compulsive disorder; some researchers are experimenting with it for Alzheimer’s disease, tinnitus, addiction and Tourette syndrome, a condition that causes sudden movements and tics. But such uses could be many years away. “DBS is a potential treatment for any condition where you have a good idea which brain regions aren’t functioning appropriately,” says Paul Holtzheimer, director of the Mood Disorders Service at Dartmouth-Hitchcock Medical Center, who collaborated on the study while at Emory. “But you need to do the clinical trials and have good evidence of the safety and efficiency to balance the invasiveness of the surgery.”

Neurologists don’t know exactly how DBS improves brain function. But there is growing recognition that the brain operates via complex electrical circuits that sometimes malfunction, and that electrical stimulation can interrupt the errant signals. Years ago, scientists noticed that Parkinson’s disease involved excess activity in the brain’s subthalamic nucleus—a spot about the size of a pea in the basal ganglia. In essential tremor, an even more common disorder with involuntary shaking, the target is the ventrointermediate nucleus, just a few millimeters away.

Pinpointing depression in the brain has been trickier, since it involves multiple brain circuits that control mood, thought, sleep, reward and other functions. Dr. Mayberg’s team spent years scanning the brains of depressed patients and noticed that many who got better had changes in Brodmann Area 25, whether they were treated with medication, psychotherapy or electroconvulsive therapy. Other researchers are targeting different spots in the brain that may play a role in depression. Larger clinical trials are under way, but Food and Drug Administration approval of DBS for depression is still several years away.

In movement disorders, the results can be dramatic—even in the operating room when the electrodes are first tested. “They say, ‘Hold up your hands and all of a sudden, there is no tremor!” says Pamela Bland, a former nurse from Dunnellon, Fla., who was diagnosed with Parkinson’s in 2000 and couldn’t walk, talk or get out of bed at the time she had the surgery at the University of Florida in Gainesville in 2008. Now she drives, kayaks and even completed a recent 5-K race. “There’s not much I can’t do,” says Ms. Bland, now 62.

It can take months to fine-tune settings on the battery pack and adjust medications to give patients optimal movement control. But in rare cases, the surgery alone seems to reset the brain circuits. Tom Rogers, a former truck driver who could no longer drive, write or drink from a glass due to severe tremor, had the electrodes implanted last summer and his shaking stopped immediately—even though the electricity has never been turned on. “My hand is steady as a rock,” marvels the 66-year-old Oswego, Ill., resident.

Researchers think the same phenomenon may explain why patients in the control groups of some DBS trials have improved after their electrodes were implanted but before the current was turned on.

That control benefit was also seen in a study published in the journal Lancet Neurology last week. Some 136 Parkinson’s patients in 15 centers in the U.S. received a DBS system made by St. Jude Medical Inc., which is hoping to win FDA approval to market it in the U.S. In half the patients, the devices weren’t turned on for three months to serve as a control group. Nearly 40% of the control subjects reported gaining at least two more hours of good movement control per day, compared with 73% of the group undergoing active stimulation. On average, those with the active devices increased their hours of good movement control from 6.3 hours to 11 hours per day. As of now, Medtronic Inc. makes the only DBS devices approved for sale in the U.S.

Only 10% to 15% of Parkinson’s patients are good candidates for DBS, says Michael Okun, medical director of the National Parkinson Foundation. It’s most useful for people experiencing tremor, stiffness and other movement problems but not other cognitive problems or health issues. DBS isn’t a cure for Parkinson’s; the disease still progresses. And as with other surgeries, there is a risk of infection, stroke or other complications. Some patients find their speech slurred after the surgery, and others report falling issues.

Still, demand for DBS is rising steadily. “In the beginning, it was tough to get patients onto the table. Now it’s the opposite,” says Dr. Okun, who performs many DBS operations a year at the University of Florida’s Center for Movement Disorders. The procedure, which costs about $60,000 including hospital fees, is generally covered by Medicare and private insurers for Parkinson’s, essential tremor and dystonia, another movement disorder.

Although some neurologists are offering DBS for depression even before it wins FDA approval, experts urge people with severe, treatment-resistant depression who are interested in DBS to enroll in a clinical trial, where they can be carefully monitored.

PROFILES OF DBS PATIENTS

Lisa Battiloro

Lisa Battiloro was diagnosed with major depressive disorder at age 22 in 1992 and began a frustrating treatment odyssey. “I tried many pharmaceuticals,” she says. “I tried cognitive-behavior therapy. I had 122 shock treatments. At first they helped, but they started to help less and less. I also had TMS (transcranial magnetic stimulation, another form of electrically recharging the brain.) I got no response to that at all.”

Her physician knew of Helen Mayberg’s work at Emory University. Ms. Battiloro went for an interview, applied, was accepted and was one of the first 17 patients in 2008. She was determined not to get her hopes up. “I was thinking, ‘If this treatment doesn’t work, there’s always suicide,’ ” she recalls.

She felt somewhat better immediately after the surgery—even though she now knows she was part of a control group whose devices weren’t turned on for another month. After the second month (with the current active), “It was a consistent climb. I was sleeping better. I wasn’t binge eating. I didn’t have any suicidal thoughts.” Ms. Battiloro has now renewed her nursing license and hopes to resume her career.

She can’t go through airport scanners or have an MRI, and she does have a scar on her chest where the battery pack is implanted. “That’s my badge of courage,” she says. “But I don’t have that feeling of dread, that numbness anymore. It’s been consistent and stable. I still have the occasional off day, but everybody does, and now I’m able to get up and get on with my life.”

* * *

Matthew Miller was 8 years old when his hands started shaking. It went away in his teenage years but returned in his 20s, when he was diagnosed with essential tremor, a movement disorder that is 10 times more common than Parkinson’s disease and often runs in families. Medications can control it temporarily, but Mr. Miller built up a tolerance to each one and he was exhausted trying to sit still and work at a computer.

“It was even difficult socially—you don’t dare go to a restaurant because your food will fly everywhere,” he says.

Mr. Miller was the first patient to be treated with Deep Brain Stimulation for essential tremor at Swedish Medical Center in Seattle in 2005. The operation, since streamlined, took 12 hours. In tremor patients, the surgeons listen for a specific kind of static on a Geiger-counter like device to know they are stimulating the right area, and other tests confirmed it. “I drank from a cup. I wrote my name. I drew a straight line,” he says. (See a video of Mr. Miller that shows the device on and off.)

His device uses a battery pack on each side of his chest, which can be programmed separately. The tremors stop naturally while he’s asleep, so he turns the DBS at night with a remote-control device.

“Once everything is turned on and working, you understand why you did this,” says Mr. Miller, now 43, who is steady enough to work as a nurse’s aide in a children’s hospital. Some tasks, like typing and shaving, are still challenging. And like other DBS patients, he finds his emotions are heightened: “Some people laugh uncontrollably. Some people cry. A friend of mine with Parkinson’s says he cries at railroad crossings.”

All in all, he says, “It’s not perfect, but it’s pretty amazing. People with this condition should try it—they don’t need to keep hiding.”

* * *

Paul and Mary Ann Kelley

Paul Kelley was only 30 when he was diagnosed with Parkinson’s disease. He had to leave his job as a probation officer in Tallahassee, Fla., and take an administrative post because he couldn’t carry a gun. By the time he decided on deep brain stimulation, at age 44, he couldn’t work or operate a computer or walk.

A few days after the electrical current was switched on, he and his wife drove from the hospital in Gainesville to Disney World in Orlando. “I couldn’t keep up with him, he was walking and talking so fast,” recalls MaryAnn Kelley.

In fact, the settings on his battery pack were too high. It took several months of adjustments to get the speed and intensity just right. Much of Mr. Kelley’s tremor and jerky movements are under control now, and he’s been able to reduce his medication from 15 pills a day to four. The procedure has made his speech more difficult, however, and left him more emotional.

The Kelleys know that Paul’s Parkinson’s disease will continue to progress in the future. But for now, DBS “has given us our life back, in a lot of ways,” says Mrs. Kelley. “He’ll never be able to work again, but he coaches our son’s baseball team. He plays golf. We go camping. We want to do as much as we possibly can as a family before we see the downside again. Next, we’re going to go white-water rafting.”

The user fee proposal is one of three such agreements that the agency is submitting to Congress for approval by lawmakers. The agreements would each charge drug manufacturers application fees for reviewing traditional drugs, generic drugs and a new class of generic biotech drugs, respectively.

The FDA has used industry fees to hire extra staff to review regular prescription drugs since 1992. One of the proposals unveiled Friday extends that approach to generic drugs, which have long had slower review times.

Whereas most new drugs are reviewed in 10 months, the typical review time for a generic drug is 30 months. The FDA has a backlog of more than 2,000 generic drug applications awaiting review, according to the Generic Pharmaceutical Association.

The FDA proposes collecting $299 million in fees annually to hire additional generic drug reviewers starting in fiscal year 2013. That figure would come from an estimated 750 generic drug applications per year as well as other fees, including the inspection of foreign drug manufacturing sites. In return for these fees, the FDA will aim to review 90 percent of generic drug applications within 10 months.

“These agreements are important because they are a substantial resource that lets the agency carry out its mission of protecting patients and ensuring important products come to market in a timely way,” said Allan Coukell, director of the Pew Charitable Trusts’ health advocacy group. “For the first time we will also have funding directed at increasing FDA’s inspection of foreign manufacturing facilities.”

Another first-of-a-kind agreement would charge companies for the review of generic versions of biotech drugs, which are complex medicines that often contain proteins and living microorganisms.

Up until 2010, the FDA did not have authority to approve knock-off versions of biotech drugs, or biosimilars, which are produced using far more complicated manufacturing processes than traditional chemical drugs. But the Obama administration’s health reform law signed into law in March 2010 instructed the FDA to begin reviewing and approving biosimilars. The FDA is still drafting instructions on how companies should submit applications for biosimilars.

The FDA also sent Congress its proposal for the traditional prescription drug user fee program, which is expected to raise more than $712.8 million in fees annually over five years. Like the other agreements, the deal must be approved and drafted into law by Congress before Oct 1, 2012, to be in place for the government’s next fiscal year.

Lawmakers already have granted three 5-year extensions to the Prescription Drug User Fee Act, which has allowed the FDA to hire hundreds of additional scientists in return for meeting certain performance goals. Under the latest version of the agreement, the FDA would be tasked with providing more meetings and updates to companies that have submitted first-of-a-kind drugs for review.

Separate but similar talks between the FDA and medical device makers are dragging out over a number of disagreements. Those companies have made shorter review times a priority, though the FDA says that goal will require significantly more funding, according to minutes from closed-door meetings between regulators and company executives.

Copyright 2012 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

 The Food and Drug Administration last year rejected the company’s drug to treat a subset of leukemia patients whose tumors had a particular genetic mutation. The main problem was not the drug itself, the agency said. Rather, ChemGenex had not specified a companion test that could reliably detect the mutation so that the drug could be given to the patients it is intended to help.

He said that when it became evident that the F.D.A. would make a decision on Xalkori earlier than expected, Abbott had to work nights and weekends to get the test ready. “Rule No. 1 is that the diagnostic can never slow down the development of the therapeutic,” he said.

Companion diagnostic developers have been pushing to share more in the bounty of a successful drug, perhaps via royalties on sales of the drug. But drug companies have resisted this.

“The value is in the combination, so why should one company get all the value?” said Mark R. Trusheim, an executive in residence at the Massachusetts Institute of Technology Sloan School of Management, who has studied the economics of companion diagnostics.

One reason the diagnostic companies do less well, Mr. Trusheim said, is that while drugs typically have market exclusivity because of patents and federal laws, tests often face instant competition.

Some laboratories at cancer hospitals, for instance, already have their own tests for the melanoma mutation that governs use of Zelboraf and are reluctant to switch to the approved test, which might be less convenient or more costly. Tests developed by a lab for its own use typically do not require F.D.A. approval.

To protect their investments, some developers of companion diagnostics want the name of the test to be specified in the label of the drug, arguing in part that unapproved tests might not be as accurate. Some pathologists oppose this.

The F.D.A. has so far taken a middle ground. The labels for Zelboraf and Xalkori state that an F.D.A.-approved test should be used. But they do not name the test, leaving open the possibility that additional tests can be approved.

Plexxikon, one of the developers of Zelboraf, said in comments submitted to the F.D.A. that linking a drug to a single approved test could allow a diagnostics company “to hold the entire drug development program hostage.”

Plexxikon, which is owned by Daiichi Sankyo, is developing a drug aimed at a type of leukemia with a particular mutation. K. Peter Hirth, Plexxikon’s chief executive, said that a company holding exclusive patent rights on the test for this mutation was “demanding incredibly high dollars in terms of upfront payments and support, which is prohibitive.”

Jeffrey E. Miller, chief executive of the company in question, Invivoscribe, said his company’s charges were reasonable considering the possible consequences of not having a validated companion test.

“The cost of developing the companion diagnostic,” he said, “is trivial compared to the cost of a failed drug.”

The many other drug and vaccine candidates for neglected diseases waiting in the pipeline for late stages of clinical development must face lengthy, inefficient review processes or non-existent regulatory capacity in the poorest, least developed countries before these technologies can reach the millions in need. Take, for example, tuberculosis (TB), a neglected disease that remains one of the largest causes of death and illness worldwide. According to a report by BIO Ventures for Global Health, there are only two vaccines and treatments for the disease in phase III trials, compared to 59 in the remainder of the pipeline. So what does it take to get a new treatment through the pipeline and into the hands of a patient who needs it?

Coordinating large multi-center trials for TB isn’t easy (or quick for that matter). A 2008 article in the Lancet cited two examples where trials had been delayed by a year or more due to regulatory hurdles for multi-national clinical trials. One of these examples, a trial studying a four-month treatment regimen, needed to obtain approvals from 18 authorities in six different countries, and was stalled for two years before patient recruitment could commence. The primary drug being evaluated in this study, Rifapetine, was approved by the FDA in 1998, but the best dosage for people living in endemic areas is still under investigation as of July 2011.

Unfortunately, this story isn’t unique. In many neglected disease-endemic countries, approval of clinical trials can take as long as six-24 months. For products that require multiple trials in different subject populations, subsequent application approvals may take an additional six-24 months or longer. And if you need to amend a trial protocol? Approval for that could take up to four months in a low-income setting. In contrast, regulatory approval for trials in the United States and the European Union can generally be obtained within 30-60 days, and trial protocol amendments take a few weeks.

Not only do these delays prevent access to effective treatments by a growing number of patients (over nine million individuals are newly infected per year by TB), they can lead to unnecessary costs that eat away at already small budgets to find new cures for neglected diseases. According to a recent report (PDF) by the G-FINDER project, in 2009, the global total spending on TB drug development was just $180 million, with 78 percent of all TB funding coming from public funders and philanthropic organizations.

In many cases delays occur because steps in the regulatory and ethical approval process need to be done in sequence, rather than simultaneously and in parallel, so that more than a year can pass between finalizing a trial protocol and completing all governmental and institutional regulatory and ethics processes. To address this, CGD’s Clinical Trials and Regulatory Pathways for Neglected Diseases Working Group recommends establishing a regional regulatory pathway that would increase regulatory capacity, reduce inconsistencies, and speed product development and delivery in neglected disease-endemic countries.

The proposed regional pathway (illustrated below), is based on a joint review model in which participating regulators and ethics committees would jointly review the application and perform the ongoing oversight of the trial.

This approach would offer a single review process with definitive timelines and requirements without undermining the sovereignty of the countries involved. Participation is voluntary for regulators and applicants alike, but those that decide to participate must use common documents, deadlines, and standards to assess applications. The pathway would be, at least initially, non-binding, but can be formalized as the trust and confidence of the participants grows. Applied to the example above, instead of the trial needing to coordinate with 18 different authorities, it would submit a single standardized application to the regional Secretariat, which would then be responsible for circulating to various regulatory authorities in parallel, who would then choose whether or not to participate within a pre-specified period of time. This aspect of the clinical trials regulation would move faster than it does currently, because ethical and regulatory standards would be consistent across the region, making it easier for clinical trials researchers to understand and comply with these standards. Following this step, the committees would offer a joint recommendation and participating national regulatory authorities would be identified.

This approach to regulatory cooperation has a track record of success. The European Union’s voluntary harmonization procedure and the World Health Organization’s African Vaccine Regulatory Forum both involve joint reviews of clinical trials and have been popular, low-cost, and implemented over a few short years. Regulatory bottlenecks extend the duration of clinical development, which the Institute of Medicine has estimated represents as much as half of the cost of conducting clinical research.

Even further, this approach would provide a useful platform for other regulatory initiatives. Regulatory cooperation that achieves more certain review times and reduces inconsistences in oversight of clinical trials could be used later to register and license safe and efficacious products. A regional approach that pools scarce country regulatory resources and provides a sustainable platform for clinical trial oversight capacity building could also do the same for post-market drug and vaccine safety surveillance, or even cost-effectiveness assessments ahead of public sector funding decisions.

Clinical trials produce goods that span entire regions and, as such, they need a system of regulations to match. Reducing inhibitory costs and bureaucratic hold-ups would benefit the estimated one billion people that suffer from neglected diseases — be it malaria, TB, or other lesser known diseases — every year.

Why not? In last month’s Journal of General Internal Medicine, a University of Michigan team pointed to some systemic problems. Analyzing more than 100 studies published during 2007 in prestigious medical journals, the researchers found that more than 20 percent excluded participants above a particular age. That actually represented considerable progress; a previous study of trials published from 1994 to 2006 found that 39 percent had excluded people over age 65.

More disturbingly, even when older people aren’t barred by age, they get left out for other reasons. More than 45 percent of the trials that didn’t have age limits excluded people for having other illnesses or cognitive impairment, for having a reduced life expectancy or physical disabilities or functional limitations, even for living in a nursing home or senior residence – all restrictions that tend to remove the elderly from the mix. Simply requiring study participants to show up at an office or clinic for regular monitoring may prevent frail elders or those who lack transportation from participating.

Dr. Donna Zulman, an internist and the study’s lead author (she’s now teaching at Stanford University), empathizes with her fellow researchers. “It’s really hard to do clinical trials, and when patients are complicated, with multiple health problems, it can be even more difficult,” she told me in an interview. “It makes for a cleaner trial if certain patients are excluded.”Nevertheless, “the study population should reflect the population that will be treated in the real world,” she said, “particularly if it’s studying a drug that will be used by older and frailer adults.”

Locating a group of perfectly healthy 85-year-olds for a drug trial — people who have no “co-morbidities” (doctorspeak for other illnesses) that might confound the experiment — is tough, agrees Dr. John Sloan, a family physician in Vancouver, British Columbia, whose book “A Bitter Pill” criticizes the prevailing treatment of older patients. But even if investigators manage to find enough of those sturdy subjects, the trial’s results won’t be very useful in his practice. Most of Dr. Sloan’s elderly patients aren’t perfectly healthy; they have multiple chronic diseases, often including dementia; they take lots of drugs and are physically fragile.

So the study’s authors call on regulators and investigators to include older adults in clinical trials and to analyze whether treatments affect them differently from younger participants. “Huge amounts of money flow into these trials,” Dr. Zulman said. “If we’re not getting results that help us take care of these most complex and expensive patients, we’re not getting much value from them.”

[Nature] Peggy Willocks was 44 when she was diagnosed with Parkinson’s disease. It progressed quickly, forcing her to retire four years later from her job as a primary-school principal in Elizabethton, Tennessee. Soon, her condition had deteriorated so much that she was often unable to dress and feed herself, take care of basic hygiene or walk unaided across a room.

Willocks enrolled in a trial for an experimental therapy called Spheramine, developed by Titan Pharmaceuticals, a biotechnology company in South San Francisco, California. Spheramine consists of cultured human retinal epithelial cells bound to specialized man-made carrier molecules. The cells are implanted into the brain, where it is hoped that they will produce the dopamine precursor levodopa, which can reduce the symptoms of Parkinson’s disease. In August 2000, Willocks became the second person ever to receive the treatment. After having a steel halo — a stereotactic frame — bolted to her skull, she was put under general anaesthesia. Surgeons then used the frame and coordinates obtained from numerous magnetic resonance imaging (MRI) scans to pinpoint the location at which to drill. They then snaked a catheter through her brain’s white matter to deliver the cells into the striatum.

At first there was no effect, but Willocks says that after 6–8 months she began to feel better. The changes were always moderate and gradual, except for once, about nine months after her surgery, when she showed what her doctor called a “radical” improvement in balance. By a year after the treatment, she and the five other patients in the phase I trial showed an improvement in motor ability of 48%, and those gains largely held 4 years later¹.

Ten years on, she says she notices her condition worsening, but is still doing much better than she was before her operation. She has no doubt that the treatment works. Investigators disagree: Spheramine was shelved in 2008 after a follow-up phase II, double-blind study found that it was no more effective than placebo². This time, the researchers compared the treatment with a ’sham’ brain surgery that copied almost every aspect of the procedure Willocks received, short of injecting cells into the brain.

For many investigators aiming to treat Parkinson’s and other neurological diseases invasively, using sham brain surgery as a control is, well, a no-brainer. And the practice is likely to expand in coming years, as researchers continue to develop experimental tissue transplants, gene therapies and stem-cell treatments. Small safety trials such as the one in which Willocks was enrolled may hint at the efficacy of a treatment, but they are not designed to prove it. And because they are ‘open label’ — both the investigators and the participants know that the drug is being administered — they are riddled with biases that can skew results. “It is so clear that open-label studies provide information that is not reliable,” says Warren Olanow, a neurologist at New York’s Mount Sinai Medical Center who has worked on cell-based neurosurgical therapies in Parkinson’s for more than two decades. “It’s almost impossible for me to imagine how a serious scientist can not desire their data or hypothesis to be tested in double-blind studies.”

Other scientists, however, say that sham brain surgery is an expensive, potentially dangerous and possibly unethical bit of biomedical theatrics. It may also be unnecessary. Clinical neuroscientist Roger Barker at the University of Cambridge, UK, contends that because there is huge variation in how these therapies are administered and in how patients respond, the protocols need to be refined in an open-label setting before going on to the next stage of development. And because cost, complexity and the small number of people eligible for such invasive therapies limit the size of the studies, a sham control provides results of limited statistical utility. Barker and his colleagues across Europe are currently enrolling patients in a €12-million (US$17-million) multicentre trial of a fetal dopaminergic nerve-cell treatment for Parkinson’s disease. The treatment may never be tested against a sham-surgery control. “There’s a sort of historical precedent” for using placebo controls, but it may not apply to neurosurgical trials, he says. Willocks and other patients go further. Placebo-controlled studies aren’t just unnecessary, they say, they are actually causing the downfall of potentially valuable treatments.

A complicating control

During the past 25 years, surgical therapies for Parkinson’s disease have travelled a rocky road. In 1987, a report by Mexican surgeons³ described seemingly miraculous effects in two patients with severe Parkinson’s who received transplants of tissue from the adrenal gland, which produces dopamine. In the next several years, hundreds of patients received the treatment, but some autopsies later showed that the cells didn’t in fact survive⁴. Around the same time, researchers started to test fetal nerve-cell transplants (similar to those in Barker’s trial) in small-scale studies, finding mixed but promising results. Two studies^5,6 comparing the treatment to sham surgery concluded, however, that the transplants were not only ineffective, but also often caused dyskinesia — the movement disorder that plagues people with Parkinson’s disease. In the past seven years, three experimental treatments (including Spheramine) that showed promise in small, open-label studies^1,7,8 failed in phase II trials^2,4,9 comparing them with a sham control (see ‘The sham wall’).

Sham brain surgery is no sugar pill. After the stereotactic frame is affixed to the skull, the patient is usually anaesthetized and surgeons drill into the skull. In most cases, the burr holes stop at the dura mater, a protective membrane covering the brain, but they sometimes go deeper: in a phase II trial testing the nerve growth factor GDNF, investigators catheterized the brain in all participants but infused saline, rather than GDNF, into the controls⁹.

“We have to stage the whole thing such that from the outside it’s completely indistinguishable” from the real thing, says Joao Siffert, chief medical officer of Ceregene, a company in San Diego, California, that is working on a therapy that delivers a gene for another nerve growth factor, called neurturin, using a viral vector. For many sham treatments, everyone in the operating room, from surgeons to nurses’ assistants, must pretend that they are busily performing the complete operation — in some cases, turning on machines to elicit appropriate noises. An extremely complex protocol ensures that no one outside the surgical team knows who got what treatment. “It’s very complicated, there are a lot of moving parts,” Siffert says. All that ratchets up the cost of a trial; Siffert estimates that between operating-theatre costs, follow-up and the unwieldy infrastructure required for data management, a 50-patient study would cost more than $10 million.

Still, at least in North America, Parkinson’s disease investigators overwhelmingly support the use of sham surgery — at a rate of 94%, according to a 2004 survey¹⁰. Around 20% said that penetrating the brain is justifiable. And proponents say the procedure is relatively safe. Although sham brain surgery has definite risks, most notably those associated with general anaesthesia, supporters note that adverse events are almost unheard of, unlike the risks of the actual treatments. And participants in the sham groups are generally promised the treatment if it is ultimately approved; in that event, they will already have the burr holes in their skulls through which it would be administered.

Sham treatments help to tease out the placebo effect and biases. In Parkinson’s disease, the placebo effect is especially strong. One reason is that patients’ expectations that they will benefit from a treatment induce the release of dopamine¹¹, the neurotransmitter that is lacking in the disease. “The placebo effect is real, it’s huge and it’s got a physiological basis,” says Jon Stoessl, a neurologist at the University of British Columbia in Vancouver, Canada, who studies Parkinson’s and the placebo effect. In one double-blind study of fetal nerve-cell transplants, patient improvement correlated with whether they believed they had received the treatment, irrespective of whether they actually had¹². And the effect can last as long as two years, Stoessl says, citing an unpublished study by his colleagues.

Many regard bias as a more significant confounder. “Investigators have a tremendous vested interest in seeing that their treatment is effective,” says Anthony Lang, a neurologist at the University of Toronto in Canada who has participated in several neurosurgical trials for experimental Parkinson’s therapies. In any trial, bias can affect how researchers assess patient responses and may inflate the patients’ expectations, further enhancing the placebo effect. Compounding the problem for Parkinsons’ research is the fact that there are no objective measures for how well a patient is doing. “It’s just a sort of perfect storm conspiring against our ability to see definitive changes in the underlying disease,” says Steven Piantadosi, a clinical-trials methodologist at Cedars-Sinai Medical Center in Los Angeles, California. “Sham surgery, properly done, can control for that.”

Barker counters that it is possible to control for investigator bias in an open-label trial by taking steps such as having blinded raters assess patients. His position is in some ways unsurprising; in Europe, sham surgery is deemed much less acceptable than it is in the United States. It has never been used in the United Kingdom. Barker is categorical about his belief that transplantation of fetal tissue works, at least for some people. “I don’t need sham surgery to show that,” he says, pointing instead to a paper¹³ published last year describing two patients treated 13 and 16 years previously who were still benefiting from the treatment, and whose brains showed functional dopamine-producing neurons at the transplant site. He attributes the mixed results in past studies to variation in the patients selected for treatment, the characteristics of the tissue being implanted and the methods used to implant it. His trial will have to demonstrate efficacy without eliciting some of the side effects found in the two sham-controlled studies. That will require some type of control study, he says, but it might take the form of comparison to an approved therapy that is known to work, such as deep brain stimulation.

But time, says Barker, will best establish efficacy. In most trials the end point is no more than a year after the treatment. That may not be long enough: implanted cells or injected growth factors might take longer than this to become fully functional, and the placebo effect may not have had time to dissipate. “We want a 3–5-year endpoint,” says Barker.

There are hints from some of the failed phase II trials that patients followed up beyond study endpoints might tell a more positive story⁴. Some say, therefore, that sham controls are sinking the prospects of valuable drugs. Anders Björklund, a neuroscientist at Lund University in Sweden who is collaborating with Barker, says that sham surgery can lead researchers to throw out a strategy prematurely if the trial fails because of technical or methodological glitches rather than a true lack of efficacy.

Advocacy and frustration

According to Perry Cohen, who leads a network of patient activists called the Parkinson Pipeline Project, that’s exactly what is happening. He had always questioned the need for sham surgery, he says, but after the string of phase II failures, “We started saying, ‘Hey, this is a problem. These trials failed, but we know they are working for some people.’”

For researchers, it is easy to dismiss patients’ concerns as being driven by emotion. “Patients want cures,” says Lang, “and they will often be convinced that the more aggressive, surgical therapies are more likely to be curative.” But Cohen counters that patients have different priorities and that researchers must take these into account. Researchers use placebo controls to weed out false positives. But for patients, the real ogre is the false negatives — which can sink a therapy before it has been optimized. The better a trial is at stamping out the former, the higher the rate of the latter — which means at best delays, and at worst dead ends. Spheramine, for example, “is still on a shelf somewhere”, Cohen says. Then there’s Amgen’s phase II trial of GDNF. The trial was halted in 2004 amid lacklustre results and potential safety concerns, which some have attributed to Amgen’s procedure, rather than to the therapy itself. Now researchers are taking a renewed interest in the molecule, but although Cohen is glad it is getting a second chance, “we lost 6 years on it”, he says.

Patients also have different perspectives on risk from researchers, Cohen says. He offers the story of Tom Intili, who had had Parkinson’s for 10 years when, at the age of 50, he signed on to the double-blind, placebo-controlled trial of neurturin. At first, Intili improved dramatically. But when the results were unblinded, he learned that he had received the sham. His condition plummeted, leaving him more debilitated than he had been before the trial. “We just don’t know what the psychological effects of unblinding are,” Cohen says.

Moreover, trying to exclude the placebo effect is simply misguided, Cohen argues. “I don’t want to subtract out the placebo effect — I want to keep it, because in real life it’s part of the treatment,” he insists. Because psychological factors are so salient in Parkinson’s, a placebo response might actually potentiate a therapy, he explains. “I want to be convinced that sham surgery is necessary. I’m looking for arguments that might change my mind, but I haven’t found any yet,” he says.

Willocks says that she is living proof that many of the recently shelved therapies are in fact salvageable. Of course from a scientific perspective, her story is an anecdote, not data. In May, the failed phase II study of Spheramine — the therapy she received a decade ago — was finally published². The paper closes with a warning about the dangers of the placebo effect and stresses the importance of controlling for it with a double-blind design. “That last paragraph bothered me,” Willocks says. “I just don’t see how they can call it a placebo effect after ten years.” 

Alla Katsnelson is a freelance science writer in New York City.

But as University of Minnesota bioethics professor Carl Elliott notes in a commentary published Friday in the New York Times, those rules will do nothing to protect people who volunteer for medical studies from an unethical marketing ploy of the pharmaceutical industry: “seeding trials.”

“In a typical seeding trial,” writes Elliott, “a pharmaceutical company will identify several hundred doctors and invite them to take part in a research study. Often the doctors are paid for each subject they recruit. As the trial proceeds, the doctors gradually get to know the drug, making them more likely to prescribe it later.”

In other words, these studies are not about science. They’re all about marketing. Their primary purpose is to get more doctors to prescribe the drug.

“In an age of for-profit clinical research, this is the new face of scandal,” Elliott says. “Pharmaceutical companies promote their drugs with pseudo-studies that have little if any scientific merit, and patients naively sign up, unaware of the ways in which they are being used.”

Seeding trials can be dangerous, Elliott points out. Three participants died (and five more experienced heart attacks) in the Advantage study, a seeding trial by Merck for the now notorious and drawn-from-the market painkiller Vioxx. And earlier this summer, as Elliott also notes (and as I reported in Second Opinion), the Archives of Internal Medicine published a scathing indictment of a 1990s seeding study conducted by Parke-Davis (now part of Pfizer) for the anti-seizure drug Neurontin (gabapentin).

“The investigators were inexperienced and untrained, and the design of the study was so flawed it generated few if any useful conclusions,” writes Elliott. “Even more alarming, 11 patients in the study died and 73 more experienced ‘serious adverse events.’ ”

Elliott calls for a revamping of institutional review boards (IRBs), the federally empowered committees that are supposed to make sure that clinical studies are safe for participants and ethically sound. As Elliott points out, IRBs are not usually equipped to judge or even identify seeding trials.

“Even worse,” he says, “many IRBs are now themselves for-profit businesses, paid directly by the sponsors of the studies they evaluate. If one IRB gets a reputation for being too strict, a pharmaceutical company can simply go elsewhere for its review.

The current IRB system “should be replaced with an oversight system that is financially and administratively independent of the research it oversees,” says Elliott. “The system must have the power to impose sanctions, and its responsibilities must extend to fraud, bribery and corruption.”

“Many patients volunteer for research in the hope that the knowledge generated will benefit others,” he adds. “When a company deceives them into volunteering for a useless study, it cynically exploits their good will, undermining the cause of legitimate research everywhere.”

At the Presidential Commission for the Study of Bioethical Issues today, Commission Chair Dr. Amy Gutmann, president of the University of Pennsylvania, asked a panel of international experts on bioethics whether the so-called Guatemala incident could happen again. In Guatemala, from 1946 to 1948, a U.S.-funded research experiment deliberately infected people in a trial with sexually transmitted diseases and in some cases did not treat them.

“Of the many things that happened there, no, it could not happen again because of informed consent,” said Dafna Feinholz, chief of the Bioethics Section, Division of Ethics and Science and Technology, Sector for Social and Human Sciences, United Nations Educational, Scientific and Cultural Organization.

But she said there was great room for improvement in the current sets of regulations guiding clinical trials. She specifically mentioned the area of “how to enter negotiations about research projects, about what is relevant, and why is it being conducted.”

Others on the panel agreed that human subjects in clinical trials remained vulnerable today.

Francis P. Crawley, executive director of the Good Clinical Practice Alliance in Europe, championed the need for more transparency around clinical trials. First, he thanked the panel and Susan Reverby, the Wellesley College professor whose research uncovered the Guatemala experiments last year, leading President Obama to ask the Commission to investigate that study as well as whether federal funded research adequately protected human subjects in trials.

“I think this work by Dr. Reverby was done in an exemplary way as a historian, ethicist, and a human being,” Crawley said. “One of the things Dr. Reverby has done is to bring something out of darkness. And that is really, really important to us.”

He continued: “We need to consider carefully what we do as ethicists. Are we protecting human subjects? Is that what we are about? Are we justifying research of subjects? Are we advancing health? How are we advancing health? What are our roles and what should be our principle objective here? I think our primary objective should be health.”

Crawley said now there was a “trust deficit” between researchers and possible subjects of trials. He said that the U.S government, European governments and the World Health Organization have all moved quickly to promote more transparency of the clinical research.

But Commission member Anita L. Allen, professor of law and philosophy at the University of Pennsylvania, questioned whether transparency was the main problem.

“It’s often said that African Americans’ distrust of clinical medicine is due to a belief if a group is low enough in social status, (abuses) can happen in broad daylight,” she said. “Slavery and the Holocaust happened in broad daylight. So is transparency the key? Or is human rights and equality really the key?”

“I agree with you entirely,” Crawley said. “ … Trust is really the key issue here. It’s very important we maintain trust in research. … Transparency is in and of itself insufficient. It will never be sufficient. It is a necessary condition, but it is not sufficient.”

Commission member Christine Grady, deputy chief of the Department of Bioethics at the National Institutes of Health Clinical Center, raised another thorny issue: Do the interests of people participating in a clinical trial trump everything else?

Gutmann asked Grady to answer her own question.

“Sometimes the interest, the immediate interest, especially the medical interest of the individual at hand are not the primary focus of what is going on,” Grady said. “… The sort of struggle that has occupied many people for many years is what level of risk do we allow people to take if they are able to make autonomous decisions in the interest of science, in the interest of developing new knowledge that will help other people. That is really a very tough question.”

Johannes J.M. van Delden, president of the Council for International Organizations of Medical Sciences, said that in many cases “clinical research cannot be beneficial for the participants. … Usually there will be procedures that are harmful, or certainly not beneficial.”

The New York company added that the death rate associated with the drug, across several studies, “is within the range of rates reported for biologic therapies” for rheumatoid arthritis.

The drug, tofacitinib, is an oral pill that Pfizer hopes can be an alternative to injectible and infused rheumatoid-arthritis drugs, including Abbott Laboratories’ Humira. It is viewed as an especially promising drug in Pfizer’s research pipeline, with analysts predicting annual sales approaching $2 billion if it reaches market.

The company needs successful new drugs to help offset an anticipated big revenue decline when its best-selling drug, cholesterol-lowering Lipitor, loses patent protection in November and becomes exposed to generic competition.

Pfizer shares fell 3% to $19.79 in 4 p.m. composite trading Thursday on the New York Stock Exchange.

A report of the deaths first appeared in a summary of the study, called ORAL Sync, that was posted online by the European League Against Rheumatism, or Eular, ahead its annual scientific conference in London.

The full results are scheduled to be presented at the meeting on May 27. The summary said four patients who received tofacitinib in a one-year, 792-patient trial had died and four contracted opportunistic infections.

Two deaths occurred during the study, one from acute heart failure and one from respiratory failure. Only the respiratory failure death was reported as “study drug-related,” Pfizer said.

After treatment was discontinued at the end of the trial, two other patients died, one from traumatic brain injury and one from rheumatoid arthritis, the study summary said. Pfizer said the brain injury death occurred 22 days after the participant stopped taking the drug while the rheumatoid arthritis patient died 42 days after discontinuing the drug.

Pfizer also said that under the design of the study, 80% of the patients got tofacitinib, while 20% got a placebo, one reason why “the majority of adverse events would be expected to occur in patients on active treatment.”

When the company recently announced preliminary findings of the study, it said tofacitinib was superior to a placebo in improving symptoms of rheumatoid arthritis among patients with active disease who hadn’t responded well to certain other drugs for the condition. The company didn’t mention any deaths and said at the time there weren’t any new safety flags found in the study.

Some analysts have voiced concern about a possible link to risk of heart failure with the drug. J.P. Morgan analyst Chris Schott said in a research note that some other rheumatoid-arthritis treatments on the market also are associated with risk of heart failure.

“While this signal clearly warrants attention, we believe Pfizer’s product would still be approvable even if a modest [heart failure] signal were present,” Mr. Schott said.