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Talk About Curing Autism (TACA) provides general information of interest to the autism community. The information comes from a variety of sources and TACA does not independently verify any of it. The views expressed herein are not necessarily TACA’s. TACA does not engage in lobbying or other political activities.

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December 2010 #1

Here is your update on TACA (Talk About Curing Autism). If you are new to our site... WELCOME! This newsletter is produced two to four times each month.

We are an autism education and support group. We want to make this e-newsletter informative for you. As always, contact us your thoughts and/or questions so we can improve it.

We focus on parent information and support, parent mentoring, dietary intervention, the latest in medical research, special education law, reviews of the latest treatments, and many other topics relating to autism. Our main goal is to build our community so we can connect, share and support each other.

Talk About Curing Autism (TACA) provides general information of interest to the autism community. The information comes from a variety of sources and TACA does not independently verify any of it. The views expressed herein are not necessarily TACA’s.

1. Find a TACA Meeting

Come to a TACA Meeting!

TACA holds monthly meetings in many locations throughout the United States that feature educational speakers on important topics and allow family members to connect with one another and stay on top of the latest information in the autism world. Each TACA group maintains a resource library of the latest autism books, CDs and DVDs that can be checked out by members at no charge.

Check out our group listings: each contains information on TACA meetings and special events as well as a contact form.

Are you wondering what happens at a TACA meeting? Watch our video.

2. Join Us for Coffee Talk!

Come and receive some extra support or to

chat all topics related to autism and meet

other TACA families at these informal,

monthly get-togethers.

3. TACA Attracts Celebrities at "Ante Up for Autism" Fundraiser

BY DONNA BUNCE, REGISTER COLUMNIST
donna@coastmagazine.com

More than $120,000 in net proceeds was raised for families who are touched by autism at Talk About Curing Autism's (TACA) Fourth Annual "Ante Up for Autism" fundraiser on November 13th at the St. Regis Monarch Beach Resort & Spa in Dana Point. With 315 guests attending, the evening included cocktails and hors d'oeuvres and a bevy of silent auction items on the resort lawn, as well as a dinner buffet, casino games and live auction in the resort's Pacific Ballroom. The big draw for many was the poker tournament, and there were poker pros on hand to give guests tips before the tournament commenced. Another draw was the contingent of celebrities and sports stars attending, which included Clifton Collins, Jr. of NBC's new hit drama, "The Event," actor Jonathan Schaech, "One Tree Hill" actress and singer Kate Voegele (who performed during the reception), "Deal or No Deal" model Leyla Milani, actor Jacob Vargas, musician Cisco Adler, actor, producer and writer Sevier Crespo, and television host and model Renee Herlocker, who hosted the VIP red carpet celebrity arrivals.

In addition, the professional athletes attending included retired NFL quarterback Jim Everett, who served as event host, world champion cyclist Brian Lopes, Olympic gold medal hurdler Felix Sanchez, Motorcross racer Ernesto Fonseca, BMX Rider Stephen Murray, professional race car and stunt driver Samuel Hubinette, retired NFL player Mike Lansford, and lacrosse player Brett Hughes.

Talk About Curing Autism (TACA) held its fourth annual "Ante Up for Autism" November 12th with a star-studded cast of celebrities and 325 guests at St. Regis Monarach Beach Resort & Spa in Dana Point. From left, were event chair Pat Mc Ilvain, actor Johnathon Schaech, TACA Executive Director Lisa Ackerman, retired NFL quarterback and event master of ceremonies Jim Everett, actress and singer Kate Voegele, and Olympic gold medal hurdler Felix Sanchez. The poker tournament and fundraiser netted $120,000 for the cause.

Everett was quick to say that he and his wife Rachel have attended all of TACA's fundraisers because of their close relationship with Pat and Stephanie McIlvain, who have an autistic son named Dylan. "We've seen how it affects the family, not only how it affects the child, but the mountain the family climbs," Jim said. Pat and Stephanie were very involved with making the event happen, with Pat serving as event chair and Stephanie as event and special guests coordinator. Pat told the crowd, "TACA gave us the ability to continue on."

Auctioneer Trey Jarvis led a jam-packed live auction, with items such as a Napa Valley wine trip, a winter wonderland getaway in Montana, a chalet in Vail, Colorado, and a stay at the Oakley Pipeline Surf House in Oahu (won twice at $6,500 each). A delighted Noah McMahon won the Lance Armstrong autographed jersey he wore on the final day in Paris of the 2010 Tour de France for $6,300.

The winners of the poker tournament were two of the poker pros Michelle Lau and Kenna James and, coming in third place, was a very happy Jim Everett.

TACA Founder and Executive Director Lisa Ackerman is the impassioned leader who started TACA 10 years ago with 10 families. She and husband Glen have a 13-year-old son with autism, who stopped talking at 15 months and didn't start again until age five. "Thankfully," Ackerman said, "Jeff received early intervention and biomedical treatments unique to his needs and is in a regular education placement today and maintaining a B average." Continuing, Ackerman said, "Every child with autism deserves this chance for a bright future. When Jeff was diagnosed, he was one in 1,000. Today, that number is one in 91." TACA currently provides support, education, information, and resources to more than 20,000 families across the country touched with autism. "These families need us more than ever," finished Ackerman.

Special thanks to our sponsors, in-kind donors & attendees! See listing and view event photos.

4. New TACA Board Member: Chad Fitzsimmons

We are so pleased to announce the new board member Chad Fitzsimmons. He has been involved with TACA for the past five years. We are pleased to welcome him aboard.

Chad is currently the Marketing Director for 93.1 Jack FM, owned and operated by CBS Radio. Before moving to Los Angeles in 2005 to launch Jack FM, Chad worked for CBS Radio in Charlotte, NC for 3 years.

Alongside his responsibilities for 93.1 Jack FM, Chad also serves in the same capacity as Marketing Director for 97.1 AMP Radio, also based out of Los Angeles.

In August of 2005, JACK FM adopted TACA as the beneficiary for Jack's First show, five years later, Chad and the Jack FM team continues to partner with TACA on various events, awareness programs and fundraising campaigns.

Chad graduated from Winona State University in 1999. He now lives in Manhattan Beach with his wife Angie.

Complete listing of all TACA board members.

5. Daily Autism Updates for Families

All news related to autism: AgeofAutism.com

6. Alternative Argument: Middletown surgeon says nontraditional autism therapies work

By PATTI MENGERS, delcotimes.com

Dr. Patrick Elliott will never forget the day one of his 6-year-old twin sons delivered a self-diagnosis to him.

“I don’t have autism anymore,” the boy announced to his father.

It was a far cry from three years earlier when both twins were diagnosed with the neurobiological affliction of unknown origin. Between the ages of 18 months and 24 months, they went from being playful and happy to ceasing eye contact with others. They had lost any language they had acquired.

“They were basically disengaged,” said Elliott, a 47-year-old general and trauma surgeon at Crozer-Chester Medical Center in Upland.

Through a combination of conventional and alternative therapies, one of his twins improved so much he was able to join his peers in the mainstream by the time he entered first grade at his local public school where he is now a fourth grader. He no longer requires therapy. At his parents’ request, his name is being withheld from this story.

His twin brother, Bradley, is in fourth grade at a private special education school in Chester County, where he reads and writes at his grade level. He still receives biomedical intervention.

“He still has issues with anxiety and (obsessive-compulsive disorder),” Elliott said, “but he has dramatically improved and we hope he’ll be mainstreamed some day,”

Born in April 2001, the twins initially developed normally as their two older brothers had at their home in Middletown. Their mother, Marie, was the first to notice changes in the twins, Elliott said.

The twin who no longer requires therapy “had horrible, aggressive behaviors, self-injurious behavior, head-banging and echolalia where he would repeat what everybody said,” Elliott said. “That’s better than no language, but it was clearly a problem.”

He noted Bradley would run around the house with his arms extended, totally disengaged, not speaking.

“We thought he had a hearing loss,” said Elliott.

Their parents suspected the twins had autism spectrum developmental disorders, which can run the gamut of children who are totally withdrawn to scholars. Symptoms can be mild to disabling and usually involve problems with social interaction, communication, repetitive behavior and obsessive interests.

“We spent six months seeing the kids not getting better, not getting answers and waiting for a developmental pediatrician to see the boys,” said Elliott.

The twins were officially diagnosed with autism in late summer 2004, but their parents were able to procure early intervention occupational and speech therapy for them through the Delaware County Intermediate Unit by February 2004.

“It took a little time, but we realized they needed intense behavioral therapy,” said Elliott.

Thus began a journey for the Elliotts that took them through a combination of standard and still unproven alternative therapies in their mission to reconnect their twins with the world.

No Holds Barred

Since applied behavioral analysis, an intense form of behavioral therapy, was not covered by health insurance at the time, the Elliotts took out a home equity loan to put together their own therapy program for their autistic sons. In October 2006, they converted their basement into a therapy area and hired a staff of 12, including two behavioral therapy coordinators and 10 college students studying speech or occupational therapy.

“We went from three hours of therapy a week each with very little progress to 25 to 35 hours a week of behavioral therapy, occupational therapy, speech therapy and floortime therapy,” said Elliott.

Each boy received six to eight hours a day of therapy, five to six days a week. It was a combination of adult-directed behavioral therapy with child-driven “floortime therapy” which the Elliotts learned from Maude LaRoux of A Total Approach in Concord.

“The kids were engaged almost all the time,” said Elliott.

His said his children made progress after two years of the integrative therapy approach.

“Six years ago, intensive behavioral therapy was not considered standard therapy” Elliott said, “and now it is covered by insurance by law as of July 2010.”

He noted that Pennsylvania law requires insurance to cover 25 hours a week of intensive behavioral therapy for autistic children.

“What we did was a little innovative at the time,” said Elliott.

While ramping up the behavioral therapy, the Elliotts were also beginning to implement what has come to be known as Defeat Autism Now Protocol, a type of biomedical intervention not yet recognized by the mainstream medical community as a proven treatment for autism.

Cause Still Uncertain

According to the Centers for Disease Control and Prevention, an average of 1 in 110 children in the United States has an autism spectrum disorder, with boys four to five times more likely to be affected than girls. If one identical twin has autism, the chances of the other having it are 60 to 96 percent, according to studies cited by the CDC that noted fraternal twins such as the Elliotts, at most, have a 24 percent chance of both having autism

Officials at the CDC maintain there is no cure for autism and that the earlier children begin behavioral therapies to help them walk, talk and interact with others, the greater their chance of improved development.

They believe there are many likely causes for autism involving environmental, biologic and genetic factors.

Natural Resources Defense Council Senior Attorney Robert Kennedy Jr. maintains the mercury-containing vaccine preservative thimerosal is responsible for the epidemic of autism in the United States.

While officials from the U.S. Public Health Service, the American Academy of Pediatrics and the American Academy of Family Physicians have said there is no evidence of harm resulting from low levels of thimerosal used in vaccines, in 1999 they recommended it be removed from vaccines routinely prescribed for infants as a precautionary measure.

Elliott noted that while thimerosal has been removed from vaccines, he believes they still contain a lot of metals, including aluminum. Although his twins began manifesting autism symptoms after their immunizations began, he does not place blame on any one vaccination.

“I believe that a combination of environmental factors, in addition to over-vaccination, contributed to an immune problem that resulted in a toxic brain injury that manifests in autism spectrum disorder,” said the doctor.

Elliott noted the incidence of autism has grown from 1 in 10,000 live births in 1980 to 1 in 110. He believes people have spent too much time trying to place blame for the surge of autism cases and not enough time investigating whether giving 40 vaccinations to a child under 5, or 30 vaccinations to a child under age 3, is safe.

“There’s never been a study that looks at the total vaccination schedule,” he maintained, “in terms of the volume of vaccinations given to children with immature immune systems and developing neurologic systems to determine, in fact, if it’s safe.”

A physician since 1988, Elliott took his beliefs about toxic brain injury into account when researching biomedical intervention as an alternative therapy for his twins.

Healing the Brain

The Defeat Autism Now Protocol includes hyperbaric oxygen chamber therapy sessions or “dives,” intravenous infusions of glutathione, vitamin B shots and other vitamins and a hypoallergenic gluten and casein-free diet.

“I was initially very skeptical of alternative intervention and not everything I tried helped my kids,” Elliott said, “but as my kids improved dramatically, I came to realize autism spectrum disorder is treatable. It has a biomedical component that is treatable.”

He said a hypoallergenic diet free of the proteins gluten and casein is utilized to help heal the injured bowel, known as “a leaky gut,” which is common in autistic children and makes it difficult for them to digest food and purge toxins from their systems.

The intravenous infusion of glutathione, a combination of three amino acids that is considered the body’s master antioxidant, is also intended to detoxify the body and boost the immune system.

The B vitamins are aimed at improving neurological function, cognition and language, said the doctor.

Hyperbaric oxygen chamber therapy, used for wound care and for treating decompression sickness in divers, is not recognized by the mainstream medical community or the U.S. Food and Drug Administration as a proven therapy for autistic children.

“The use of hyperbaric oxygen therapy in the treatment of autistic disorders and traumatic brain injury is ‘off label.’ It is not an accepted indication because there’s not enough data to support its use,” Elliott said. “It is not covered by insurance.”

However, he believes 100 percent oxygen under pressure helps decrease inflammation, improve blood flow and promote healing of injured brain tissue.

“Most recently, hyperbaric oxygen is being studied by the U.S. government and the Veterans Administration for treatment of traumatic brain injury and post-concussive syndrome,” said Elliott, who is a board-certified trauma surgeon.

He introduced biomedical intervention and hyperbaric oxygen therapy to his children at home, along with the intense behavioral therapy.

“None of these alternative interventions are cure-alls for autism. There is no magic bullet, but I have found that many of these interventions help many children, including my own,” Elliott said. “My children improved significantly, more than they would with just behavioral and speech therapy.”

Autism Treatment Center

While he had a portable or “soft” hyperbaric therapy chamber at home that could administer 21 to 30 percent oxygen to his children, Elliott felt Bradley could progress better with 100 percent oxygen administered through a “hard” chamber.

He took Bradley to a hyperbaric oxygen therapy center in Newtown Square where he had 188 “dives” between 2007 and 2008. The center closed around June 2009 and reopened last March as Hyperbaric Therapy USA. Lou Granda is president of the Staten Island, N.Y.-based company.

“Bradley continues to get biomedical intervention, including hyperbaric oxygen therapy, nutritional support and, recently, neurotherapy,” said Elliott.

Hyberbaric Therapy USA is a corporate sponsor of Talk About Curing Autism, a nonprofit organization that provides information, resources and support to families affected by autism. The Autism Treatment Center of Newtown Square, dedicated on Nov. 16, is now on the second floor of Hyberbaric Therapy USA and shares the same administrative staff.

Motivated by the improvement he has seen with his twin sons, Elliott said he volunteered to be medical director for the Autism Treatment Center, which is a profit-making venture for Hyperbaric Therapy USA.

“We don’t diagnose, we give people a plan and help them access standard therapies and offer alternative therapies that help many children,” Elliott said. “We make no guarantees.”

The Autism Treatment Center staff includes three hyperbaric technicians, a clinical coordinator, Elliott and another physician, a behavioral therapy consultant, a neurofeedback technician and an occupational therapist who does interactive metronome therapy.

“We don’t prey on the desperation of parents of autistic children looking for a cure,” Elliott said. “None of this is curative, but the combination of these therapies help many children.”

Although he acknowledge the center is meant to turn a profit, Elliott does not charge clients for initial consultations.

“The reason I don’t charge is that my children got better and I had the resources to do it,” said Elliott.

The doctor does encourage clients to try hyperbaric oxygen chamber therapy, which costs $130 a dive. He usually recommends 40 dives over eight weeks. He also encourages clients to try the hypoallergenic diet for which there are laboratory costs. In addition, there are charges for vitamins, as well as for interactive metronome therapy and neurofeedback.

“It’s kind of like a co-op,” Elliott said. “We make sure our prices are reasonable.”

He noted that the Autism Treatment Center of Newtown Square has about 30 clients in a hyperbaric oxygen therapy regimen and about 30 more in biomedical intervention programs. They range in age from 18 months to 27 years old.

“We’re not an educational center, we’re an alternative treatment center,” said Elliott. “We’re offering a ‘one-stop shop’ where parents can come and get a comprehensive treatment plan for their children.”

Elliott said the Autism Treatment Center has attracted visitors from some of the intermediate units in the area, although the Delaware County Intermediate Unit was not among them as of mid-November.

Tried and True

The Delaware County Intermediate Unit, one of 29 regional educational agencies established by the Pennsylvania Legislature in 1970, is educating 245 autistic clients ranging in age from 3 to 21, said Melanie Sharps, assistant director of special programs.

“That number will continue to rise as school districts send more students to us and as early intervention continues to identify students,” said Sharps.

She noted autism diagnoses are increasing due to earlier identification by pediatricians, improved diagnostic techniques, the opening of hospital diagnostic centers, increased parental awareness and increased autism research, among other factors.

At a public cost of about $44,000 per student, plus related services, Delaware County Intermediate Unit officials administer their autism program at the Marple Education Center, which includes prekindergarten through 12th grade and an early intervention program.

None of the teaching techniques employed there are considered alternative.

“We use best practices and have two programs in particular that reflect best practices in teaching students with autism — the Verbal Behavior Model and the Competent Learner Model,” said Sharps.

She noted there is no one program that works for all students.

“That’s why teachers have a multitude of strategies to use with each student,” Sharps said, “to see what works best for that student.”

She is familiar with hyperbaric oxygen therapy, biomedical intervention and other alternative treatments for autism.

“Parents have tried many of these and some say that they see an improvement in their child,” Sharps said, “and some say they don’t.”

She feels it is up to parents to decide whether to try alternative treatments for their autistic children.

For Elliott, he has no doubt a combination of alternative and proven therapies has plugged his twins back into the world.

“I often say I got into alternative medicine because mainstream medicine gave me no alternative to help my children,” the surgeon said.

He still remembers the panic and desperation he felt when his twins were diagnosed with autism six years ago.

“They gave us a diagnosis, a social worker and little hope for improvement or recovery for our children,” said Elliott.

His son who is now mainstreamed and no longer requires therapy has already informed Elliott he intends to be a lawyer. Although Bradley still is undergoing therapy for autism, he plays football with his brothers, swims in the ocean and cracks jokes. Elliott fully expects Bradley will one day be mainstreamed in school just like his twin brother.

“We have our sons back,” the doctor said.

The Autism Treatment Center is on the second floor of the Hyperbaric Therapy USA building at 3744 West Chester Pike in Newtown Square. For more information call 610-355-1748 or access www.hbtusa.com.

7. UC Davis study finds children with autism have mitochondrial dysfunction

www.eurekalert.org

(CHICAGO) -- Children with autism are far more likely to have deficits in their ability to produce cellular energy than are typically developing children, a new study by researchers at UC Davis has found. The study, published today in the Journal of the American Medical Association (JAMA), found that cumulative damage and oxidative stress in mitochondria, the cell's energy producer, could influence both the onset and severity of autism, suggesting a strong link between autism and mitochondrial defects.

After the heart, the brain is the most voracious consumer of energy in the body. The authors propose that deficiencies in the ability to fuel brain neurons might lead to some of the cognitive impairments associated with autism. Mitochondria are the primary source of energy production in cells and carry their own set of genetic instructions, mitochondrial DNA (mtDNA), to carry out aerobic respiration. Dysfunction in mitochondria already is associated with a number of other neurological conditions, including Parkinson's disease, Alzheimer's disease, schizophrenia and bipolar disorder.

"Children with mitochondrial diseases may present exercise intolerance, seizures and cognitive decline, among other conditions. Some will manifest disease symptoms and some will appear as sporadic cases," said Cecilia Giulivi, the study's lead author and professor in the Department of Molecular Biosciences in the School of Veterinary Medicine at UC Davis. "Many of these characteristics are shared by children with autism."

The researchers stress that these new findings, which may help physicians provide early diagnoses, do not identify the cause or the effects of autism, which affects as many as 1 in every 110 children in the United States, according to the U.S. Centers for Disease Control and Prevention.

While previous studies have revealed hints of a connection between autism and mitochondrial dysfunction, these reports have been either anecdotal or involved tissues that might not be representative of neural metabolism.

"It is remarkable that evidence of mitochondrial dysfunction and changes in mitochondrial DNA were detected in the blood of these young children with autism," said Geraldine Dawson, chief science officer of Autism Speaks, which provided funding for the study. "One of the challenges has been that it has been difficult to diagnose mitochondrial dysfunction because it usually requires a muscle biopsy. If we could screen for these metabolic problems with a blood test, it would be a big step forward."

For the study, Giulivi and her colleagues recruited 10 autistic children aged 2 to 5, and 10 age-matched typically developing children from similar backgrounds. The children were randomly selected from Northern California subjects who previously had participated in the 1,600-participant Childhood Autism Risk from Genetics and the Environment (CHARGE) Study and who also consented to return for a subsequent study known as CHARGE-BACK, conducted by the UC Davis Center for Children's Environmental Health and Disease Prevention.

The children with autism met stringent diagnostic criteria for autism as defined by the two most widely used and rigorous assessment tools. Though the total number of children studied was small, it is generally representative of the much larger CHARGE cohort, and that increases the significance of the study results, the authors said.

The researchers obtained blood samples from each child and analyzed the metabolic pathways of mitochondria in immune cells called lymphocytes. Previous studies sampled mitochondria obtained from muscle, but the mitochondrial dysfunction sometimes is not expressed in muscle. Muscle cells can generate much of their energy through anaerobic glycolysis, which does not involve mitochondria. By contrast, lymphocytes, and to a greater extent brain neurons, rely more heavily on the aerobic respiration conducted by mitochondria.

The researchers found that mitochondria from children with autism consumed far less oxygen than mitochondria from the group of control children, a sign of lowered mitochondrial activity. For example, the oxygen consumption of one critical mitochondrial enzyme complex, NADH oxidase, in autistic children was only a third of that found in control children.

"A 66 percent decrease is significant," Giulivi said. "When these levels are lower, you have less capability to produce ATP (adenosine triphosphate) to pay for cellular work. Even if this decrease is considered moderate, deficits in mitochondrial energy output do not have to be dismissed, for they could be exacerbated or evidenced during the perinatal period but appear subclinical in the adult years."

Reduced mitochondrial enzyme function proved widespread among the autistic children. Eighty percent had lowered activity in NADH oxidase than did controls, while 60 percent, 40 percent and 30 percent had low activity in succinate oxidase, ATPase and cytochrome c oxidase, respectively. The researchers went on to isolate the origins of these defects by assessing the activity of each of the five enzyme complexes involved in mitochondrial respiration. Complex I was the site of the most common deficiency, found in 60 percent of autistic subjects, and occurred five out of six times in combination with Complex V. Other children had problems in Complexes III and IV.

Levels of pyruvate, the raw material mitochondria transform into cellular energy, also were elevated in the blood plasma of autistic children. This suggests the mitochondria of children with autism are unable to process pyruvate fast enough to keep up with the demand for energy, pointing to a novel deficiency at the level of an enzyme named pyruvate dehydrogenase.

Mitochondria also are the main intracellular source of oxygen free radicals. Free radicals are very reactive species that can harm cellular structures, including DNA. Cells are able to repair typical levels of such oxidative damage. Giulivi and her colleagues found that hydrogen peroxide levels in autistic children were twice as high as in normal children. As a result, the cells of children with autism were exposed to higher oxidative stress.

Mitochondria often respond to oxidative stress by making extra copies of their own DNA. The strategy helps ensure that some normal genes are present even if others have been damaged by oxidation. The researchers found higher mtDNA copy numbers in the lymphocytes of half of the children with autism. These children carried equally high numbers of mtDNA sets in their granulocytes, another type of immune cell, demonstrating that these effects were not limited to a specific cell type. Two of the five children also had deletions in their mtDNA genes, whereas none of the control children showed deletions.

Taken together, the various abnormalities, defects and levels of malfunction measured in the mitochondria of autistic children imply that oxidative stress in these organelles could be influencing autism's onset.

"The various dysfunctions we measured are probably even more extreme in brain cells, which rely exclusively on mitochondria for energy," said Isaac Pessah, director of the Center for Children's Environmental Health and Disease Prevention, a UC Davis MIND Institute researcher and professor of molecular biosciences at the UC Davis School of Veterinary Medicine.

Giulivi cautions that these findings do not amount to establishing a cause for autism.

"We took a snapshot of the mitochondrial dysfunction when the children were 2-to-5 years old. Whether this happened before they were born or after, this study can't tell us," she said. "However, the research furthers the understanding of autism on several fronts and may, if replicated, be used to help physicians diagnose the problem earlier."

"Pediatricians need to be aware of this issue so that they can ask the right questions to determine whether children with autism have vision or hearing problems or myopathies," Giulivi said. Exercise intolerance in the form of muscle cramps during intensive physical activity is one of the characteristics of mitochondrial myopathies.

The chemical fingerprints of mitochondrial dysfunction also may hold potential as a diagnostic tool. Giulivi and colleagues are now examining the mitochondrial DNA of their subjects more closely to pinpoint more precise differences between autistic and non-autistic children.

"If we find some kind of blood marker that is consistent with and unique to children with autism, maybe we can change the way we diagnose this difficult-to-assess condition," she said.

The study also helps refine the search for autism's origins.

"The real challenge now is to try and understand the role of mitochondrial dysfunction in children with autism," Pessah said. "For instance, many environmental stressors can cause mitochondrial damage. Depending on when a child was exposed, maternally or neonatally, and how severe that exposure was, it might explain the range of the symptoms of autism."

"This important exploratory research addresses in a rigorous way an emerging hypothesis about potential mitochondrial dysfunction and autism," said Cindy Lawler, program director at the National Institute of Environmental Health Sciences (NIEHS), which provided funding for the study. "Additional research in this area could ultimately lead to prevention or intervention efforts for this serious developmental disorder."

8. New Version of an Old Drug Could Treat Autism (and Addiction Too)

By Maia Szalavitz, Time.com

One night in 2006, Kathy Roberts rushed her autistic daughter, Jenny, to the hospital. Nothing had been able to stop the young woman, then in her mid-20s, from vomiting. Jenny had recently suffered several major seizures and her entire gastrointestinal system was going haywire.

To try to calm Jenny's GI tract, doctors at Massachusetts General Hospital prescribed baclofen, an antispasmodic drug that is also being studied as a potential treatment for alcoholism and other addictions. The drug relieved Jenny's vomiting, but it did something else too — a completely unexpected and welcome side effect. (More on TIME.com: Could Anorexia Be a 'Female' Form of Autism?)

"Within 24 hours, I saw a change," says Roberts. "Right away, I saw that it was globally calming. I've always described a state that she would get into where it seemed like she wasn't comfortable in her own skin, and was trying to crawl out. I saw that calmed down."

Roberts, founder of the Giant Step school for children with autism in Southport, Conn., called Mark Bear, professor of neuroscience at MIT and advisory board member of Giant Step. In 2005, Bear had co-founded a drug company called Seaside Therapeutics to develop treatments for autism and other developmental disorders. Roberts told Bear about baclofen's effect on her daughter, and a new line of research was born. (More on TIME.com: Picky Eating May Be Early Sign of Autism)

In September, Seaside announced positive results from a phase II clinical trial of STX209, an experimental drug that is chemically related to baclofen. In the trial, which was not blinded or placebo controlled, STX209 led to a reduction in agitation and related emotional outbursts in autistic people. Such behavior is common in people with autism — often, a result of anxiety caused by extreme sensory oversensitivity or frustration over being unable to communicate their needs. To cope, autistic people often develop behavioral mechanisms, include tantrums, social withdrawal or repetitive behaviors like rocking or hand flapping.

STX209, while not a cure, appeared to ease anxiety. "We're seeing reductions in a lot of types of outbursts and irritable behavior, along with increased communication and social behavior," says Dr. Randall Carpenter, co-founder, president and CEO of Seaside.

Carpenter says his team has conducted two clinical studies of STX209. One trial included 32 people with autism spectrum disorders. The other involved 63 people with Fragile X syndrome, a family of inherited developmental disorders linked with autism that are caused by changes in a single gene, the FMR1 gene. Fragile X is the most common known single-gene cause of autism, associated with 2% to 6% of all autism cases. About 25% of people with Fragile X have full-blown autism, but "pretty much 100% are on the spectrum," according to Carpenter. (More on TIME.com: Autism and the 'Intense World' Brain)

"A common characteristic in Fragile X is that people would like to be social, but [their condition] makes them very anxious," Carpenter says. Children with the disorder often shy away from new people — or approach them and then withdraw into repetitive motions.

But when these children take STX209, Carpenter says, "What we end up seeing is that they are more sociable. They communicate more, they make friends, they interact more and are less withdrawn."

What Is Baclofen — and STX209?
Like many drugs, baclofen contains two types of its main molecule, which are mirror images of each other. Often, one is an active ingredient, while the other is not. STX209, also known as arbaclofen, contains only the "right-handed" molecule of baclofen, the drug's active component. (More on Time.com: Building a Bridge to My Autistic Son: A Father's Photo Journey)

According to Carpenter, STX209 is about 10 times more potent than baclofen. In mice with a genetic mutation similar to the one that produces Fragile X in humans, Seaside's research found that the baclofen's left-handed molecule did not have the same effect as STX209 and, in fact, actually increased anxiety-related behavior.

Baclofen itself is a very old drug. It has been used since the 1920s as a treatment for muscle spasticity in conditions like cerebral palsy. Because of the way it affects a neurotransmitter called GABA, it has also been studied in animals since the 1980s as a potential treatment for addiction. Recently, it got a boost from a French doctor who himself suffers from alcoholism, who published a book on his recovery via baclofen called The End of My Addiction in 2009. (More on TIME.com: Can This Pill Replace Abstinence?)

Increasing GABA action calms the brain: drugs like Valium (benzodiazepines) and alcohol increase the neurotransmitter's activity. But unlike these drugs, which can produce an addictive high, baclofen eases anxiety without the euphoria. For all the time its been on the market, it has never become a drug of abuse. (Baclofen can cause withdrawal symptoms, however, if stopped abruptly.)

And interestingly, treating anxiety could be one key to treating addiction. Alcoholics and addicts often describe themselves without their drug of choice as being "not being comfortable in my own skin"— exactly the expression Roberts used to describe her daughter's state of discomfort before taking baclofen. (More on Time.com: Special Report: Kids and Mental Health)

Anectodally, baclofen has shown notable success at keeping alcoholics from drinking. But while some clinical trials have found positive results for addiction ranging from nicotine to cocaine, some found no effect. The most recent study, a double-blind placebo-controlled trial involving 80 alcoholics, saw neither a reduction in heavy drinking nor an increase in abstinence. However, that study used a 30-mg dose of baclofen, much lower than the 80-mg dose typically used by individuals and physicians who have reported success with the drug.

"Our research didn't find a separation of baclofen from placebo on drinking outcomes," says James Garbutt, a psychiatry professor at the University of North Carolina-Chapel Hill and author of the study, which was published in Alcoholism: Clinical and Experimental Research in November. "But it did reduce anxiety. We're actually interested in trying to do another trial with a higher dose."

Garbutt adds, "I really don't know a lot about autism but there does seem to be an anti-anxiety effect of baclofen...[and] if the fear circuitry is thought to be involved in autism, potentially, it could be of value." (More on Time.com: What Goes on Inside the Brain of a Misbehaving Boy?)

What GABA and Fear Have to Do with Autism
Animal models of autism and Fragile X suggest that part of the problem in these disorders is overactivity in a brain region called the amygdala, which is associated with fear and anxiety, and is normally calmed by GABA. Another problem may be a general reduction in activity in the whole brain's inhibitory circuitry, which relies on GABA as its main neurotransmitter.

A study published in the Journal of Neuroscience in July found that mice missing the same gene that fails in Fragile X not only had fewer inhibitory brain connections in general, but also had reductions in GABA availability in a key part of the amygdala. In these mice, a drug that increased GABA action (via a different route than that used by STX209) reduced the overactivity in the amygdala that resulted from the GABA deficit.

In another animal model of autism which found amygdala effects, researchers exposed pregnant rats to a drug called valproic acid (VPA). One in 10 human babies whose mothers have taken valproic acid during pregnancy develop autism. Rat pups born to exposed mothers were found to have increased activity in the amygdala and a resulting intensification of fear, compared with rats with mothers that didn't get the drug. VPA rats were quicker than unexposed rats to learn to fear a situation; they were also more likely to generalize that fear to other similar experiences, and slower to learn when the scary situation was rendered safe. They also showed other, autistic-like behavior. (More on Time.com: Addiction Files: Recovering From Drug Addiction, Without Abstinence)

Kamila Markram, director of the Autism Project at the Brain Mind Institute of the École Polytechnique Fédérale de Lausanne in Switzerland, has studied the VPA rat. She also has a stepson with an autistic condition. "We tried quite a lot of medications and therapies, from sports to different diets and all kinds of things," she says. "We did see that reducing anxiety in him was one of things that worked." Markram has not tried baclofen or STX209 for her stepson, but calls the idea of developing such a drug for autism "absolutely interesting."

What Is the Future of STX209?
Carpenter hopes to complete clinical trials of STX209 for autism and Fragile X in 2011. He says that the soonest a drug could possibly hit the market, if all goes well, would be 2013. Meanwhile, some parents are already using baclofen to treat autistic children "off label," a legal practice since the drug is approved for other uses. (More on Time.com: Study: Some Autistic Brains Really Are Wired Differently)

Carpenter says that participants in both of Seaside's STX209 trials were offered the option to switch to baclofen once the trial was complete, if they thought their children had been helped. "After about eight or 10 people tried it, the parents and clinicians were up in arms because they didn't think [baclofen] was working as well as what they'd seen in trial," he says. "The FDA allowed us to continue [treating people with STX209] under its provisions for compassionate use. Some are coming up on a year now and they continue to see improvement and stay on. Very few have dropped out."

Whether the drug will prove safe and effective in the long term, of course, is yet to be seen. But with no drugs approved for Fragile X and only two to treat autism — both aimed at relieving symptoms rather than treating the underlying problem — the development of STX209 will undoubtedly be closely watched, both by parents and the pharmaceutical industry.

9. Deadly Medicine

VanityFair.com

Prescription drugs kill some 200,000 Americans every year. Will that number go up, now that most clinical trials are conducted overseas—on sick Russians, homeless Poles, and slum-dwelling Chinese—in places where regulation is virtually nonexistent, the F.D.A. doesn’t reach, and “mistakes” can end up in pauper’s graves? The authors investigate the globalization of the pharmaceutical industry, and the U.S. Government’s failure to rein in a lethal profit machine.

By Donald L. Barlett and James B. SteeleJanuary 2011

TAKE TWO ASPIRIN
More and more clinical trials for new drugs are being outsourced overseas and conducted by companies for hire. Is oversight even possible? Photographs © Imagebroker/Alamy, from Image Source/Jupiter Images, © Vincent O’Byrne/Alamy (skulls); © Jason Salmon/Alamy (capsule).

You wouldn’t think the cities had much in common. Ias¸i, with a population of 320,000, lies in the Moldavian region of Romania. Mégrine is a town of 24,000 in northern Tunisia, on the Mediterranean Sea. Tartu, Estonia, with a population of 100,000, is the oldest city in the Baltic States; it is sometimes called “the Athens on the Emajõgi.” Shenyang, in northeastern China, is a major industrial center and transportation hub with a population of 7.2 million.

These places are not on anyone’s Top 10 list of travel destinations. But the advance scouts of the pharmaceutical industry have visited all of them, and scores of similar cities and towns, large and small, in far-flung corners of the planet. They have gone there to find people willing to undergo clinical trials for new drugs, and thereby help persuade the U.S. Food and Drug Administration to declare the drugs safe and effective for Americans. It’s the next big step in globalization, and there’s good reason to wish that it weren’t.

Once upon a time, the drugs Americans took to treat chronic diseases, clear up infections, improve their state of mind, and enhance their sexual vitality were tested primarily either in the United States (the vast majority of cases) or in Europe. No longer. As recently as 1990, according to the inspector general of the Department of Health and Human Services, a mere 271 trials were being conducted in foreign countries of drugs intended for American use. By 2008, the number had risen to 6,485—an increase of more than 2,000 percent. A database being compiled by the National Institutes of Health has identified 58,788 such trials in 173 countries outside the United States since 2000. In 2008 alone, according to the inspector general’s report, 80 percent of the applications submitted to the F.D.A. for new drugs contained data from foreign clinical trials. Increasingly, companies are doing 100 percent of their testing offshore. The inspector general found that the 20 largest U.S.-based pharmaceutical companies now conducted “one-third of their clinical trials exclusively at foreign sites.” All of this is taking place when more drugs than ever—some 2,900 different drugs for some 4,600 different conditions—are undergoing clinical testing and vying to come to market.

Some medical researchers question whether the results of clinical trials conducted in certain other countries are relevant to Americans in the first place. They point out that people in impoverished parts of the world, for a variety of reasons, may metabolize drugs differently from the way Americans do. They note that the prevailing diseases in other countries, such as malaria and tuberculosis, can skew the outcome of clinical trials. But from the point of view of the drug companies, it’s easy to see why moving clinical trials overseas is so appealing. For one thing, it’s cheaper to run trials in places where the local population survives on only a few dollars a day. It’s also easier to recruit patients, who often believe they are being treated for a disease rather than, as may be the case, just getting a placebo as part of an experiment. And it’s easier to find what the industry calls “drug-naïve” patients: people who are not being treated for any disease and are not currently taking any drugs, and indeed may never have taken any—the sort of people who will almost certainly yield better test results. (For some subjects overseas, participation in a clinical trial may be their first significant exposure to a doctor.) Regulations in many foreign countries are also less stringent, if there are any regulations at all. The risk of litigation is negligible, in some places nonexistent. Ethical concerns are a figure of speech. Finally—a significant plus for the drug companies—the F.D.A. does so little monitoring that the companies can pretty much do and say what they want.

Consent by Thumbprint

Many of today’s trials still take place in developed countries, such as Britain, Italy, and Japan. But thousands are taking place in countries with large concentrations of poor, often illiterate people, who in some cases sign consent forms with a thumbprint, or scratch an “X.” Bangladesh has been home to 76 clinical trials. There have been clinical trials in Malawi (61), the Russian Federation (1,513), Romania (876), Thailand (786), Ukraine (589), Kazakhstan (15), Peru (494), Iran (292), Turkey (716), and Uganda (132). Throw a dart at a world map and you are unlikely to hit a spot that has escaped the attention of those who scout out locations for the pharmaceutical industry.

The two destinations that one day will eclipse all the others, including Europe and the United States, are China (with 1,861 trials) and India (with 1,457). A few years ago, India was home to more American drug trials than China was, thanks in part to its large English-speaking population. But that has changed. English is now mandatory in China’s elementary schools, and, owing to its population edge, China now has more people who speak English than India does.

While Americans may be unfamiliar with the names of foreign cities where clinical trials have been conducted, many of the drugs being tested are staples of their medicine cabinets. One example is Celebrex, a non-steroidal anti-inflammatory drug that has been aggressively promoted in television commercials for a decade. Its manufacturer, Pfizer, the world’s largest drug company, has spent more than a billion dollars promoting its use as a pain remedy for arthritis and other conditions, including menstrual cramps. The National Institutes of Health maintains a record of most—but by no means all—drug trials inside and outside the United States. The database counts 290 studies involving Celebrex. Companies are not required to report—and do not report—all studies conducted overseas. According to the database, of the 290 trials for Celebrex, 183 took place in the United States, meaning, one would assume, that 107 took place in other countries. But an informal, country-by-country accounting by VANITY FAIR turned up no fewer than 207 Celebrex trials in at least 36 other countries. They ranged from 1 each in Estonia, Croatia, and Lithuania to 6 each in Costa Rica, Colombia, and Russia, to 8 in Mexico, 9 in China, and 10 in Brazil. But even these numbers understate the extent of the foreign trials. For example, the database lists five Celebrex trials in Ukraine, but just “one” of those trials involved studies in 11 different Ukrainian cities.

The Celebrex story does not have a happy ending. First, it was disclosed that patients taking the drug were more likely to suffer heart attacks and strokes than those who took older and cheaper painkillers. Then it was alleged that Pfizer had suppressed a study calling attention to these very problems. (The company denied that the study was undisclosed and insisted that it “acted responsibly in sharing this information in a timely manner with the F.D.A.”) Soon afterward the Journal of the Royal Society of Medicine reported an array of additional negative findings. Meanwhile, Pfizer was promoting Celebrex for use with Alzheimer’s patients, holding out the possibility that the drug would slow the progression of dementia. It didn’t. Sales of Celebrex reached $3.3 billion in 2004, and then began to quickly drop.

“Rescue Countries”

One big factor in the shift of clinical trials to foreign countries is a loophole in F.D.A. regulations: if studies in the United States suggest that a drug has no benefit, trials from abroad can often be used in their stead to secure F.D.A. approval. There’s even a term for countries that have shown themselves to be especially amenable when drug companies need positive data fast: they’re called “rescue countries.” Rescue countries came to the aid of Ketek, the first of a new generation of widely heralded antibiotics to treat respiratory-tract infections. Ketek was developed in the 1990s by Aventis Pharmaceuticals, now Sanofi-Aventis. In 2004—on April Fools’ Day, as it happens—the F.D.A. certified Ketek as safe and effective. The F.D.A.’s decision was based heavily on the results of studies in Hungary, Morocco, Tunisia, and Turkey.

The approval came less than one month after a researcher in the United States was sentenced to 57 months in prison for falsifying her own Ketek data. Dr. Anne Kirkman-Campbell, of Gadsden, Alabama, seemingly never met a person she couldn’t sign up to participate in a drug trial. She enrolled more than 400 volunteers, about 1 percent of the town’s adult population, including her entire office staff. In return, she collected $400 a head from Sanofi-Aventis. It later came to light that the data from at least 91 percent of her patients was falsified. (Kirkman-Campbell was not the only troublesome Aventis researcher. Another physician, in charge of the third-largest Ketek trial site, was addicted to cocaine. The same month his data was submitted to the F.D.A. he was arrested while holding his wife hostage at gunpoint.) Nonetheless, on the basis of overseas trials, Ketek won approval.

As the months ticked by, and the number of people taking the drug climbed steadily, the F.D.A. began to get reports of adverse reactions, including serious liver damage that sometimes led to death. The F.D.A.’s leadership remained steadfast in its support of the drug, but criticism by the agency’s own researchers eventually leaked out (a very rare occurrence in this close-knit, buttoned-up world). The critics were especially concerned about an ongoing trial in which 4,000 infants and children, some as young as six months, were recruited in more than a dozen countries for an experiment to assess Ketek’s effectiveness in treating ear infections and tonsillitis. The trial had been sanctioned over the objections of the F.D.A.’s own reviewers. One of them argued that the trial never should have been allowed to take place—that it was “inappropriate and unethical because it exposed children to harm without evidence of benefits.” In 2006, after inquiries from Congress, the F.D.A. asked Sanofi-Aventis to halt the trial. Less than a year later, one day before the start of a congressional hearing on the F.D.A.’s approval of the drug, the agency suddenly slapped a so-called black-box warning on the label of Ketek, restricting its use. (A black-box warning is the most serious step the F.D.A. can take short of removing a drug from the market.) By then the F.D.A. had received 93 reports of severe adverse reactions to Ketek, resulting in 12 deaths.

During the congressional hearings, lawmakers heard from former F.D.A. scientists who had criticized their agency’s oversight of the Ketek trials and the drug-approval process. One was Dr. David Ross, who had been the F.D.A.’s chief reviewer of new drugs for 10 years, and was now the national director of clinical public-health programs for the U.S. Department of Veterans Affairs. When he explained his objections, he offered a litany of reasons that could be applied to any number of other drugs: “Because F.D.A. broke its own rules and allowed Ketek on the market. Because dozens of patients have died or suffered needlessly. Because F.D.A. allowed Ketek’s maker to experiment with it on children over reviewers’ protests. Because F.D.A. ignored warnings about fraud. And because F.D.A. used data it knew were false to reassure the public about Ketek’s safety.”

Trials and Error

To have an effective regulatory system you need a clear chain of command—you need to know who is responsible to whom, all the way up and down the line. There is no effective chain of command in modern American drug testing. Around the time that drugmakers began shifting clinical trials abroad, in the 1990s, they also began to contract out all phases of development and testing, putting them in the hands of for-profit companies. It used to be that clinical trials were done mostly by academic researchers in universities and teaching hospitals, a system that, however imperfect, generally entailed certain minimum standards. The free market has changed all that. Today it is mainly independent contractors who recruit potential patients both in the U.S. and—increasingly—overseas. They devise the rules for the clinical trials, conduct the trials themselves, prepare reports on the results, ghostwrite technical articles for medical journals, and create promotional campaigns. The people doing the work on the front lines are not independent scientists. They are wage-earning technicians who are paid to gather a certain number of human beings; sometimes sequester and feed them; administer certain chemical inputs; and collect samples of urine and blood at regular intervals. The work looks like agribusiness, not research.

What began as a mom-and-pop operation has grown into a vast army of formal “contract-research organizations” that generate annual revenue of $20 billion. They can be found conducting trials in every part of the world. By far the largest is Quintiles Transnational, based in Durham, North Carolina. It offers the services of 23,000 employees in 60 countries, and claims that it has “helped develop or commercialize all of the top 30 best-selling drugs.”

Quintiles is privately owned—its investors include two of the U.S.’s top private-equity firms. Other private contractors are public companies, their stock traded on Wall Street. Pharmaceutical Product Development (P.P.D.), a full-service medical contractor based in Wilmington, North Carolina, is a public company with 10,500 employees. It, too, has conducted clinical trials all around the world. In fact, it was involved in the clinical trials for Ketek—a P.P.D. research associate, Ann Marie Cisneros, had been assigned to monitor Dr. Anne Kirkman-Campbell’s testing in Alabama. Cisneros later told the congressional investigating committee that Kirkman-Campbell had indeed engaged in fraud. “But what the court that sentenced her did not know,” Cisneros said, was that “Aventis was not a victim of this fraud.” Cisneros said she had reported her findings of fraud to her employer, P.P.D., and also to Aventis. She told the congressional committee, “What brings me here today is my disbelief at Aventis’s statements that it did not know that fraud was being committed. Mr. Chairman, I knew it, P.P.D. knew it, and Aventis knew it.” Following her testimony the company released a statement saying it regretted the violations that occurred during the study but was not aware of the fraud until after the data was submitted to the F.D.A.

The F.D.A., the federal agency charged with oversight of the food and drugs that Americans consume, is rife with conflicts of interest. Doctors who insist the drug you take is perfectly safe may be collecting hundreds of thousands of dollars from the company selling the drug. (ProPublica, an independent, nonprofit news organization that is compiling an ongoing catalogue of pharmaceutical-company payments to physicians, has identified 17,000 doctors who have collected speaking and consulting fees, including nearly 400 who have received $100,000 or more since 2009.) Quite often, the F.D.A. never bothers to check for interlocking financial interests. In one study, the agency failed to document the financial interests of applicants in 31 percent of applications for new-drug approval. Even when the agency or the company knew of a potential conflict of interest, neither acted to guard against bias in the test results.

Because of the deference shown to drug companies by the F.D.A.—and also by Congress, which has failed to impose any meaningful regulation—there is no mandatory public record of the results of drug trials conducted in foreign countries. Nor is there any mandatory public oversight of ongoing trials. If one company were to test an experimental drug that killed more patients than it helped, and kept the results secret, another company might unknowingly repeat the same experiment years later, with the same results. Data is made available to the public on a purely voluntary basis. Its accuracy is unknown. The oversight that does exist often is shot through with the kinds of ethical conflicts that Wall Street would admire. The economic incentives for doctors in poor countries to heed the wishes of the drug companies are immense. An executive at a contract-research organization told the anthropologist Adriana Petryna, author of the book When Experiments Travel: “In Russia, a doctor makes two hundred dollars a month, and he is going to make five thousand dollars per Alzheimer’s patient” that he signs up. Even when the most flagrant conflicts are disclosed, penalties are minimal. In truth, the same situation exists in the United States. There’s just more of a chance here, though not a very large one, that adverse outcomes and tainted data will become public. When the pharmaceutical industry insists that its drugs have been tested overseas in accordance with F.D.A. standards, this may be true—but should provide little assurance.

The F.D.A. gets its information on foreign trials almost entirely from the companies themselves. It conducts little or no independent research. The investigators contracted by the pharmaceutical companies to manage clinical trials are left pretty much on their own. In 2008 the F.D.A. inspected just 1.9 percent of trial sites inside the United States to ensure that they were complying with basic standards. Outside the country, it inspected even fewer trial sites—seven-tenths of 1 percent. In 2008, the F.D.A. visited only 45 of the 6,485 locations where foreign drug trials were being conducted.

The pharmaceutical industry dismisses concerns about the reliability of clinical trials conducted in developing countries, but the potential dangers were driven home to Canadian researchers in 2007. While reviewing data from a clinical trial in Iran for a new heart drug, they discovered that many of the results were fraudulent. “It was bad, so bad we thought the data was not salvageable,” Dr. Gordon Guyatt, part of the research group at McMaster University in Hamilton, told Canada’s National Post.

In addition to monitoring trials abroad, which it does not really do, the F.D.A. is responsible for inspecting drug-manufacturing plants in other countries, which it also does not really do. In 2007 and 2008, hundreds of patients taking the blood thinner heparin, which among other purposes is used to prevent blood clots during surgery and dialysis, developed serious allergic reactions as a result of a contaminant introduced at a Chinese manufacturing facility. It took months for the F.D.A., its Chinese counterpart, and Baxter International, the pharmaceutical company that distributed the drug, to track the source of contamination to Changzhou, a city of 3.5 million on the Yangtze River.

The delay was perhaps understandable, given the manufacturing process. The raw material for Baxter’s heparin comes from China’s many small pig farms. To be precise, it’s derived from the mucous membranes of the intestines of slaughtered pigs; the membranes are mixed together and cooked, often in unregulated family workplaces. By the time the source of the contaminant was pinpointed, many more patients in the United States had experienced severe reactions, and as many as 200 had died. It later turned out that the F.D.A. had indeed inspected a Chinese plant—but it was the wrong one. The federal regulators had confused the names.

The good news was that, in this instance, the F.D.A. at least knew which country the heparin had come from. The bad news is that it does not always know where clinical trials are being conducted, or even the names or types of drugs being tested, or the purpose for which they will be prescribed once approved. Companies may withhold the foreign test data until they actually submit the application to the F.D.A. for approval. By then the agency has lost the ability to see whether the trials were managed according to acceptable standards, and whether the data collected was manipulated or fabricated.

$350 per Child

If the globalization of clinical trials for adult medications has drawn little attention, foreign trials for children’s drugs have attracted even less. The Argentinean province of Santiago del Estero, with a population of nearly a million, is one of the country’s poorest. In 2008 seven babies participating in drug testing in the province suffered what the U.S. clinical-trials community refers to as “an adverse event”: they died. The deaths occurred as the children took part in a medical trial to test the safety of a new vaccine, Synflorix, to prevent pneumonia, ear infections, and other pneumococcal diseases. Developed by GlaxoSmithKline, the world’s fourth-largest pharmaceutical company in terms of global prescription-drug sales, the new vaccine was intended to compete against an existing vaccine. In all, at least 14 infants enrolled in clinical trials for the drug died during the testing. Their parents, some illiterate, had their children signed up without understanding that they were taking part in an experiment. Local doctors who persuaded parents to enroll their babies in the trial reportedly received $350 per child. The two lead investigators contracted by Glaxo were fined by the Argentinean government. So was Glaxo, though the company maintained that the mortality rate of the children “did not exceed the rate in the regions and countries participating in the study.” No independent group conducted an investigation or performed autopsies. As it happens, the brother of the lead investigator in Santiago del Estero was the Argentinean provincial health minister.

In New Delhi, 49 babies died at the All India Institute of Medical Sciences while taking part in clinical trials over a 30-month period. They were given a variety of new drugs to treat everything from high blood pressure to chronic focal encephalitis, a brain inflammation that causes epileptic seizures and other neurological problems. The blood-pressure drugs had never before been given to anyone under 18. The editor of an Indian medical journal said it was obvious that the trials were intended to extend patent life in Western countries “with no consequence or benefit for India, using Indian children as guinea pigs.” In all, 4,142 children were enrolled in the studies, two-thirds of them less than one year old. But the head of the pediatrics department at the All India Institute maintained that “none of the deaths was due to the medication or interventions used in clinical trials.”

For years, American physicians gave anti-psychotic medicines to children “off label,” meaning that they wrote prescriptions based on testing for adults, sometimes even for different conditions. That didn’t work out so well for the children, who, when it comes to medicine, really are not just little adults. To provide the pharmaceutical industry with an incentive to conduct clinical trials on children’s versions of adult drugs, Congress in 1997 enacted legislation, known as the Pediatric Exclusivity Provision, extending the patent life of certain drugs by six months. It worked so well that the industry has, in the ensuing years, been able to put younger and younger children on more and more drugs, pocketing an extra $14 billion. Between 1999 and 2007, for instance, the use of anti-psychotic medications on children between the ages of two and five more than doubled.

A study of 174 trials under the Pediatric Exclusivity Provision found that 9 percent of them did not report the location or number of sites of the clinical trials. Of those that did, two-thirds had been conducted in at least one country outside the United States, and 11 percent were conducted entirely outside the United States. Of the 79 trials with more than 100 subjects participating, 87 percent enrolled patients outside the United States. As is the case with adult studies, many children’s trials conducted abroad are neither reported nor catalogued on any publicly accessible government database. There is no public record of their existence or their results.

In the mid-90s, Glaxo conducted clinical trials on the antidepressant Paxil in the United States, Europe, and South America. Paxil is a member of a class of drugs called selective serotonin re-uptake inhibitors. The class includes Zoloft, Prozac, and Lexapro. In the United Kingdom, Paxil is sold as Seroxat. The clinical trials showed that the drug had no beneficial effect on adolescents; some of the trials indicated that the placebo was more effective than the drug itself. But Glaxo neglected to share this information with consumers; annual sales of the drug had reached $5 billion in 2003. In an internal document obtained by the Canadian Medical Association Journal, the company emphasized how important it was to “effectively manage the dissemination of these data in order to minimize any potential negative commercial impact.” The memo went on to warn that “it would be commercially unacceptable to include a statement that efficacy had not been demonstrated.” After the document was released a Glaxo spokesperson said that the “memo draws an inappropriate conclusion and is not consistent with the facts.”

“Smoke and Mirrors”

It may be just a coincidence, but as controversy swirls around new drugs, and as the F.D.A. continues to slap medicines with new warning labels—especially the black-box warnings that indicate the most serious potential reactions—most of the problematic drugs have all undergone testing outside the United States. Clinical-trial representatives working for GlaxoSmithKline went to Ias¸i, Romania, to test Avandia, a diabetes drug, on the local population. Glaxo representatives also showed up in other cities in Romania—Bucures¸ti, Cluj-Napoca, Craiova, and Timis¸oara—as well as multiple cities in Latvia, Ukraine, Slovakia, the Russian Federation, Poland, Hungary, Lithuania, Estonia, the Czech Republic, Bulgaria, Croatia, Greece, Belgium, the Netherlands, Germany, France, and the United Kingdom. That was for the largest of the Avandia clinical trials. But there have been scores of others, all seeking to prove that the drug is safe and effective. Some took place before the drug was approved by the F.D.A. Others were “post-marketing” studies, done after the fact, as the company cast about for ways to come up with more positive results so it could expand Avandia’s use for other treatments. Based on the initial evaluations, Avandia was expected to—and did—become another Glaxo multi-billion-dollar best-seller.

While sales soared, so, too, did reports of adverse reactions—everything from macular edema to liver injury, from bone fractures to congestive heart failure. In 2009 the Institute for Safe Medication Practices, a Pennsylvania-based nonprofit group that monitors the prescription-drug field, linked the deaths of 1,354 people to Avandia, based on reports filed with the F.D.A. Studies also concluded that people taking the drug had an increased risk of developing heart disease, one of the very conditions that doctors treating diabetics hope to forestall. The risk was so high that worried doctors inside and outside the F.D.A. sought to have the drug removed from the market, an incredibly difficult task no matter how problematic the medicine. As always, the F.D.A. was late to the party. In 2008 the American Diabetes Association and the European Association for the Study of Diabetes had warned against using Avandia. The Saudi Arabian drug-regulatory agency yanked it from the market, and the Indian government asked Glaxo to halt 19 of its Avandia trials in that country. In September 2010 the European Medicines Agency pulled Avandia from the shelves all across Europe. The F.D.A. still could not bring itself to take decisive action. This even though the F.D.A. knew that Glaxo had withheld critical safety information concerning the increased risk of heart attacks, and the F.D.A. itself had estimated that the drug had caused more than 83,000 heart attacks between 1999 and 2007. The agency settled for imposing new restrictions on the availability of the drug in the United States. Glaxo released a statement saying that it “continues to believe that Avandia is an important treatment for patients with type 2 diabetes,” but that it would “voluntarily cease promotion of Avandia in all the countries in which it operates.”

The Avandia case and others like it have prompted the U.S. Justice Department to mount an investigation under the Foreign Corrupt Practices Act. While it is legal for doctors in this country to accept money from drug companies for acting as consultants, this is not the case abroad, where doctors often are government employees, and such payments can be considered bribes. There are other legal issues. So far, Glaxo has paid out more than $1 billion to settle lawsuits arising from claims against Avandia and other drugs. The Senate Finance Committee calculates that, since May 2004, seven drug companies have paid out more than $7 billion in fines and penalties stemming from unlawful drug dealings. Pfizer paid the largest such fine in history—$2.3 billion for promoting off-label uses of the arthritis drug Bextra.

In theory, pharmaceutical companies are barred from selling a drug for any purpose other than the one that the F.D.A. has approved on the basis of clinical testing. But the reality is different. The minute a drug receives the green light from the F.D.A. for a specific treatment, the sponsoring company and its allies begin campaigns to make it available for other purposes or for other types of patients. The antidepressant Paxil was tested on adults but sold off-label to treat children. Seroquel, an anti-psychotic, was marketed as a treatment for depression. Physicians, often on retainer from pharmaceutical companies, are free to prescribe a drug for any reason if they entertain a belief that it will work. This practice turns the population at large into unwitting guinea pigs whose adverse reactions may go unreported or even unrecognized.

To secure the F.D.A.’s approval for Seroquel, which ultimately would go to treat schizophrenia, bipolar disorders, and manic episodes associated with bipolar disorder, AstraZeneca, the fifth-largest pharmaceutical company, conducted clinical trials across Asia, Europe, and the United States. Among the sites: Shenyang and more than a dozen other cities in China, and multiple cities in Bulgaria, Estonia, Hungary, Latvia, Lithuania, Croatia, Indonesia, Malaysia, Poland, the Russian Federation, Serbia, Ukraine, and Taiwan. The F.D.A. initially approved the drug for the treatment of schizophrenia. But while schizophrenia may have opened the door, off-label sales opened the cash register. Money poured in by the billions as AstraZeneca promoted the drug for the treatment of any number of other conditions. It was prescribed for children with autism-spectrum disorders and retardation as well as for elderly Alzheimer’s patients in nursing homes. The company touted the drug for treatment of aggression, anxiety, anger-management issues, attention-deficit hyperactivity disorder, dementia, and sleeplessness. Up to 70 percent of the prescriptions for Seroquel were written for a purpose other than the one for which it had been approved, and sales rose to more than $4 billion a year.

It turned out, however, that AstraZeneca had been less than candid about the drug’s side effects. One of the most troubling: patients often gained weight and developed diabetes. This meant a new round of drugs to treat conditions caused by Seroquel. In an internal e-mail from 1997 discussing a study comparing Seroquel with an older anti-psychotic drug, Haldol, a company executive praised the work of the project physician, saying she had done a great “smoke-and-mirrors job,” which “should minimize (and dare I venture to suggest) could put a positive spin (in terms of safety) on this cursed study.” After the e-mail was disclosed, in February 2009, the company said that the document cannot “obscure the fact that AstraZeneca acted responsibly and appropriately as it developed and marketed” the drug. In April, AstraZeneca reached a half-billion-dollar settlement with the federal government over its marketing of Seroquel. The U.S. attorney in Philadelphia, where the settlement was filed, declared that the company had “turned patients into guinea pigs in an unsupervised drug test.” Meanwhile, the company was facing more than 25,000 product-liability lawsuits filed by people who contended the drug had caused their diabetes.

Death Toll

The only people who seem to care about the surge of clinical trials in foreign countries are the medical ethicists—not historically a powerhouse when it comes to battling the drug companies. A team of physician-researchers from Duke University, writing last year in the New England Journal of Medicine, observed that “this phenomenon raises important questions about the economics and ethics of clinical research and the translation of trial results to clinical practice: Who benefits from the globalization of clinical trials? What is the potential for exploitation of research subjects? Are trial results accurate and valid, and can they be extrapolated to other settings?” The Duke team noted that, in some places, “financial compensation for research participation may exceed participants’ annual wages, and participation in a clinical trial may provide the only access to care” for those taking part in the trial. In 2007, residents of a homeless shelter in Grudziadz, Poland, received as little as $2 to take part in a flu-vaccine experiment. The subjects thought they were getting a regular flu shot. They were not. At least 20 of them died. The same distorting economic pressures exist for local hospitals or doctors, who may collect hundreds of dollars for every patient they enroll. In theory, a federal institutional review board is supposed to assess every clinical trial, with special concern for the welfare of the human subjects, but this work, too, has now been outsourced to private companies and is often useless. In 2009 the Government Accountability Office conducted a sting operation, winning approval for a clinical trial involving human subjects; the institutional review board failed to discover (if it even tried) that it was dealing with “a bogus company with falsified credentials” and a fake medical device. This was in Los Angeles. If that is oversight in the U.S., imagine what it’s like in Kazakhstan or Uganda. Susan Reverby, the Wellesley historian who uncovered the U.S. government’s syphilis experiments in Guatemala during the 1940s, was asked in a recent interview to cite any ongoing experimental practices that gave her pause. “Frankly,” she said, “I am mostly worried about the drug trials that get done elsewhere now, which we have little control over.”

The pharmaceutical industry, needless to say, has a different view. It argues that people participating in a clinical trial may be getting the highest quality of medical care they have ever received. That may be true in the short term. But, unfortunately, the care lasts only until the trial is completed. Many U.S. medical investigators who manage drug trials abroad say they prefer to work overseas, where regulations are lax and “conflict of interest” is a synonym for “business as usual.” Inside the United States, doctors who oversee trials are required to fill out forms showing any income they have received from drug companies so as to guard against financial biases in trials. This explains in part why the number of clinical-trial investigators registered with the F.D.A. fell 5.2 percent in the U.S. between 2004 and 2007 while increasing 16 percent in Eastern Europe, 12 percent in Asia, and 10 percent in Latin America. In a recent survey, 70 percent of the eligible U.S. and Western European clinical investigators interviewed said they were discouraged by the current regulatory environment, partly because they are compelled to disclose financial ties to the pharmaceutical industry. In trials conducted outside the United States, few people care.

In 2009, according to the Institute for Safe Medication Practices, 19,551 people died in the United States as a direct result of the prescription drugs they took. That’s just the reported number. It’s decidedly low, because it is estimated that only about 10 percent of such deaths are reported. Conservatively, then, the annual American death toll from prescription drugs considered “safe” can be put at around 200,000. That is three times the number of people who die every year from diabetes, four times the number who die from kidney disease. Overall, deaths from F.D.A.-approved prescription drugs dwarf the number of people who die from street drugs such as cocaine and heroin. They dwarf the number who die every year in automobile accidents. So far, these deaths have triggered no medical crusades, no tough new regulations. After a dozen or so deaths linked to runaway Toyotas, Japanese executives were summoned to appear before lawmakers in Washington and were subjected to an onslaught of humiliating publicity. When the pharmaceutical industry meets with lawmakers, it is mainly to provide campaign contributions.

And with more and more of its activities moving overseas, the industry’s behavior will become more impenetrable, and more dangerous, than ever.