Pharma and Drug Trials
More details emerge on fateful French drug trial
By Martin Enserink
A day after news broke about a clinical research tragedy in France, more details are beginning to emerge about what happened at Biotrial, the private research company in Rennes where the phase I study took place. An information sheet for prospective trial participants, posted yesterday at the French regional news site Breizh-info.com, provides an overview of the study's goal and procedures, while also offering a glimpse of what it's like to partake in a lengthy drug safety study.
According to the document, which is in French, participants in this particular study group were to receive €1900, including travel expenses; in return, they agreed to stay at Biotrial's facility in Rennes for 2 weeks, swallow a drug on 10 consecutive days, undergo extensive medical tests, and provide at least 40 blood samples.
Meanwhile, the Portuguese pharmaceutical company that sponsored the trial, Bial, confirmed in a statement issued last night that the drug tested in the study was an inhibitor of fatty acid amide hydrolase (FAAH), an enzyme that breaks down so-called endocannabinoids in the brain. FAAH inhibitors have been proposed as a possible treatment against chronic pain.
The study was halted on Monday, and all six patients who had taken the drug were hospitalized; one is brain dead, four others have neurological symptoms of varying severity, while one is under observation but without symptoms, neurologist Gilles Edan of the University of Rennes Hospital Center said yesterday. MRI imaging has shown "deep, necrotic and hemorrhagic lesions in the brain" of the patients, Edan said.
Neither Biotrial nor Bial have confirmed the authenticity of the document on Breizh-info.com. But several details suggest it is indeed the information provided to healthy volunteers who were considering participating in the study before it started. The sheet describes a study of BIA 10-2474, a compound that Bial lists as being in phase I tests on its drug pipeline. Several potential therapeutic applications mentioned in the sheet match information provided by French health minister Marisol Touraine at a press conference yesterday.
The timing is consistent as well; according to the document, participants in this particular trial group had to stay at the Biotrial facility from 4 January through 18 January; the first of 10 daily doses of BIA 10-2474 was to be administered on the third day of their stay. (Touraine said yesterday that drug administration began on 7 January.) Breizh-info.com says the document was provided by someone who applied to be enrolled but was rejected.
According to the document, the trial enrolled nonsmoking men and women aged between 18 and 55 who had a body mass index between 19 and 30. The plan was to give patients BIA 10-2474 every day between the third and thirteenth day of their stay at the clinic, while they underwent an extensive battery of tests and sampling—including as many as nine blood collections on some days. On the first and last day of drug administration, patients' heart rates were to be monitored around the clock while all of their urine was collected for analysis. (Between day 3 and 9, however, all they apparently had to do was take BIA 10-2474 and provide a single blood sample.) They were due to be released on 18 January but had to come back for a final check-up and more sampling on 1 February.
FAAH breaks down a series of compounds in the body called endogenous cannabinoids, the best known of which is anandamide. These molecules activate cannabinoid receptors—the same ones that bind THC, the key component of cannabis. BIA 10-2474 is designed to inhibit FAAH, and thus slow the breakdown of endogenous cannabinoids, which might help fight pain. But Biotrial's information sheet lists a wide range of other possible therapeutic applications, including anxiety, motor problems in Parkinson's disease, multiple sclerosis, cancer, hypertension, and obesity.
Pfizer tested another FAAH inhibitor as a possible painkiller for patients with osteoarthritis of the knee, but reported in 2012 that it didn't work in a phase II study. The trial didn't reveal any serious side effects from that drug, however.
Why BIA 10-2474 would cause such severe damage is unclear. Bial says that the new drug had already been administered to 108 patients "without any moderate or serious adverse reaction." But phase I clinical trials usually start with single or lower doses; the six patients may have been the first to receive multiple doses.
It's possible that BIA 10-2474 drug has completely unexpected effects because it binds to another target besides FAAH, molecular pharmacologist Stephen Alexander of the University of Nottingham in the United Kingdom said in a statement distributed by the Science Media Center (SMC) today; such "off-target" interactions might only become dangerous with more extensive exposure. "Another option is a dosing accident, where patients were given far more than clinicians thought was in the dosage form," neuropharmacologist Ben Whalley of the University of Reading added, also in an SMC statement.
French authorities have already announced three investigations into the tragedy, with which Bial promised to cooperate. "Several BIAL representatives are currently at the site to monitor the situation with the research center and the hospital, ensuring the necessary cooperation with these entities, as well as with the relevant authorities," the statement says.
Source : Science Mag (January 2016)
HHS Told To Probe ‘Unethical’ Novartis Trials
The federal government was asked by a watchdog group to investigate several allegedly “unethical long-term, placebo-controlled studies” for indacterol, a Novartis drug for treating moderate to severe chronic obstructuve pulmonary disease. Why? “The studies were marred by a failure to minimize risk to subjects and inadequate information provided to subjects,” according to Public Citizen. In a letter sent to the Office for Human Research Protections at the US Department of Health and Human Services, the group alleges there six “unethical” studies in which placebo-control subjects received prolonged substandard care. Put another way, Public Citizen charges the patients were prevented from using widely acknowledged standard care and that informed consent was likely inadequate because placebo patients would not have known substandard care would be offered.
“The scientific question of whether indacaterol was better than placebo for treating moderate to severe COPD was not an important or clinically useful question, given the existing state of knowledge about COPD treatment at the time these studies were conducted. Rather, the important question is whether indacaterol is at least as good as currently available bronchodilator therapy,” the group writes.
Specifically, the watchdog group writes that more than 1700 subjects were assigned to placebo groups for three to 12 months and were allowed to use daily inhaled steroids and short-acting beta-agonists, but were not permitted to use any long-acting beta-agonists or short- or long-acting inhaled anticholinergics or to start inhaled corticosteroids.
The move comes just one week after an FDA panel voted 13 to 4 to back the med, but only at 75 mg, a lower dose than used in Europe. However, the same advisory committee voted 12 to 5 against endorsing the 150 mg dose. Two years ago, the FDA declined to approve the drug over safety issues and asked Novartis to look at lower doses.
However, Public Citizen does not want the FDA to look into this. Why? “It is clear FDA has a conflict of interest and should not be asked to investigate our allegations because Novartis conducted these placebo-controlled trials with the full knowledge and endorsement of the FDA. Therefore, since FDA is complicit in this unethical research, we urge OHRP to take the lead in investigating our allegations” (read the letter here).
Asia: Guinea Pigs Aplenty for Drug Giants
Bangkok, Thailand — Before any pill reaches the pharmacy shelf, it must first pass through a gauntlet of human guinea pigs: the “clinical subjects” paid to take trial drugs so specialists can observe their symptoms.
But like call centers and high-end hospitals, drug trials too are rapidly shifting to India and Asia with Thailand as the region’s favored frontrunner.
For Western pharmaceutical giants such as Pfizer and GlaxoSmithKline, Asia offers a glut of people willing to accept less money for testing out trial medicines. Softer regulation is another big draw, as are improvements in Asian hospitals’ facilities and an increase in Western-educated doctors.
How Fast is Asia's Drug Trial Industry Growing?
Very fast. Just eight years ago, only 6 percent of the world’s drug trial patients were tested in Asia and India. The figure is now 11 percent, according to CMR International, which produces the leading study on pharmaceutical research.
In that same eight-year stretch, North America’s share of patients dropped from 53 to 32 percent. Asia was mostly responsible for eroding that share, though the number of patients increased slightly in Europe and Latin America.
While China and Japan conduct the most studies, Thailand has become the region’s most desirable location, according to the CMR report. In the past year alone, its ongoing studies have jumped 36 percent to 800 open trials.
What do Drug Trial Volunteers Have to Do?
Their experiences will vary wildly depending on the trial. One typical test, which measures the speed of blood stream absorption, can require volunteers to consume a pill and submit to more than 35 blood draws throughout a weekend. Two weekends of testing, in the United States, would pay approximately $1,000. Volunteers in Thailand would more likely receive less than $50.
Other disease-specific trials test experimental drugs on patients over a series of weeks or months. The “payment” in these studies typically isn’t cash but rather the promise of cutting-edge treatment.
Generally, a study conducted in Thailand is about one-third the cost of a U.S.-based study, said Sasitorn Kittivoravitkul, director of Bangkok clinical study firm Bio-Innova & Synchron.
Why is Thailand Now Favored by Drug Firms?
Its people are largely healthy and eligible for testing thanks to a 90-cents-per-visit public healthcare scheme. Its hospitals are staffed by English-speaking physicians and specialists educated abroad.
There’s also no single Thai regulatory body responsible for approving trials — both a convenience and source of frustration for pharmaceutical firms.
In a departure from Western standards, trial supervisors don’t have to report what the industry calls “Unexpected Suspected Adverse Drug Reactions” — meaning worrisome side-effects of prototype drugs don’t have to be documented. (Draft legislation could change this.)
“Thailand’s leading position is largely due to the lack of uniform legislation regarding clinical trials,” according to Paul Russell, who monitors regulatory law for the Bangkok-based Tilleke & Gibbins law firm. “Since there is no central regulation, companies feel more comfortable conducting clinical trials in Thailand.”
Thailand’s favored status is no accident. The Thai public health ministry and the Board of Investment — a state-owned arm devoted to luring in foreign investors — have worked in synch to court Western pharmaceutical giants. The government continues to lure in foreign pharmaceutical firms and expects its bio-technology industry to produce $882 million in revenue by 2011.
What are Thailand's Drawbacks?
Slippery legislation can also make trouble for Big Pharma. Major drug firms despise “compulsory licensing,” a government’s decision to ignore copyright and cheaply mass-produce a drug in the name of improving public health. Thailand hijacked patents for HIV and heart medicines in 2006 after a military coup installed a nationalist leadership willing to upset major drug firms.
This outraged the Pharmaceuticals and Manufacturers of America, a D.C. lobby that claimed the patent violations caused a “a very unpredictable business environment” that undermines positive perceptions of Thailand’s emerging drug trials industry.
What's Next for Drug Trials in Asia?
Many studies in Thailand involve testing “bio-equivalence,” which mostly involves ensuring generic drugs work as well as the more-expensive drugs they’re meant to imitate. The process is much less scientifically strenuous than testing a totally original drug. So far, there’s still too little infrastructure or stability to invite a major wave of higher-end drug trials.
This presents an opportunity for India, which is beginning to attempt more sophisticated, high-risk trials. India shows the “strongest inclination to invest in innovative research & development,” according to the CMR report. Still, excluding Japan, India and the rest of Asia receive less than 1 percent of pharmaceutical research expenditure worldwide.
Source : Truthout
Link to Source
By Martin Enserink
A day after news broke about a clinical research tragedy in France, more details are beginning to emerge about what happened at Biotrial, the private research company in Rennes where the phase I study took place. An information sheet for prospective trial participants, posted yesterday at the French regional news site Breizh-info.com, provides an overview of the study's goal and procedures, while also offering a glimpse of what it's like to partake in a lengthy drug safety study.
According to the document, which is in French, participants in this particular study group were to receive €1900, including travel expenses; in return, they agreed to stay at Biotrial's facility in Rennes for 2 weeks, swallow a drug on 10 consecutive days, undergo extensive medical tests, and provide at least 40 blood samples.
Meanwhile, the Portuguese pharmaceutical company that sponsored the trial, Bial, confirmed in a statement issued last night that the drug tested in the study was an inhibitor of fatty acid amide hydrolase (FAAH), an enzyme that breaks down so-called endocannabinoids in the brain. FAAH inhibitors have been proposed as a possible treatment against chronic pain.
The study was halted on Monday, and all six patients who had taken the drug were hospitalized; one is brain dead, four others have neurological symptoms of varying severity, while one is under observation but without symptoms, neurologist Gilles Edan of the University of Rennes Hospital Center said yesterday. MRI imaging has shown "deep, necrotic and hemorrhagic lesions in the brain" of the patients, Edan said.
Neither Biotrial nor Bial have confirmed the authenticity of the document on Breizh-info.com. But several details suggest it is indeed the information provided to healthy volunteers who were considering participating in the study before it started. The sheet describes a study of BIA 10-2474, a compound that Bial lists as being in phase I tests on its drug pipeline. Several potential therapeutic applications mentioned in the sheet match information provided by French health minister Marisol Touraine at a press conference yesterday.
The timing is consistent as well; according to the document, participants in this particular trial group had to stay at the Biotrial facility from 4 January through 18 January; the first of 10 daily doses of BIA 10-2474 was to be administered on the third day of their stay. (Touraine said yesterday that drug administration began on 7 January.) Breizh-info.com says the document was provided by someone who applied to be enrolled but was rejected.
According to the document, the trial enrolled nonsmoking men and women aged between 18 and 55 who had a body mass index between 19 and 30. The plan was to give patients BIA 10-2474 every day between the third and thirteenth day of their stay at the clinic, while they underwent an extensive battery of tests and sampling—including as many as nine blood collections on some days. On the first and last day of drug administration, patients' heart rates were to be monitored around the clock while all of their urine was collected for analysis. (Between day 3 and 9, however, all they apparently had to do was take BIA 10-2474 and provide a single blood sample.) They were due to be released on 18 January but had to come back for a final check-up and more sampling on 1 February.
FAAH breaks down a series of compounds in the body called endogenous cannabinoids, the best known of which is anandamide. These molecules activate cannabinoid receptors—the same ones that bind THC, the key component of cannabis. BIA 10-2474 is designed to inhibit FAAH, and thus slow the breakdown of endogenous cannabinoids, which might help fight pain. But Biotrial's information sheet lists a wide range of other possible therapeutic applications, including anxiety, motor problems in Parkinson's disease, multiple sclerosis, cancer, hypertension, and obesity.
Pfizer tested another FAAH inhibitor as a possible painkiller for patients with osteoarthritis of the knee, but reported in 2012 that it didn't work in a phase II study. The trial didn't reveal any serious side effects from that drug, however.
Why BIA 10-2474 would cause such severe damage is unclear. Bial says that the new drug had already been administered to 108 patients "without any moderate or serious adverse reaction." But phase I clinical trials usually start with single or lower doses; the six patients may have been the first to receive multiple doses.
It's possible that BIA 10-2474 drug has completely unexpected effects because it binds to another target besides FAAH, molecular pharmacologist Stephen Alexander of the University of Nottingham in the United Kingdom said in a statement distributed by the Science Media Center (SMC) today; such "off-target" interactions might only become dangerous with more extensive exposure. "Another option is a dosing accident, where patients were given far more than clinicians thought was in the dosage form," neuropharmacologist Ben Whalley of the University of Reading added, also in an SMC statement.
French authorities have already announced three investigations into the tragedy, with which Bial promised to cooperate. "Several BIAL representatives are currently at the site to monitor the situation with the research center and the hospital, ensuring the necessary cooperation with these entities, as well as with the relevant authorities," the statement says.
Source : Science Mag (January 2016)
HHS Told To Probe ‘Unethical’ Novartis Trials
The federal government was asked by a watchdog group to investigate several allegedly “unethical long-term, placebo-controlled studies” for indacterol, a Novartis drug for treating moderate to severe chronic obstructuve pulmonary disease. Why? “The studies were marred by a failure to minimize risk to subjects and inadequate information provided to subjects,” according to Public Citizen. In a letter sent to the Office for Human Research Protections at the US Department of Health and Human Services, the group alleges there six “unethical” studies in which placebo-control subjects received prolonged substandard care. Put another way, Public Citizen charges the patients were prevented from using widely acknowledged standard care and that informed consent was likely inadequate because placebo patients would not have known substandard care would be offered.
“The scientific question of whether indacaterol was better than placebo for treating moderate to severe COPD was not an important or clinically useful question, given the existing state of knowledge about COPD treatment at the time these studies were conducted. Rather, the important question is whether indacaterol is at least as good as currently available bronchodilator therapy,” the group writes.
Specifically, the watchdog group writes that more than 1700 subjects were assigned to placebo groups for three to 12 months and were allowed to use daily inhaled steroids and short-acting beta-agonists, but were not permitted to use any long-acting beta-agonists or short- or long-acting inhaled anticholinergics or to start inhaled corticosteroids.
The move comes just one week after an FDA panel voted 13 to 4 to back the med, but only at 75 mg, a lower dose than used in Europe. However, the same advisory committee voted 12 to 5 against endorsing the 150 mg dose. Two years ago, the FDA declined to approve the drug over safety issues and asked Novartis to look at lower doses.
However, Public Citizen does not want the FDA to look into this. Why? “It is clear FDA has a conflict of interest and should not be asked to investigate our allegations because Novartis conducted these placebo-controlled trials with the full knowledge and endorsement of the FDA. Therefore, since FDA is complicit in this unethical research, we urge OHRP to take the lead in investigating our allegations” (read the letter here).
Asia: Guinea Pigs Aplenty for Drug Giants
Bangkok, Thailand — Before any pill reaches the pharmacy shelf, it must first pass through a gauntlet of human guinea pigs: the “clinical subjects” paid to take trial drugs so specialists can observe their symptoms.
But like call centers and high-end hospitals, drug trials too are rapidly shifting to India and Asia with Thailand as the region’s favored frontrunner.
For Western pharmaceutical giants such as Pfizer and GlaxoSmithKline, Asia offers a glut of people willing to accept less money for testing out trial medicines. Softer regulation is another big draw, as are improvements in Asian hospitals’ facilities and an increase in Western-educated doctors.
How Fast is Asia's Drug Trial Industry Growing?
Very fast. Just eight years ago, only 6 percent of the world’s drug trial patients were tested in Asia and India. The figure is now 11 percent, according to CMR International, which produces the leading study on pharmaceutical research.
In that same eight-year stretch, North America’s share of patients dropped from 53 to 32 percent. Asia was mostly responsible for eroding that share, though the number of patients increased slightly in Europe and Latin America.
While China and Japan conduct the most studies, Thailand has become the region’s most desirable location, according to the CMR report. In the past year alone, its ongoing studies have jumped 36 percent to 800 open trials.
What do Drug Trial Volunteers Have to Do?
Their experiences will vary wildly depending on the trial. One typical test, which measures the speed of blood stream absorption, can require volunteers to consume a pill and submit to more than 35 blood draws throughout a weekend. Two weekends of testing, in the United States, would pay approximately $1,000. Volunteers in Thailand would more likely receive less than $50.
Other disease-specific trials test experimental drugs on patients over a series of weeks or months. The “payment” in these studies typically isn’t cash but rather the promise of cutting-edge treatment.
Generally, a study conducted in Thailand is about one-third the cost of a U.S.-based study, said Sasitorn Kittivoravitkul, director of Bangkok clinical study firm Bio-Innova & Synchron.
Why is Thailand Now Favored by Drug Firms?
Its people are largely healthy and eligible for testing thanks to a 90-cents-per-visit public healthcare scheme. Its hospitals are staffed by English-speaking physicians and specialists educated abroad.
There’s also no single Thai regulatory body responsible for approving trials — both a convenience and source of frustration for pharmaceutical firms.
In a departure from Western standards, trial supervisors don’t have to report what the industry calls “Unexpected Suspected Adverse Drug Reactions” — meaning worrisome side-effects of prototype drugs don’t have to be documented. (Draft legislation could change this.)
“Thailand’s leading position is largely due to the lack of uniform legislation regarding clinical trials,” according to Paul Russell, who monitors regulatory law for the Bangkok-based Tilleke & Gibbins law firm. “Since there is no central regulation, companies feel more comfortable conducting clinical trials in Thailand.”
Thailand’s favored status is no accident. The Thai public health ministry and the Board of Investment — a state-owned arm devoted to luring in foreign investors — have worked in synch to court Western pharmaceutical giants. The government continues to lure in foreign pharmaceutical firms and expects its bio-technology industry to produce $882 million in revenue by 2011.
What are Thailand's Drawbacks?
Slippery legislation can also make trouble for Big Pharma. Major drug firms despise “compulsory licensing,” a government’s decision to ignore copyright and cheaply mass-produce a drug in the name of improving public health. Thailand hijacked patents for HIV and heart medicines in 2006 after a military coup installed a nationalist leadership willing to upset major drug firms.
This outraged the Pharmaceuticals and Manufacturers of America, a D.C. lobby that claimed the patent violations caused a “a very unpredictable business environment” that undermines positive perceptions of Thailand’s emerging drug trials industry.
What's Next for Drug Trials in Asia?
Many studies in Thailand involve testing “bio-equivalence,” which mostly involves ensuring generic drugs work as well as the more-expensive drugs they’re meant to imitate. The process is much less scientifically strenuous than testing a totally original drug. So far, there’s still too little infrastructure or stability to invite a major wave of higher-end drug trials.
This presents an opportunity for India, which is beginning to attempt more sophisticated, high-risk trials. India shows the “strongest inclination to invest in innovative research & development,” according to the CMR report. Still, excluding Japan, India and the rest of Asia receive less than 1 percent of pharmaceutical research expenditure worldwide.
Source : Truthout
Link to Source