experimental drug trials gone wrong

The Drug Trial That Went Wrong: What Happened To The Infamous 'Elephant Men' from 2006

Senior Editor, HuffPost UK

More than 11 years ago, eight healthy young men took part in a clinical trial of an experimental leukaemia drug known as TGN1412.

The drug, which manipulated the immune system , had been successfully tested on monkeys although never on humans.

But what should have been a routine clinical trial at an independent clinic at north west London’s Northwick Park Hospital, soon spiralled into one of the most infamous medical emergencies in recent British history.

Within an hour of receiving the drug, six of the volunteers had been rushed to intensive care where they were fighting for their lives.

As a BBC Two drama documentary airing on Tuesday night recounts: “It was all manic, everything was happening all at once, they were vomiting, they were screaming in pain, people fainting.”

This combination of symptoms known as a “cytokine storm” saw the men’s temperatures soar, their organs fail, and some of their bodies swell so severely that they became known in newspapers around the world as the ‘Elephant Men’.

More than a decade on, The Drug Trial: Emergency At The Hospital tells the story of what really happened during the trial, during those critical hours as medical staff fought to save the patients’ lives, and through the aftermath as the authorities sought to understand what had occurred.

It features candid personal testimony from doctors who struggled to bring the clinical catastrophe under control: “This was a mystery, we had no way of predicting how severe it was going to get. There was no rule book for how to deal with this.”

Volunteer Rob Oldfield had signed up to the trial for a fee of £2,000, with no clue of the trauma that would follow.

He said: “I remember being sick into a biohazard bag, and all of us being very ill. But the worrying point for me was when one guy, they drew the curtains around him, then these guys with gowns came up, like from an operating theatre.”

The then-31-year-old’s immune system crashed and his liver, kidneys and lungs were failing. For two weeks after he was stabilised, his blood was filtered 24 hours a day, BBC Magazine reports .

Fluid had seeped into his lungs and he had to breathe air through a mask, while a direct line pumped vital drugs into his heart. Oldfield finally left hospital three weeks later.

David Oakley was the first to receive the drug and at 3.30am he was so gravely ill that his fiancée Katrina was told to come to the hospital, where she prepared for the worst.

She said: “I don’t think anything could prepare you for what you saw when you first went in.

“His cheeks were very swollen, so much that his eyes looked more like slits. His face was just round like a ball and his stomach was huge. It was pretty scary to see somebody you love so disfigured.”

Ryan Wilson spent four months in hospital and had his toes and parts of his feet and fingers amputated after battling the symptoms of pneumonia, septicaemia and dry gangrene. In an interview with the Guardian in 2007, Wilson said he is still haunted by the words of his father, who told him the night before the trial: “Don’t do it. Your body is a temple.”

The investigators tasked with discovering what went wrong told the broadcasters: “This was treated as a crime scene. Something could have been tampered with, sabotaged, poisoned and that these folk might have been the victims of such foul play.”

Parexel, the company which ran the clinic where the drug trial was carried out, was found to have acted within its protocols in an interim review by the Medicines and Healthcare products Regulatory Agency.

A final report however stated the trial had not properly considered the safe dosage of the drug for humans.

It is understood that some volunteers have received confidential compensation payments, but still suffer from weakened immune systems and other side effects, and will never know the true legacy of the drug which so nearly cost them their lives.

The Drug Trial: Emergency At The Hospital will air on BBC Two at 9pm on Tuesday

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The troubled history of clinical drug trials

Clinical trials that went wrong in recent years have had unexpected and devastating consequences on volunteers, article bookmarked.

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One person has been left brain-dead and five others hospitalised after a clinical trial of a drug went wrong, t he French health ministry announced today.

Sadly, the news from Rennes, in south-western France, is not the first – or most likely the last – high-profile incident of its kind, in which the lives of volunteers have been lost or irreversibly altered.

France’s medicines agency, ANSM, has launched an investigation into the Biotrial laboratory where a “serious accident” led to the abandonment of the experimental painkiller trial and the recall of all volunteers.

Medical trials commonly have three phases to determine how safe and effective a potential drug will be.

The first phase focuses on safety, typically with a small cohort of volunteers.

Phases two and three tend to be larger trials examining the drug’s effectiveness, as well as safety.

Here are three other clinical trials that went wrong in recent years - with unexpected and devastating consequences:

The ‘elephant man’ drug trial, UK, 2006

Six healthy young men were treated for organ failure within hours of taking part in the early stages of a trial for a drug, TGN1412, to treat conditions such as rheumatoid arthritis and leukaemia, run by private US company Parexel on-site at London’s Northwick Park Hospital’s research unit.

The men were admitted to intensive care, where some of their heads swelled up – giving the incident its nickname, ‘the elephant man’ trial – after 19 th Century Englishman Joseph Carey Merrick, whose severe deformities led to him being exhibited as a human curiosity.

The worst-affected of the men lost fingers and toes, and all the men were subsequently told they would be likely to develop cancers or auto immune diseases as a result of exposure to the drug.

Some of the men later described how the drug had made them feel like their brains were on fire and that their eyeballs would pop out.

Parexel said it had followed all of the recommended regulatory, clinical and medical guidelines and that such cases were extremely rare.

But a report into the trial said the company was not clear about what was a safe dose to start testing on humans was and found that it should have tested the drug on one person at a time.

The report made a number of recommendations, including the Medicines and Health Products Regulatory Agency – which had approved Parexel’s trial – ensuring that committees considered pre-clinical data to decide whether the first dose of the drug to be tested on a human was the right dose.

The anti-psychotic drug trial, US, 2004

Dan Markingson, 26, a mentally-ill man, took part in a clinical trial for the anti-psychotic drug Seroquel conducted by the University of Minnesota’s Centre for Bioethics in Minneapolis.

Six months after starting the trial, he stabbed himself to death, reportedly leaving behind a suicide note.

He was being treated with the drug for delusions, including the belief that he was about to be summoned by a secret group and asked to murder people.

An investigation by the US Food and Drug Administration in 2005 cleared the university of any responsibility for Mr Markingson’s death.

But there are those who maintain that ethical guidelines were apparently broken by the university, including claims that Mr Markingson was not competent to consent to the study and, warnings that he was in danger of committing suicide were ignored.

Clinical trial for gene therapy, US, 1999

18-year-old Jesse Gelsinger is understood to be the first person publicly identified as having died in a clinical trial for gene therapy.

The teenager suffered from a liver disease caused by a genetic mutation and joined a clinical trial run by the University of Pennsylvania’s Institute for Human Gene Therapy that wanted to develop treatment for infants born with a severe form of the disease.

He was injected with an adenoviral vector carrying a corrected gene to test the safety of the procedure.

Mr Gelsinger died four days later, reportedly of multiple organ failure and brain death.

An investigation by the US Food and Drug Administration reportedly found that the scientists involved in the trial, including Dr James M. Wilson, who headed the institute and was a co-investigator, broke rules of conduct.

Among other factors, it found that Mr Gelsinger’s inclusion in the trial even though he had high ammonia levels – as a substitute for another volunteer who had dropped out – should have led to his exclusion.

The university settled a wrongful death lawsuit brought by the Gelsinger family for an undisclosed sum.

Speaking to Scientific American magazine in 2009, Dr Wilson said: “The university here, the field and the families who were relying on us to succeed – I just feel as if I’ve disappointed all of them.

“ Quite frankly I don’t know how many different ways I can say it. [I feel] regret, remorse, awful. I’m sorry.”

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Program: The drug trial that went wrong...very, very wrong

Program: Science Friction

Presented by

It captured headlines worldwide. A drug trial gone terrifyingly wrong.

Clinical trials are absolutely vital for the development of new treatments and medicines, but who protects the human subjects who sign up?

Now the drug at the centre of the controversy, TGN1412, is back. It's been renamed, rebranded and is being trialled again.

A survivor speaks.

This program was first broadcast in December 2017.

Rob Oldfield Actor UK Dr Marcel Kenter Director Paul Janssen Futurelab Leiden Netherlands

Further reading:

Final report of the investigation into the TGN1412 Trial Expert Scientific Group on Phase One Clinical Trials, 2006 Establishing risk of human experimentation with drugs: lessons from TGN1412 MJH Kenter, AF Cohen. The Lancet, Volume 368, No. 9544, p1387–1391, 14 October 2006 TGN1412: From Discovery to Disaster H Attarwala J Young Pharm. 2010 Jul-Sep; 2(3): 332–336 The rise and fall of the CD28 superagonist TGN1412 and its return as TAB08: a personal account Thomas Hünig The FEBS Journal, Volume 283, Issue 18, Pages 3325–3334, September 2016 Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412 Ganesh Suntharalingam et al N Engl J Med 2006; 355:1018-1028, September 7, 2006 From TGN1412 to TAB08: the return of CD28 superagonist therapy to clinical development for the treatment of rheumatoid arthritis D. Tyrsin, S. Chuvpilo, A. Matskevich, D. Nemenov, P. Römer, P. Tabares, T. Hünig Clinical and Experimental Pharmacology, 2016 Vol.34, 4 ,Suppl. 98 Dose escalation study of TAB08 in Patients with Advanced Solid Neoplasms (TAB08) Current clinical trial listed by Russian biotech company Theramab (as of 2019) Implications of the BIA‐102474‐101 study for review of first‐into‐human clinical trials Michael Eddleston et al Br J Clin Pharmacol. 2016 Apr; 81(4): 582–586. After French drug trial tragedy, European Union issues new rules to protect study volunteers New clues to why a French drug trial went horribly wrong

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Brendan I. Koerner

Blood, Lies, and a Drug Trials Lab Gone Bad

The email that Joe Hagood received in August 2017 was vague and brief, but too unsettling to ignore.

Hagood worked at Medpace, a Cincinnati company that tests new drugs for pharmaceutical manufacturers. His job was to supervise the independent research centers that Medpace pays to handle the nitty-gritty of human trials: finding volunteers, dispensing medications, tracking side effects. The author of the unsettling email, Justina Bruinekool, was a staffer at one of those centers. She claimed to have an urgent reason for writing: Her employer was fraudulently conducting a major trial that Hagood was overseeing.

This article appears in the November 2021 issue.  Subscribe to WIRED .

The email contained no evidence to support this jarring allegation, so Hagood thought it wise to tread cautiously; he worried that Bruinekool might be a disgruntled employee out to make trouble. In his reply, he thanked her for the tip and politely encouraged her to reach him on his cell phone.

A week passed before Bruinekool called. As soon as he picked up the phone, he could tell by her voice that she was genuinely frightened. A 36-year-old mother of three, including a daughter who would soon be off to college, Bruinekool could not afford to lose her $17-an-hour position at Mid-Columbia Research, the center where she worked. She asked for assurances that Medpace would never reveal her identity to her company's owner, whom she knew had a vindictive streak.

After Hagood agreed to do his best to keep her name in confidence, Bruinekool spent the next hour detailing the transgressions she'd witnessed—and committed—while helping to study CAM2038, a medicine being tested on people with chronic back pain. She said Mid-Columbia recruited test subjects who shouldn't have been in the trial, including several who had no back pain at all. When those patients missed appointments, as happened every day, she and some of her colleagues would squirt the medications down the sink and fabricate vital signs to cover up the absences. The binders that Mid-Columbia used to chronicle the study's progress, she said, were filled with lies.

Throughout his long career, Hagood had never encountered a scandal like the one Bruinekool described, and a piece of him wanted to believe she was exaggerating. But Bruinekool's stories were so vivid, so specific, that he sensed they must be true. That meant the entire CAM2038 trial, which was blending anonymized data from multiple research centers, could be in peril. As soon as he hung up, Hagood started to help organize a team to fly out to Richland, Washington, a desert town just 30 miles north of the Oregon border. They needed to find out what was going on at Mid-Columbia.

By Matt Burgess

By Sachi Mulkey

By Andy Greenberg

By Matthew Gault

Since Medpace's main purview was to safeguard the CAM2038 study, its investigators would uncover just a fraction of Mid-Columbia's scientific wrongdoing. The research center had, in fact, been willfully churning out false data for years, thereby tainting the clinical trials for more than two dozen prescription drugs. The fraud was blatant enough to draw scrutiny from time to time—Medpace was not the first watchdog to learn of the mess in Richland. But Mid-Columbia kept dodging meaningful consequences because the clinical-trials industry, like so many of our most vital institutions, operates on the assumption that even the most grievous errors are made in good faith. It is a system ill-equipped to identify and stop those rare individuals—and the scale of Mid-Columbia's misconduct was exceedingly rare—who consider the trust of others a vulnerability to exploit.

While Hagood was orchestrating Medpace's crisis response in Cincinnati, Bruinekool sat in her car outside Mid-Columbia's beige stucco headquarters, trying to compose herself before clocking in at work. A reserved woman whose ruddy face and sun-worn hair hint at her love for the outdoors, she had struggled to muster the courage to blow the whistle. Now that she'd done so, she hoped better days lay ahead. There were plenty of decent people at Mid-Columbia, people like her who were wracked with guilt over what they'd done to keep their paychecks coming. Perhaps the inevitable Medpace audit would give the company the nudge it needed to let its employees do honest research.

But Mid-Columbia's owner was so perversely devoted to his business model, which he'd engineered to profit from dishonesty, that he was unlikely ever to mend his ways. Bruinekool, of all people, should have known that: This was a man who'd spent months that past summer literally siphoning off her blood.

There's an adage I heard in the Tri-Cities—an arid swath of Washington state that encompasses Kennewick, Pasco, and Richland—that neatly captures its economic landscape: “Everyone here is either a nuclear scientist or works in retail.” The original engine of the area's growth was the Hanford Site , a plutonium production facility built during World War II to supply the Manhattan Project. Though the massive complex, situated on nearly 600 square miles of scrubland north of Richland, shut down its last reactor in 1987, it still employs 11,000 workers to clean up the waste left behind. But most jobs in the Tri-Cities seem to be found in the endless strip malls of Kennewick and Pasco, where sun-baked subdivisions teem with refugees from the West Coast's pricier areas.

This polarized job market can frustrate locals like Jay Cruto, who returned home in 2014 after earning a biology degree from Western Washington University. A warm and ambitious Filipino American who took pride in being the first member of his family to graduate from college, Cruto was eager to land a gig that would help burnish his résumé for medical school. After months of searching, then, he was overjoyed to come across an online listing from Zain Research, a Richland company that billed itself as “one of the largest global providers” of clinical-trial services.

During his interview at Zain, Cruto was introduced to two men whom he understood to be the company's key figures. The older of the men was Cheta Nand, a soft-spoken psychiatrist who also ran a sleep-disorder clinic in the same building; his younger counterpart introduced himself as Dr. Sami Anwar, a slightly built man in his mid-thirties with a thick brow, stylish eyeglasses, and a healthy mane of well-moussed black hair. Cruto was offered an entry-level job on the spot. And though he blanched at the $14-an-hour pay—“I thought it would be a little more because you're not, like, flipping burgers”—he agreed to accept a position as an assistant, soon becoming Zain's clinical data manager.

Cruto was quick to learn where Zain fit in the clinical-trials system. At the top are the pharmaceutical corporations that pour billions into developing new drugs. Those drugs, of course, can't be sold to customers until the Food and Drug Administration deems them safe for human consumption and more effective than placebos. To gather that proof, the Pfizers and Mercks of the world hire so-called contract research organizations . These firms specialize in designing and managing the trials that yield the data necessary to satisfy the FDA's regulators.

Contract research organizations, in turn, outsource the nuts and bolts of those studies to thousands of research centers like Zain—businesses that find volunteers who, in exchange for cash and a chance to try an experimental treatment, agree to subject themselves to in-depth monitoring of their health. As they collect patient data over a matter of months, the centers are regularly inspected by monitors from the contract research organizations, who are responsible for ensuring that the specific protocols for each study are followed in full. Those monitors routinely catch and correct minor errors, which typically involve a missing document or an unintentional deviation from a study's research guidelines.

Zain was just one and a half years old when Cruto was hired, but it was already operating a slew of trials involving drugs designed to treat diabetes, hypertension, nicotine addiction, and a host of other ailments. On the paperwork for these studies, Nand was listed as the principal investigator. But many of the staffers I spoke to told me that Nand spent most of his time at his sleep clinic.

Anwar, by contrast, was omnipresent at the company. Fueled by a diet of Red Bull and Snickers, he would pace the office and peer over employees' shoulders to make sure they were staying on task. Virtually every former Zain employee I spoke to also mentioned that Anwar would aggressively berate and belittle them during daily meetings—the joke around the company was that you didn't attend those meetings, you survived them.

But Anwar had an endearing side too. On occasion, he would join in employee banter about weight lifting or romantic exploits. And he held himself up as a mentor to employees whose moxie he professed to admire. “He said that I was a lot like him when he was younger,” Cruto says. “He said that he built everything from the ground up, that he was cleaning toilets before he got here, all this stuff. In person he was very charismatic.”

Jay Cruto was excited to land a job at Zain Research but quickly became alarmed by what he saw there.

Before too long, however, Cruto grew uneasy with some of Anwar's demands. Cruto's job was transferring data from the handwritten notes kept in binders into the software used by the contract research organizations. But the documents, he says, were often incomplete or riddled with glaring errors—blood-pressure readings that were too consistent to be true, for example. Yet when Cruto flagged these problems, he says that Anwar would tell him to fill in the blanks with old data so the software would mark the patient visits as complete—a process he says Anwar referred to as “cleaning up.” And though Nand, as the main principal investigator and a licensed physician, was the only person authorized to review and sign documents for the studies he supervised, Anwar would forge his partner's signature all the time.

The arc of Cruto's career at Zain—from excitement to alarm in just weeks—was common among the recent college graduates Anwar liked to hire. Shortly after joining the company in early 2014, for example, 21-year-old Billy Birge was put in charge of multiple studies, a big responsibility for a psychology major fresh out of Washington State University. An upbeat guy with a gym rat's physique, Birge quickly became apprehensive about how Zain did business, particularly when it came to patient screening. “The way [the study protocols] are written, it's pretty hard to get into a clinical trial,” he says. The ideal patient is someone who suffers from the disorder being targeted by the experimental drug but is otherwise healthy. But according to Birge, Zain put little effort into seeking out such hard-to-find candidates. “In reality,” he told me, “we were probably approving, like, 90 percent of the people that came in.”

Birge got particularly nervous about a patient in a cirrhosis study who confided to him that she could no longer tolerate the drug's side effects. Her itchy skin was driving her crazy and her period hadn't stopped for more than a month. Birge says that he relayed this information to Anwar and told him that the patient wanted to pull out of the study. “His reaction was to ask me if we could pay her more money,” Birge told me. “His idea was to pay her double.”

When Birge said that wasn't possible due to the contract research organization's billing policies, Anwar talked to the woman in private, Birge says. She stayed in the study.

Though he bristled whenever an employee failed to address him as “Doctor,” Sami Anwar was not, in fact, a licensed physician in the US. He earned a medical degree in his native Pakistan in 2003, after which he claims to have spent five years working at a series of hospitals in the city of Karachi. According to his résumé, his duties were mostly administrative. (Birge says Anwar boasted that he completed a brain procedure himself when the surgeon stepped outside for a cigarette.)

In 2008, Anwar immigrated to the St. Louis area, where his aunt was a geriatric doctor and his uncle was an oncologist. Soon thereafter, he married a woman from California named Warda Chaudhary, whose parents expected him to follow in his aunt's and uncle's footsteps. Anwar studied to take the exams that medical graduates must pass to join an American residency program. But he never cleared the hurdles to becoming a doctor in the United States, to his in-laws' vocal disappointment. (It's not clear whether Anwar failed the exams or never completed them.)

Anwar instead found work in a less selective medical field: He became a research study coordinator at a psychiatric practice in St. Louis, according to his résumé. He left after a year to cofound a clinical-trials company in Missouri called Scientella.

As would become a pattern in Anwar's professional life, Scientella rapidly disintegrated in a swirl of acrimony. In 2014, Anwar sued his business partner for allegedly concealing the full extent of the company's profits; the partner filed a counterclaim, alleging that Anwar had used Scientella's corporate credit card to enrich himself. (The cases were dismissed in 2016 by mutual consent.) Claiming penury due to Scientella's collapse, Anwar looked to make a fresh start in the Tri-Cities, where he had a tenuous connection—a local doctor named Farrukh Hashmi, who had attended medical school with his aunt and uncle. As a favor to his old classmates, the doctor offered to help Anwar establish a clinical-trials company in Washington: Zain Research.

Hashmi was colleagues with the quiet psychiatrist Cheta Nand, whom Anwar convinced to become a principal investigator at Zain. Anwar then built Zain's reputation among contract research organizations by enrolling patients at a much faster clip than his competitors. The company aggressively recruited volunteers at doctors' offices, at county fairs, on Facebook and Craigslist; in one instance, according to an observer I interviewed, Anwar dispatched a van to a skate park to collect smoking teenagers for an addiction study.

Because Zain was so indiscriminate with its enrollment, it often ended up with unreliable test subjects—needy people lured in by the prepaid debit cards the company offered; they'd grab the quick payout, then fail to materialize for their follow-ups. That was a problem for Zain because of how contract research organizations typically structure their contracts: Centers like Anwar's get paid per completed patient visit. His solution was for his employees to fabricate data for any no-shows.

Employees pushed back against those instructions at times, but Anwar would argue that Zain was in the moral right for aiding the Tri-Cities' less fortunate. “If you were to present a terrible situation, he would know how to spin it and make it sound, like, ‘Oh, I guess it's not that bad,’” says Lucia Dawson, a Zain study coordinator and former Army truck driver whom I met in the Tri-Cities. “At some point you're like, ‘Oh, well, that's true, these people don't have a lot of money, so this $75 is going to help them buy groceries.’”

When employees persisted with their complaints, however, Anwar could turn vicious. Ashley Galvan, a plainspoken study coordinator from Chicago who aimed to become a neuroscientist, told me she got under Anwar's skin by warning Nand he could lose his medical license if Zain's methods ever came to light. Upon learning that Galvan had gone around his back to his partner, an enraged Anwar called her into his office. “If you ever want a job in the Tri-Cities again,” she recalls him yelling, “I'll take that away from you.”

One evening after that confrontation, Galvan told me, she and her fiancé took their dog for a walk along the Columbia River. In the midst of their stroll, Galvan says, she received a call from Anwar. “Do you always hold your boyfriend's hand when you're walking?” he hissed into the phone. The incident did nothing to alleviate the depression and anxiety that Galvan told me she'd developed due to the misery of working at Zain. (She left the company in August 2014.)

Galvan was hardly the only Zain employee to quit after a short, unpleasant tenure; turnover at the company was high. But Zain nevertheless flourished, often raking in hundreds of thousands of dollars per study while paying hourly wages in the $10 to $15 range. This created a sizable profit for Anwar, who could be a lavish spender. He purchased a $700,000 hilltop home with a majestic view of wineries and orchards, leased an ever changing lineup of Mercedes and other luxury cars, and took regular trips to London and the United Arab Emirates.

Anwar also plowed a lot of money back into Zain; according to people familiar with his plans, he dreamed of somehow transforming the company into a legitimate research hospital. In early 2015, he took a step toward that grandiose goal by moving the company to new quarters, the eastern wing of a seedy, 100,000-square-foot shopping plaza that housed Richland's Chuck E. Cheese. One side of the building became a doctors' office called Zain Medical Center; the other side was reserved for the expanding Zain Research.

Anwar spared no expense in turning the drab space into a state-of-the-art facility. He purchased the highest-quality diagnostic equipment for the exam rooms, imported exquisite tiles for the floors, and wired the whole building with an 85-camera surveillance system.

Ashley Galvan dreamed of becoming a neuroscientist. She quit her job at Zain in 2014.

Before Zain moved into the new space, Jay Cruto decided the time had come to try to persuade Anwar to straighten up. “At that point, I thought I had enough pull because I was so involved in cleaning up the studies,” he says. “And basically I was telling him, Let's come clean, start new. We're moving to a new building; let's start fresh over there, and everything will be great.”

Cruto told me that once he was done making his pitch, Anwar flashed him an enigmatic look. “When a general goes out to battle,” he responded, “will the soldiers let him die?” Cruto knew Anwar well enough to grasp the meaning of that coded message: Nothing would change after the move, and he was expected to never snitch.

Though the staff at Zain generally tried to stay quiet about their malfeasance, the monitors from the contract research organizations could tell something was awry. Geoff Heywood, a former cardiac nurse who was a monitor for the Dublin-based firm Icon , recalls thumbing through the binders for a cholesterol study during one of his visits to Zain. He was aghast to discover that the binders rarely included written evidence affirming that the volunteers were qualified—or, for that matter, real. “They would have data entered for the patients, but there weren't any source documents to prove that those entries were authentic,” Heywood told me. “We have no documentation that these people exist.”

When Heywood would request to meet with Nand, Anwar would insist on being present for the conversation. Anwar would then jump in to answer questions directed at his partner, while Nand silently took notes with his eyes cast downward. “You've met people who think they're way slicker than everybody else in the room? Yeah, that's Sami,” Heywood says. “You could see this guy was a con artist after spending five minutes with him.”

Geoff Heywood was assigned to monitor the activity at Anwar’s clinic. “You could see this guy was a con artist after spending five minutes with him,” Heywood says.

Heywood and several other monitors were keen to fix the mess at Zain, but they were limited in what they could do. That is largely because the monitors and their superiors have access only to the data from the trials they've commissioned. So on the rare occasions that a center's behavior seems fishy, it's almost impossible for a contract research organization to establish a widespread pattern of deceit. “I was taught that monitors can't even utter the word ‘fraud,’” Heywood says. “It's a legal issue, and we're not lawyers qualified to determine whether fraud exists.” Heywood had to settle for trying to teach Zain's underqualified, inexperienced staff how to produce better research.

Cruto left Zain in early 2015. In a bid to clear his conscience, he decided to call an FDA hotline and report the misconduct he'd abetted. The agency sent two investigators to the Tri-Cities to interview him; during the meeting, Cruto shared the usernames and passwords he'd used to log in to the contract research organizations' software. (Zain hadn't canceled those credentials.) When the investigators asked him if anyone else associated with the company might talk, the first name that popped into his mind was Billy Birge.

Birge was still at Zain, but he wasn't sure how much longer he could stick it out. There was one incident that haunted him, involving an elderly man who was participating in an Alzheimer's study. One day the man's wife arrived at the clinic alone with the sad news that her husband of many years had passed away. Birge had to wonder if Zain's shoddy work was at fault: The man had attacked his wife while experiencing a bout of dementia during the trial, but the center had never reported the incident. Birge told me he notified Anwar that they needed to inform the contract research organization about the death—any adverse event must be reported, even if it's unrelated to the trial. Anwar brushed him off, he says.

So Birge also met with the FDA investigators and told them all he knew. He quit Zain shortly thereafter, lying to Anwar that he'd found a better job at an auto body shop.

Armed with the information provided by Cruto and Birge, the FDA showed up, unannounced, at Zain in October 2015 to conduct an audit. All employees were required to remain onsite during the inspection. According to Lucia Dawson, however, Anwar ordered her to sneak out and not return until he said it was OK. When she asked why, he suggested that she was a soldier who couldn't be trusted to protect her general: “If they ask you a question,” he said, “you'll tell them everything.”

The FDA audit confirmed much of what Cruto and Birge had divulged: Zain was enrolling patients inappropriately, keeping records that contained unverified information, and failing to report dangerous side effects. But the FDA chose not to pursue a course of action that might lead to the closure of Zain. Instead, in March 2016, the agency issued a seven-page warning letter that laid out all of the “objectionable conditions” its inspectors had identified at Zain. Because they're publicly available on the internet, warning letters can be a kiss of death for any clinical-trials business; they pop up whenever a contract research organization or pharmaceutical company performs due diligence on a potential contractor. Per the FDA's policy, the letter was addressed to Cheta Nand, the principal investigator. But though both Sami Anwar and Zain Research are mentioned numerous times throughout the confidential audit report, those names appear nowhere in the public letter. That fact created all the opportunity Anwar needed to keep his operation going.

The research center was headquartered in a seedy shopping plaza in Richland, Washington.

While working at a community health center in central Washington in 2016, Justina Bruinekool heard a salacious bit of office gossip about two of her fellow employees engaging in questionable behavior. A retiring sort who wanted no part of the drama, Bruinekool kept her lips sealed. That decision ended up costing her dearly: When the center's management learned of the breach, it fired Bruinekool and another staffer who'd failed to report the impropriety.

Bruinekool, who had no education beyond the program she'd completed to get her medical-assistant license, spent the next year scrounging for work. In a region with a large Mexican and Central American population, her inability to speak Spanish was a major strike against her. Her five-person family was in perilous straits when, in June 2017, she finally found an opening at Zain Medical Center, a state-of-the-art doctors' office about 45 miles east of her rural home.

Bruinekool was assigned to assist an ob-gyn and an internist: She prepped patients for exams and managed referrals. After a few weeks, the head of human resources, Warda Chaudhary, called her in for a meeting. She complimented her work and informed her that she was being given a new assignment: a position at a clinical trials company called Mid-Columbia Research that occupied the other half of the building. She was told her new direct supervisor would be Chaudhary's husband, a doctor named Sami Anwar.

By July 2017, Anwar had rebooted his business, forming a new corporation with a new name and ceasing to use Nand—the FDA warning letter's sole addressee—as his principal investigator. His new principal investigator was Lucien Megna, an internist who had fallen on hard financial times due to tax problems and a costly divorce. Anwar paid Megna $19,000 a month and asked little in return, besides the right to use the doctor's name on official documents.

Mid-Columbia had the same address as the one on Nand's warning letter, and the building still had a huge sign that said “Zain” above the front doors. Yet contract research organizations still came calling. By the time Bruinekool joined Mid-Columbia in July 2017, the company was testing drugs for asthma, scabies, and back pain, among others.

Though Bruinekool had no experience with clinical trials, she was uncomfortable right away. Anwar was now hiring employees who were less educated and more economically and physically vulnerable than the postcollegiate types who'd been at Zain. Among Bruinekool's colleagues, for example, was a woman with lupus whose two previous jobs had been at AutoZone and Taco Bell. Anwar would use his Nest camera system to watch this new team from his office, barking commands over the public address system.

Employees say they were required to gather in a conference room and fill out patient diaries with false information. Anwar also pressured them to enroll their own family members in the studies, something protocols typically forbid. One staffer placed her 3-year-old daughter in a trial for an ointment for scabies, an ailment the girl didn't have; the medicine left permanent blotches on her skin.

Then there was the CAM2038 study, the one Bruinekool would soon flag to Medpace. The trial was designed to test whether the drug, delivered via weekly or monthly injections, could replace opioids as a treatment for chronic back pain. Mid-Columbia was given large amounts of hydrocodone and morphine to serve as “rescue medications” in case any opioid-dependent patients, particularly those who received placebos in the trial, needed to get back on their previous drug regimens.

The study ended up filled with volunteers who should have been excluded, people who didn't have chronic back pain or weren't using opioids; many vanished after receiving their initial payment. But the protocol for this trial called for blood work to be submitted at each visit. Anwar's solution to this, which he articulated to the study coordinator, was straightforward: “Just draw somebody's blood.”

That somebody often ended up being Bruinekool, who happened to have veins that were easy to locate. For several months that summer, a coworker drew a vial of her blood nearly every day—sometimes two or three vials, depending on how many patients went missing. Over time, Bruinekool says, she felt more and more dazed after the procedure, though she feared being yelled at or terminated if she complained. After a draw one day, she says, blood kept seeping out of her arm and spattering on the floor, even after she was bandaged up. After that, the CAM2038 team switched to filching blood from the medical center's supply of samples whenever possible.

Though Bruinekool was spared further daily bloodletting, she alleges that Anwar still pushed her to participate in other schemes. One day in August, Nand showed up at the medical center, where he continued to hold a minority ownership stake, and asked an employee he knew for help with a computer problem. Anwar interrupted their conversation and, according to a police report, began to curse and scream at his former principal investigator; the two men were enmeshed in a long-running dispute over money that had been tied up in the defunct Zain Research. When Nand raised his phone to record the encounter, Anwar snatched the device and deleted the video while fleeing to the parking lot—a stunt that resulted in his being arrested for misdemeanor theft. (The charge is still pending.)

To get back at his former partner, Anwar asked Bruinekool and two other employees to file sexual-harassment complaints against Nand with the state's Department of Health. Though she knew that every word of the complaint would be a lie, Bruinekool agreed to do Anwar's bidding; she feared she'd be fired if she refused, and she couldn't stomach the thought of putting her family through another year or more of deprivation while she looked for work. (The complaints that Bruinekool and her colleagues filed all used the same copy-pasted text.)

One evening after work, Bruinekool was watching the news when a segment came on about a woman who'd died from an opioid overdose. The story made her think of her father, who took hydrocodone to manage pain from a herniated disc. And then, for reasons she can't quite explain, something clicked for her: The false data she was helping to pump into the clinical-trials system might someday harm people, including those she loved. “Every light bulb in my head went off,” she told me. “I don't think I've ever had so many light bulbs.”

Justina Bruinekool worked at the research center for seven months and finally decided to blow the whistle.

Bruinekool convinced others at Mid-Columbia to join her in approaching Anwar about their concerns. After the group aired their complaints, Bruinekool says, Anwar turned on the charm and argued that Mid-Columbia's deceit served a greater good—the same strategy he'd used when challenged by the young college graduates at Zain. Bruinekool recalls Anwar telling them that they were just “recertifying” drugs that had already been proven safe and that they were helping unfortunate souls who needed money to survive on the Tri-Cities' margins.

Nothing changed in the days after the group meeting with Anwar. So in mid-August, Bruinekool started looking for someone higher up the clinical-trial food chain to talk to. She Googled the CAM2038 study and found the name and email address for a Medpace manager named Joe Hagood.

About six weeks after Bruinekool's first and only conversation with Hagood, a team of people from both Medpace and Braeburn Pharmaceuticals—the company behind the back-pain drug—showed up in Richland. During their two days at Mid-Columbia, the investigators made a host of troubling discoveries: “Data on subject diaries could not be attributed to the subjects themselves,” for example, and “Subject eligibility could not be confirmed with provided source documents.” Braeburn hastily terminated its relationship with Mid-Columbia and contacted the FDA, which began to discuss conducting an audit of the center in spring 2018. Anwar, meanwhile, had his lawyer send Braeburn an invoice for more than $135,000, which he claimed he was still owed.

Craig Tom, a US Drug Enforcement Administration agent based in Seattle, specializes in cases involving controlled substances intended for medical and scientific purposes. One of the more mundane aspects of that beat is reviewing applications from companies that need drugs for which there is strong black-market demand. In August 2017, Tom received one such application from Lucien Megna, who was listed as the principal investigator at Mid-Columbia Research. Mid-Columbia had won a contract for a study of gamma hydroxybutyrate , or GHB, for the treatment of narcolepsy. Since GHB is often used by sexual predators to incapacitate victims, Tom knew he'd have to inspect the applicant's facility to make sure it could lock down its supply. He dropped a friendly email to Megna to introduce himself and explain how the approval process worked.

But Megna did not reply to that email, nor to a subsequent message that Tom left at the phone number listed on the application. Puzzled by the silence, Tom decided to look into whether Megna had recently used his DEA license to obtain any other controlled substances. He found the doctor's name on a sizable purchase order for morphine and hydrocodone from a supplier in North Dakota. He subpoenaed that supplier's records and discovered that the drugs were intended to be used in a back-pain study sponsored by Braeburn Pharmaceuticals.

When he got in touch with Braeburn in November 2017, Tom found out about the audit and the termination of the contract with Mid-Columbia. He asked Braeburn if he could talk to its whistleblower, but the company could only promise to pass along Tom's request.

Not long after, a Braeburn representative gave Tom's phone number to Bruinekool, who had stayed at Mid-Columbia because of her financial straits, and told her she could call him if she wished. The caveat was that if she cooperated with the DEA, she risked being outed as the whistleblower. The choice was up to her.

Bruinekool was torn. Despite losing the CAM2038 contract, Anwar was showing no signs of having learned a lesson; getting the government involved might be the only way to make Mid-Columbia a tolerable place to work. But Bruinekool also feared Anwar's wrath should she be exposed as Mid-Columbia's informant.

Still, she kept coming back to a simple moral calculus that gradually eclipsed all her other concerns: She'd done awful things during her time at Mid-Columbia, and now she was being given a chance to atone. And so, for the second time, she decided to place her trust in a stranger and blow the whistle.

On the morning of January 24, 2018, a phalanx of DEA agents descended on Mid-Columbia's offices. As the officers in dark windbreakers scoured the building, Anwar seemed to suspect that there was a traitor in his midst. The DEA agents ushered employees into conference rooms, one by one. Bruinekool worried that Anwar had noticed she was jittery when she went in for her interview. Sure enough, as she drove home that evening, she says, Anwar called and peppered her with questions: Why had she been with the agents for so long? What had they asked about? What had she told them?

The DEA found hundreds of opioids stashed throughout the building—the rescue medications from the CAM2038 trial that were never dispensed to patients assigned the placebo. (Falsified records said some of them had been given.) They also found heaps of empty syringes that had once held doses of CAM2038; thanks to Bruinekool, the agents knew that Mid-Columbia had squeezed those shots down the sink instead of doling them out to patients.

Shortly after the raid, Bruinekool texted Heather Ellingford, a former Mid-Columbia regulatory manager who had left the company in December 2017, to tell her Tom was still in town and eager to speak to anyone who had information about Mid-Columbia's mishandling of controlled substances. Ellingford, who had long been haunted by her failure to expose Anwar's misdeeds, agreed to meet Tom at the Kennewick library. She brought along a flash drive containing gigabytes' worth of internal documents she'd surreptitiously downloaded during her last week at Mid-Columbia; as she told me when we met for beers in the Tri-Cities this past summer, a piece of her had always known she'd someday be called upon to help bring the company to justice.

Three days after the raid, Bruinekool tendered her resignation. But a strangely upbeat Anwar talked her out of leaving: He promised her medical benefits and acted as if the DEA investigation didn't bother him. Bruinekool made yet another puzzling decision by choosing to stay on at Mid-Columbia.

On February 2, Anwar called an all-hands meeting. He made it clear that no one could bring any outside items—phones, purses, jackets. Anwar told his cowed employees that a study binder had gone missing the previous day and that Mid-Columbia's human resources manager would be searching everyone's car to find it. After the meeting, Bruinekool saw a young woman who worked at Zain Medical Center standing by her desk. The woman was putting down a key fob that looked just like the one Bruinekool used for her Nissan Altima.

The missing binder was found in the trunk of that Altima. In the back seat were two bottles of a hypertension drug that had been prescribed to a Zain Medical Center patient. Mid-Columbia called the local police to report the supposed theft. Bruinekool suspects the staff meeting was called to give the young woman the chance to plant the binder and drugs; the edict against taking purses into the meeting meant that Bruinekool's keys would be easy to grab from her desk.

The scheme failed. The responding police officer noted that the binder, which had supposedly been missing for at least 24 hours, was neatly positioned atop other items in the trunk. The cop reasoned that the binder would have slid off such a precarious perch during Bruinekool's long commute to work over backcountry roads. No charges were filed, but Mid-Columbia used the incident as grounds to fire Bruinekool.

She filed for unemploment benefits, but Anwar contested the claim, saying she'd been terminated for gross misconduct that included enrolling ineligible patients in clinical trials. Washington's Employment Security Department ruled in Anwar's favor, ordering Bruinekool to pay back more than $7,000. As a result, Bruinekool's eldest daughter had to drop out of college and move home.

In the wake of the DEA raid, employees began to leave Mid-Columbia in droves. And Anwar was acting increasingly unhinged as his workforce slipped away. Doctors at Zain Medical Center, several of whom were listed as subinvestigators on Mid-Columbia studies, said he made overt threats to them. One physician says Anwar told her that he had close ties to international drug lords. She says she took to sleeping in the same bed as her 6-year-old daughter while holding a knife.

Heather Ellingford, meanwhile, could scarcely go a week without mysteriously having all the tires on her car slashed. She filed half a dozen police reports and tried to elude her tormentor by borrowing her brother's car, but the slashings did not stop. Her ex-husband used the vandalism as a reason to threaten to file for a more favorable custody arrangement; he contended that the attacks indicated their young son was in danger. (The court did not alter custody, and no one was ever charged in the slashings.)

Yet no amount of Anwar's meddling could change the course of the DEA's investigation. During the January raid, Craig Tom had obtained records for 40 patients involved in the CAM2038 trial. Many of the documents had the same copy-pasted text; no one had even bothered to delete references to pregnancy when the supposed patient was male. (The documents gathered in the raid also helped Tom realize that the phone number and email address listed on the GHB application belonged to Anwar, not Lucien Megna.) The slipshod records made Tom think the rot at Mid-Columbia was deeper than he'd imagined. So in July 2018 he got another warrant and searched the Richland building again. He was looking for evidence that might help the Justice Department build a sweeping criminal case.

With the walls closing in, Anwar tried to use the same maneuver he'd pulled off after the FDA issued its warning letter in 2016: He began setting up a new corporation, GS Trials. Once again he listed the company's location at the very same address.

But Anwar never managed to complete the transition. On November 7, 2018, a federal grand jury indicted him on 47 counts of fraud related to the corruption of 26 separate clinical trials. After his arrest the following day, prosecutors successfully argued that he be held without bail due to his penchant for threatening and harassing anyone he perceived as disloyal. (The accounts of Anwar's activities in this article, unless attributed to interviews, are based largely on court records.)

Ninety-eight percent of federal criminal defendants choose to reach plea agreements rather than go to trial, since a jury conviction on a full list of charges usually results in a harsh sentence. Anwar elected to go to trial. His attorney argued that other individuals were responsible for much of what had occurred at Zain and Mid-Columbia—that the enterprise was a collaborative effort between principal investigators and disgruntled former business associates and employees. But that narrative was overwhelmed by a parade of witnesses who spoke frankly about the awful things they'd done and endured in Anwar's orbit. All but one of them agreed to testify without cutting a deal for immunity from prosecution. That was a risky move, but it bolstered their credibility. (None was subsequently charged with a crime disclosed at the trial.)

Anwar declined to testify at his three-week trial, held in November 2019. After only six hours of deliberation, the jury came back with a verdict: guilty on all 47 counts. Brought before the trial judge for sentencing in October 2020, Anwar expressed neither remorse nor defiance. The judge ordered him to spend more than 28 years in prison and forfeit $5.9 million. While explaining his unusual decision to hand down a term even harsher than the one recommended in the presentence report, the judge said: “There was no step that you would not take to advance your fraud and imperil countless lives.” Anwar, he said, was “a vengeful human being who sought to punish anybody who jeopardized [his] scheme.” It was only in the waning moments of the proceeding that Anwar finally piped up to express his displeasure about something: a typo in a legal document—one that he tried to argue would cause him to forfeit too much money as part of his punishment. He was unsuccessful.

When I was deep into reporting this story, I was struck by an upsetting thought: The potential for the misinterpretation and misuse of this piece was high. A cynic, conspiracy theorist, or state-sponsored troll might point to what occurred in the Tri-Cities and claim there must surely be other Zains and Mid-Columbias strewn throughout the clinical-trials industry. By doing so, they would further erode trust in a system of scientific research that has produced an incalculable amount of good.

The truth is that the Anwar saga is exceedingly atypical. Between 2010 and 2019, the FDA conducted inspections of more than 3,900 research centers, which led to the issuing of just 61 warning letters, many of which cite minor violations. When the US attorneys who prosecuted Zain searched for similar incidents, including by consulting with the FDA, they could not find anything even remotely comparable. And the contract research organization veterans I spoke with were flabbergasted by the extent of what had happened in Richland. “In my 16 years as a monitor, I've never seen a site as bad as this, where the fraud was blatant,” says Geoff Heywood, the Icon monitor who was among the first to be alarmed by the misdeeds at Zain Research. “All the other [centers] that I worked with, some may have had their problems, but it wasn't malicious, it wasn't intended. This was.”

Though three years have passed since Anwar was forced out of business for good, the FDA is still trying to assess the extent of the damage his companies caused. As of last report, the agency is analyzing the 26 studies that were corrupted with data from Zain and Mid-Columbia, seeking to determine whether their results were meaningfully skewed by fraud. Many of those studies were large enough that a single batch of fabrications might have little chance of spoiling the whole project. The CAM2038 study, for example, involved 676 patients recruited by nearly 70 different research centers. But there are smaller clinical trials, too, in which Zain or Mid-Columbia played outsize roles—the study for the scabies ointment, for instance, used just 140 patients from three centers.

Whatever the outcome of the FDA's review, the Anwar case revealed that when confronted with an outlier like Anwar—a man willing to flout the most basic standards to achieve his selfish ends—the clinical trials industry proved disconcertingly vulnerable. Though all evidence suggests that such bad-faith actors are extremely rare, the system still needs hardier defenses against the likes of Anwar.

Now a year into his sentence, Anwar is incarcerated at FCI Sheridan, a medium-security prison in northwest Oregon. (He was caught with a cell phone in jail while awaiting his sentencing, which may explain why he wasn't assigned to a lower-security facility.) I wrote to him there, hoping to get his perspective on what might have driven him to make such self-destructive decisions. Somewhat to my surprise, he responded with a kindly email in which he expressed an eagerness to talk. He said that he had been diagnosed with lymphoma and alleged that the Bureau of Prisons had been denying him adequate medical care as he fought the disease. He wanted me to write about his plight but asked that I first get permission from his lawyer.

The attorney's reply to my inquiry, which he copied to Anwar's immediate family, said there would be no further comment. After that, Anwar stopped replying to my emails. (Anwar is also appealing his conviction on the grounds that he had ineffective counsel at trial, a typical stratagem by federal inmates.) Anwar's attorney did not respond to a list of detailed fact-checking questions. Nand declined to comment, and neither Megna nor Chaudhary responded to requests for comment.

The precise nature of Anwar's animating force may have eluded me, but I did develop a vivid sense of how his greed and narcissism altered so many lives. Justina Bruinekool, for example, now works part-time cleaning school classrooms, and she supplements her income by raising chickens, ducks, geese, and turkeys on her rural property. This more isolated existence suits her fine. “I don't trust people,” she says. “I don't trust anyone.”

That bone-deep sense of paranoia is not the only reminder of her time at Mid-Columbia. Due to Anwar's successful objection to her 2018 unemployment claim, Bruinekool continues to submit repayments to Washington's Employment Security Department whenever she can. With interest, she still owes the state more than $1,000.

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Samanth Subramanian

Hannah Zeavin

Nilesh Christopher

Dexter Thomas

Steven Brill

Looking back on the chequered past of drug trials

Professor; Coordinator, History & Philosophy of Science, UNSW Sydney

Disclosure statement

Nicolas Rasmussen receives funding from the Australian Research Council and the National Science Foundation (USA).

UNSW Sydney provides funding as a member of The Conversation AU.

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CLINICAL TRIALS – Human clinical trials are an important last hurdle in the development of new drugs and therapies. Today, The Conversation takes a closer look at this vital scientific endeavour with three articles that look at different aspects of the process.

When we see our doctor, we often walk away with a prescription. We suppose the doctor knows what she is doing when she writes it, so we take our medicine.

But how does she know? What grounds the scientific reasoning for the prescription that she doubtless can offer? Biological science has never been an entirely reliable guide to clinical care because people are complicated and different to the lab organisms from which biology draws its knowledge.

The surest science on which prescribing can be based is the controlled clinical trial, in which a defined intervention is either given or not given to a group of similar patients with a carefully defined condition and the outcomes compared.

Doctors read the results of these trials in medical journals, and they are also cited in drug marketing. We, and they, typically assume these published trial results are both truthful and representative of the drug’s effects.

Sadly, we are wrong. Their truthfulness is often debatable (depending on definitions of “truth”, naturally), even if every published sentence considered separately contains no falsehood.

Still worse, it is a well-established fact that the clinical trial literature represents new drugs in a falsely favourable light – especially trials sponsored by the drugs’ manufacturers . In effect, the scientific publications are advertising, as surely as the glossy ads on the pages of the same medical journals.

How did we get here, and what exactly is the problem with this situation?

The early years

At the end of the 19th century, the practise of medicine had very little to do with science. Still, science was affecting the way doctors thought; in its theoretical basis, the ancient Western art of healing was undergoing a revolution. Laboratory experimentation with animals had recently revealed the chemical and physical functions of the organs, and many diseases had been traced to microbes that could be studied outside the body.

In new secular hospitals, recently placed under the authority of medical schools, it became possible to study large numbers of patients with similar conditions. These investigations produced much more reliable descriptions of diseases, and their natural course. They also enabled accurate assessment of the impact of treatments on death rates.

Large prospective studies, some of the earliest clinical trials, showed that the West’s traditional therapies, such as bleeding and purging as well as drugs, did more harm than good. Many physicians devoted themselves to research in the hope that science could also find a way forward.

Eventually, late in the century, breakthroughs were achieved, especially against germs. In the 1860s and 1870s, Joseph Lister and other surgeons found that keeping wounds sterile greatly improved surgical recovery rates; in the 1880s, Louis Pasteur developed a vaccine that cured rabies; in the 1890s, Paul Ehrlich and Emil Adolf Von Behring developed a serum that cured the common, deadly diphtheria infection.

These treatments were first tested on animals, and then tried on patients in a condition poor enough that, based on historical observation of similar cases, survival was doubtful. While such tests were not supported by careful statistical analysis, the benefits of the treatments were dramatic enough to convince even sceptics of their value. Their triumphant passage from lab bench to bedside solidified the status of science as the key to medical progress.

Enter the pharmaceutical industry

The scientific trend in medicine at first had limited impact on the pharmaceuticals industry, whose leading products at the turn of the century – and indeed, three decades later – were brand-named tonic concoctions of old and mostly (apart from the ubiquitous cocaine and opium) useless herbs, often concealed by secret formulas.

During the first half of the century, many countries introduced laws requiring the truthful listing of active ingredients and eventually, in a few, regulations requiring toxicity testing with animals. But no country required clinical trials – that is, systematic testing in people. So even the best manufacturers continued to market new drugs on the basis of testimonials – enthusiastic case reports from friendly doctors given free “trial” samples.

Still, a few firms showed that cooperating with the reforms could be profitable, by sourcing new drugs from the latest lab research, testing them under controlled conditions, and turning them into products acclaimed by scientific medicine. Key examples included the anti-syphilis drug Salvarsan marketed by Hoechst in 1910, and the insulin preparation discovered at University of Toronto and manufactured by Lilly from 1922.

To encourage the scientific drug development trend, reforming medical professors and journal editors in the United States organised an expert panel to review scientific evidence behind safety and efficacy claims in drug advertising. Without the evidence to win the panel’s seal of approval, drugs could not be advertised in the major journals.

By the 1930s, the medical elite’s efforts to reshape the thinking and values of practitioners along more scientific lines had affected the pharmaceuticals market. Since doctors wanted to prescribe modern treatments developed through laboratory science, and were impressed with clinical trials showing drugs to be effective by careful comparison with another treatment (or placebo), drug firms wanted to offer such products.

As a result, major drug companies began routinely sponsoring rigorous clinical trials of their new products. In general, they relied on medical academics and other reputable physician-investigators to win the scientific credibility that they sought. These clinical investigators typically recruited their own patients, both in private practice and in the hospital services they often oversaw, just as they did when conducting clinical research on their own account.

Among both the clinical trials organised by drug firms and those by researchers seeking only knowledge, it was uncommon to inform patients fully before enrolling them in a clinical trial. As a result, many patients were not offered the choice of standard therapies with known efficacy. This occurred despite the undisputed acceptance of the principle, enunciated in the Nazi doctors’ trials at Nuremburg, that people should not unwillingly be subjected to experiments with a significant chance of leaving them worse off.

Western doctors evidently felt secure in their humanitarian motives, even though they typically were paid for their participation in commercially sponsored trials. It was also typical that their “unsuccessful” clinical trials would remain unpublished by sponsor preference, depriving medicine of the opportunity to learn from its mistakes. At the time, this too was not recognised as an ethical problem.

Rise of Big Pharma

Although no country had laws requiring clinical testing proving a drug effective before it could be marketed, by the 1950s it had become almost a commercial necessity to claim a new drug’s clinical superiority when introducing it. And the 1950s mark the high point of the drug industry’s chemical ingenuity, with hundreds of new compounds entering the market each year.

As a result, there was an explosion of clinical testing – but not much of it meeting the new gold standard of quality, the double blind randomised controlled trial (RCT), featuring multiple checks to ensure that those conducting a study cannot unwittingly influence the outcome.

By the 1960s this wild west situation gave rise to scandalous abuses . Clinical testing was important both to advertising claims and to medical careers, but no impartial body monitored either trial rigour or patient treatment (including the American journal editors whose system lapsed in the 1950s). In some cases it emerged that claimed animal safety testing or clinical trials for efficacy had in fact not been conducted and the results fabricated.

In other cases, patients with curable illnesses were left untreated so that they could serve more effectively as the control group, without their knowledge. In a few, patients were actually given illnesses and then denied effective treatment – if any existed.

Stronger regulatory laws were enacted, requiring that new drugs show at least equal efficacy and safety in humans compared with existing therapies, and forcing companies to make patient data in sponsored trials available to regulators. Human subject protection regulations were also established, most based on the principle of autonomy – that patients must make free and informed decisions about participating in experiments.

Conflict of interest began to achieve some recognition as an ethical problem too, although for a long time disclosure of financial links between trial sponsors and physician investigators were restricted to private documents like grant applications and internal ethics applications.

Modern rigour

The 1970s were the age of rigour in clinical trials, with the treatment of human subjects, and especially the design of trials more circumscribed.

But it was not to last. In the 1980s patient activists, those with cancer and soon after with AIDS, became convinced by enthusiastic researchers that cures were available but withheld by overly stringent testing requirements. They developed the political muscle to “access” unproven new drugs, on the common ( but false ) presumption that new drugs are much better than old ones.

Drug companies quickly recognised activists as allies in their efforts to get their products on the market as quickly as possible. Responding to the pressure, governments began establishing trial registries where companies and other trial organisers could announce clinical trials and recruit suitable patients as subjects. These were not compulsory, but drug firms found them useful.

However the defenders of scientific rigour in clinical testing found an opportunity of their own in trial registration: with most trials publicly registered, it became easier to identify those whose findings were never published (those unfavourable to a new product, for example). And it even became conceivable to require trial results to be posted in the same registries.

Leading research journals once again banded together to pressure the industry, refusing to publish clinical trials that were not registered at initiation, and requiring trial reports to list trial sponsors and payments to authors.

Ethical arguments were made that when patients agree to act as experimental subjects to advance medicine, those using them to conduct a trial are obliged to make all results available to medical science. Recent lawsuits have included the release of previously secret, unsuccessful trials as part of the settlement. Drug companies have protested every step of the way against publishing what they call commercial secrets.

We are now moving very close to government-mandated, universal release of all clinical trial data. What is the next stage in the century long battle over the clinical trial – as an instrument to constrain commerce, as a commercial tool in itself — we no doubt shall quickly learn. Whatever it is, we would be well advised to remember the ancient Greeks, who used the same word (pharmakon) to denote both poison and drug. For any drug strong enough to heal can also maim when used unwisely.

Click the links below for other articles in the package:

Abandoning clinical trial safeguards won’t boost local industry

Care and consent: the fraught ethics of international clinical trials

And from our archives:

Clinical trials are useful – here’s how we can ensure they stay so

What Australia should do to ensure research integrity

Register all trials, report all results – it’s long overdue

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More than 200 people have been treated with experimental CRISPR therapies

But at a global genome-editing summit, exciting trial results were tempered by safety and ethical concerns.

• Jessica Hamzelou archive page

This article is from The Checkup, MIT Technology Review's weekly biotech newsletter. To receive it in your inbox every Thursday, sign up here .

I’ve spent the last few days thinking about how, when, and if we should use gene-editing tools to change the human genome. These are huge questions, and very emotive ones—especially when it comes to editing embryos.

I watched scientists, ethicists, patient advocacy groups, and others wrestle with these topics at the Third International Summit on Human Genome Editing in London earlier this week.

There’s plenty to get excited about when it comes to gene editing. In the decade since scientists found they could use CRISPR to edit cell genomes, multiple clinical trials have sprung up to test the technology’s use for serious diseases. CRISPR has already been used to save some lives and transform others.

But it hasn’t all been smooth sailing. Not all of the trials have gone to plan, and some volunteers have died. Successful treatments are likely to be expensive, and thus limited to the wealthy few. And while these trials tend to involve changes to the genes in adult body cells, some are hoping to use CRISPR and other gene-editing tools in eggs, sperm, and embryos. The specter of designer babies continues to loom over the field.

It was at the last summit, held in Hong Kong in 2018, that He Jiankui, then based at the Southern University of Science and Technology in Shenzhen, China, announced that he had used CRISPR on human embryos. The news of the first “CRISPR babies,” as they became known, caused a massive ruckus, as you might imagine. “We’ll never forget the shock,” Victor Dzau, president of the US National Academy of Medicine, told us.

He Jiankui ended up in prison and was released only last year . And while heritable genome editing was already banned in China at the time—it has been outlawed since 2003—the country has since enacted a series of additional laws designed to prevent anything like that from happening again. Today, heritable genome editing is prohibited under criminal law, Yaojin Peng of the Beijing Institute of Stem Cell and Regenerative Medicine told the audience.

There was much less drama at this year’s summit. But there was plenty of emotion. In a session about how gene editing might be used to treat sickle-cell disease, Victoria Gray, a 37-year-old survivor of the disease, took to the stage. She told the audience about how her severe symptoms had disrupted her childhood and adolescence, and scuppered her dreams of training to be a doctor. She described episodes of severe pain that left her hospitalized for months at a time. Her children were worried she might die.

But then she underwent a treatment that involved editing the genes in cells from her bone marrow. Her new “super cells,” as she calls them, have transformed her life. Within minutes of receiving her transfusion of edited cells, she felt reborn and shed tears of joy, she told us. It took seven to eight months for her to feel better, but after that point, “I really began to enjoy the life that I once felt was just passing me by,” she said. I could see the typically stoic scientists around me wiping tears from their eyes.

Victoria is one of more than 200 people who have been treated with CRISPR-based therapies in clinical trials , said David Liu of the Broad Institute of MIT and Harvard, who has led the development of new and improved forms of CRISPR . Trials are also underway for a range of other diseases, including cancers, genetic vision loss, and amyloidosis.

Liu highlighted the case of Alyssa, a teenager in the UK who was diagnosed with a form of leukemia that affects a type of white blood cells called T cells. Chemotherapy didn’t work, and neither did a bone marrow transplant. So doctors at Great Ormond Street Hospital in London tried a CRISPR-based approach.

It involved taking healthy T cells from a donor and using CRISPR to modify them. The treated cells were altered so that they wouldn’t be rejected by Alyssa’s immune system, but they would be able to track down and attack Alyssa’s own cancerous T cells. These cells were then given to Alyssa as a treatment. It seems to have worked.

“As of now, approximately 10 months after treatment, her cancer remains undetectable,” Liu said.

It really is incredible that we are hearing such success stories already. But there are concerns.

The question of equity came up again and again at the summit. Gene-editing therapies are expected to cost a lot of money—likely millions of dollars. Who will be able to afford them? Probably not the people living in low- and middle-income countries, multiple attendees worried.

For now, CRISPR therapies are still considered experimental, and none have been approved, so the only way for people to access them is through clinical trials. The majority of these are being run in the rich world. Natacha Salomé Lima, a psychologist and bioethicist at the University of Buenos Aires in Argentina, pointed out that while 70% of global cancer cases are in low- and middle-income countries, two-thirds of gene-therapy cancer trials are taking place in wealthy countries.

I could tell that the summit’s organizers had made an effort to feature speakers from all over the world, and to include people who have the disorders being targeted by gene editing. But some attendees felt that some voices were still missing from the discussion. “What about the LGBTQ community?” Marc Dusseiller of ETH Zurich in Switzerland, who describes himself as a “workshopologist” interested in biohacking and bio art, asked me.

It’s also worth pointing out that not all CRISPR treatments have been a success. Multiple researchers noted that we still don’t fully understand how the treatment works. We know we can cut DNA, and swap either DNA bases or chunks of genetic code. But we can’t be sure about unintended effects elsewhere in the genome. It’s possible that you could accidentally trigger some genetic change elsewhere—one that might have harmful consequences.

Last year, 27-year-old Terry Horgan died while participating in a clinical trial of a CRISPR treatment designed to treat his Duchenne muscular dystrophy, a fatal disease that causes muscle degeneration. The cause of his death—and whether or not it might have been related to the treatment—has not been made clear.

And there’s always a risk that rogue scientists will set up companies offering unapproved procedures to desperate individuals who are willing to pay for them, said Robin Lovell-Badge, a stem-cell biologist at the Crick Institute, where the summit took place. They might even sell unauthorized procedures designed to enhance people rather than treat them.

On the first day of the summit, a couple of protesters stood at the entrance of the venue, holding a banner reading “Stop designer babies.” This sentiment is shared by a lot of scientists. They are particularly worried about future attempts to edit the genes of eggs, sperm, or embryos.

In theory, you could change the DNA of an embryo to prevent a baby from developing a heritable disease. But research into early embryos (scientists are generally allowed to study them for only 14 days before having to destroy them) suggests that they are even more likely to be affected by unintended, potentially harmful effects of gene editing. And these changes would be passed on to the next generation, too.

Most attendees focused on technical and ethical worries, but Dusseiller had another concern. The summit was too dry, he told me; the serious issues surrounding gene editing can be addressed with some degree of humor. “We need more weirdness,” he argued. “We need more jokes .”

Read more from Tech Review's archive

There are more than 50 experimental studies underway that use gene editing in people to treat cancer, HIV, blood diseases, and more. Most of them involve CRISPR, my colleague Antonio Regalado reported earlier this week.

And last year, a volunteer in New Zealand became the first to receive an experimental CRISPR treatment to lower her cholesterol. One of the scientists behind the work thinks the approach could potentially benefit almost everyone .

CRISPR is also being explored for an inherited form of blindness. The first volunteer underwent the experimental treatment in 2020 .

He Jiankui’s work was never published. It was rejected by the leading medical journals it was submitted to. But Antonio got hold of the manuscript, and showed it to four experts . Their verdicts were damning. He’s claims were not supported by his results, the babies’ parents may have been under pressure to agree to join the experiment, and the researchers went ahead without fully understanding what they were doing.

The summit was focused on human genome editing, but CRISPR is also being explored to make farmed animals bigger and stronger . One team of scientists has put an alligator gene into catfish in an attempt to make them more resistant to disease, for example.

From around the web

A microbiologist found a forgotten beef soup at the back of her fridge had turned bright blue. So she set out on a scientific quest to find out why. ( Twitter )

Governments around the world are using algorithms to control access to various services. A system that flags people who might be committing benefits fraud in Rotterdam appears to discriminate on the basis of ethnicity and gender, according to an investigation. ( Wired )

Last year, biotech company Retro Biosciences announced its launch with $180 million in funding. It turns out that all of that is from Sam Altman, the CEO of OpenAI. ( MIT Technology Review )

Biotechnology and health

What’s next for mdma.

The FDA is poised to approve the notorious party drug as a therapy. Here’s what it means, and where similar drugs stand in the US. 

• Cassandra Willyard archive page

FDA advisors just said no to the use of MDMA as a therapy

The studies demonstrating MDMA’s efficacy against PTSD left experts with too many questions to greenlight the treatment.

Beyond Neuralink: Meet the other companies developing brain-computer interfaces

Companies like Synchron, Paradromics, and Precision Neuroscience are also racing to develop brain implants

My biotech plants are dead

Two ‘Firefly petunias’ perished in a shipping misadventure, but other customers have had better luck.

• Antonio Regalado archive page

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An N.Y.U. Study Gone Wrong, and a Top Researcher Dismissed

By Benedict Carey

• June 27, 2016

New York University’s medical school has quietly shut down eight studies at its prominent psychiatric research center and parted ways with a top researcher after discovering a series of violations in a study of an experimental, mind-altering drug.

A subsequent federal investigation found lax oversight of study participants, most of whom had serious mental issues. The Food and Drug Administration investigators also found that records had been falsified and researchers had failed to keep accurate case histories.

In one of the shuttered studies, people with a diagnosis of post-traumatic stress caused by childhood abuse took a relatively untested drug intended to mimic the effects of marijuana, to see if it relieved symptoms.

“I think their intent was good, and they were considerate to me,” said one of those subjects, Diane Ruffcorn, 40, of Seattle, who said she was sexually abused as a child. “But what concerned me, I was given this drug, and all these tests, and then it was goodbye, I was on my own. There was no follow-up.”

It’s a critical time for two important but still controversial areas of psychiatry: the search for a blood test or other biological sign of post-traumatic stress disorder , which has so far come up empty, and the use of recreational drugs like ecstasy and marijuana to treat it.

At least one trial of marijuana, and one using ecstasy, are in the works for traumatized veterans, and some psychiatrists and many patients see this work as having enormous promise to reshape and improve treatment for trauma. But obtaining approval to use the drugs in experiments is still politically sensitive. Doctors who have done studies with these drugs say that their uncertain effects on traumatic memory make close supervision during treatment essential.

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Clinical trials do go wrong: how many human subjects are injured by scientific research each year.

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This is not a scare story, this is a “just the facts” story.

Last month in France, research of an experimental drug intended to treat mood, anxiety, and movement disorders went tragically wrong, resulting in the death of one participant and hospitalization of five others. As reported by Reuters , the six men who fell ill had been in good health until taking the pill under study. In a statement , Biotrial, the laboratory testing the drug which is made by Bial, a Portuguese company, says they complied with international standards for research. As the post-mortem investigation continues it’s natural to ask the obvious question: How many people die or get hurt during research studies?

“No one knows,” Liz Woeckner, president of Citizens for Responsible Care and Research, Inc. ( CIRCARE ), tells Medical Daily.

Getting the Facts

In a 2001 paper , Dr. Adil Shamoo estimates 19 million human subjects participate in clinical research trials, both public and private, each year. Clinical trials investigate whether a drug, device, or even a treatment strategy is safe and effective for humans after testing in the lab and on animals.

Because their purpose is to produce decision-making data, clinical trials follow strict protocols meant to generate reliable results and also to protect participants. Along with pre-testing and strict standards, institutional review boards, made up of doctors, researchers, and members of the community, oversee each clinical trial to make sure they are ethical and the welfare of the participants are protected. Yet terrible things do happen as indicated by the incident in France and another recent well-publicized case of six healthy men experiencing organ failure after taking a research drug in London’s Northwick Park Hospital .

Scratch the surface and you will soon discover these recent cases reported in the American Journal of Bioethics : Nicole Wan, 19, who died within 2 days after receiving a lethal dose of lidocaine in a 1996 University of Rochester research project; Jesse Gelsinger, an 18-year-old with liver disease, who died during a gene therapy experiment at the University of Pennsylvania; and Ellen Roche, a 24-year-old healthy volunteer, who died after inhaling a chemical that induces asthma during a study at Johns Hopkins University.

While all of these incidents received some publicity, it is likely that other, more difficult to find cases also exist.

Serious Adverse Events

A clinical trial must report any “serious adverse events” to its institutional review board. As the FDA defines, serious adverse events (SAEs), include: Death; life-threatening harms; hospitalization; disability or permanent damage; birth defects; injuries requiring intervention to prevent impairment; or any other serious event.

If these are the rules, how often are they followed?

“Inadequate and underreporting of trial results, especially safety results, is common,” wrote the authors of a 2015 study published in BMC Medicine. Their analysis of 300 trials with SAEs found that slightly more than a quarter simply did not publish their results, while nearly a third did not correctly publish the number of SAEs. For the remaining trials, 13 percent did not mention SAEs, two percent reported no SAEs, and 16 percent did not report the total number of SAEs per treatment group.

In fact, only 11 percent accurately published and described their serious events. “Although we do not know which the ‘true’ results are, we believe that these discrepancies clearly outline problems in the reporting of SAEs,” concluded the authors.

Another 2014 study explored discontinued randomized clinical trials. Here an international team of researchers discovered “discontinuation was common.” Nearly a quarter of all trials ended early, yet little more than a third reported to ethics committees. When they did, the most frequent reason cited for discontinuation was poor recruitment, yet a small percentage (2.4 percent) ended due to “harm,” while the same proportion were aborted for “unknown” reasons.

Importantly, these two studies used data from only publicly-funded trials listed with ClinicalTrials.gov. Yet “the lion’s share” of trials are conducted by industry (pharmaceutical companies and other private interests) that do not have to report, according to Woeckner. As she explained, even if you had the raw numbers of people harmed during trials, “you’d have to adjudicate each case.”

Human Volunteers

In a 2001 paper, Shamoo finds 878 institutional incident reports filed, 41 investigations made, and only 8 deaths reported to the Office for Human Research Protections (among the 70 million human subjects), during a 10-year period ending August 2000. Of the incident reports, he found 44 percent included adverse events.

Because any death, whether occurring in a car crash, by suicide, or as a result of the research itself, must be reported, Shamoo calculates 8 deaths is too small a number for those millions of people and this leads him to the “inescapable conclusion that research institutions supported by the NIH are failing to report, or are not accurately reporting adverse events including deaths.”

For an inside look at drug trials, Guinea Pig Zero is the go-to source. Describing itself as “an occupational jobzine for people who are used as medical or pharmaceutical research subjects,” GPZ features first-person accounts of volunteers who enlist for clinical trials often to earn a small honorarium (paycheck). While some contributors recount the tedium of a particular clinical trial, others relive their personal (and witnessed) experiences of research horrors.

And so the research continues, with distressing reports of accidental bleeding or other calamities arising from the misty bog on occasion. Last year the World Health Organization called for disclosure of unreported clinical trial data, while industry contemplates "open science " policy complete with data sharing. Honesty is not so easily decreed.

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The Drug Trial: Emergency At The Hospital

“It was all manic, everything was happening all at once, they were vomiting, they were screaming in pain, people fainting.”

Just over a decade later and this BBC special tells the tale of what happened through interviews with those involved and accurate dramatisation of the events as they unfolded. We also learn how this one event changed the way in which first in man clinical trails are conducted internationally.

8 Comments / User Reviews

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I’m sorry, but without human trials we wouldn’t be where we are today as a society. People signing up and participating know the risks. No one forced them to get injected with some new drug. Sucks that they went through that though.

This info present here is very great for me and the drug companys give us many helping durg’s so i also thanks for him. https://mcdvoice.me/

Disgusting how drug companys arnt held to account

Meanwhile in the 2020’s……………

Hey doesn’t that one guy look and sound a lot like Boba Fett? Lol pretty neat.

2017 documentary

really interesting documentary but a very brutal one as well, would not recommend doing a trail and i will never do it as well, must of been hard for people who was in the trial but very intresting.

Wot the drug woz ment be for people will try anything

Interesting

What do Pfizer’s 1996 drug trials in Nigeria teach us about vaccine hesitancy?

Subscribe to global connection, belinda archibong and belinda archibong david m. rubenstein fellow - global economy and development @belindaarch francis annan fa francis annan assistant professor of economics - university of california, berkeley @fannan2316.

December 3, 2021

Vaccinations are essential to responding to epidemics, and the current COVID-19 pandemic is no exception. Yet, globally, many choose not to get vaccinated for reasons that have, only recently, gained attention among researchers, policymakers, and the wider public. Among the reasons cited is a general distrust in the government and health institutions in charge of vaccination. But where does this distrust come from? Some recent evidence links the distrust to negative past experiences with government institutions because of discrimination in the health care system and unethical medical trials , among other explanations.

In 1996, Nigeria experienced one of the worst meningitis epidemics in its history with 109,580 cases and 11,717 deaths. Bacterial meningitis is an infection of the lining of the brain that is especially virulent in children. Northern Nigeria is also a majority-Muslim region, with around 99 percent of residents in Kano state identifying as Muslim. At a hospital in Kano, Doctors Without Borders treated children with chloramphenicol, a well-known antibiotic endorsed by the World Health Organization (WHO) to treat bacterial meningitis.

Over the same period, Pfizer, a U.S. pharmaceutical company, tried to launch a new antibiotic drug, Trovan. While Pfizer had tested the drug on adults, it had not yet been tested on children. Additionally, early testing on adults had shown some serious side effects of the drug, including liver problems and cartilage abnormalities. After learning of the meningitis epidemic, Pfizer decided to use it as an opportunity to test the efficacy of Trovan in pediatric settings. Pfizer set up a site beside the Doctors Without Borders testing area and over two weeks, selected a sample of 200 children between 3 months and 18 years old to participate. A month later, 11 of the children that had participated were dead. Additionally, numerous parents of children involved in the trials reported disabilities among their children, including paralysis and liver failure.

In December 2000, The Washington Post published a series of exposés, alleging Pfizer’s fault in the deaths and disabilities of multiple children and accusing Pfizer of conducting unethical experimental trials without attaining informed consent from the participants. Parents alleged that they had not been informed of the experimental nature of the trials, with many reporting that they thought they were receiving the standard medication issued in the neighboring Doctors Without Borders area.

The reporting sparked a series of protests in Muslim states in northern Nigeria in 2001. Protesters, led by Muslim religious leaders, highlighted the deaths of Muslim children and the fact that the trials had been conducted in a Muslim state as evidence for the claim that Pfizer and its associated “Western” institutions were targeting and trying to kill Muslims with vaccines. Pfizer denied any wrongdoing, stating that the children died of meningitis rather than their drug. An investigation by a panel of experts hired by the Nigerian government found Pfizer at fault in the children’s deaths and guilty of conducting human trials without informed consent. In subsequent years, several lawsuits were filed against Pfizer by parents and the Kano state government. An out-of-court settlement was reached for, allegedly, $75 million to Kano state and $175,000 to four families of dead children in 2009.

The incident heightened distrust among Muslims toward vaccination campaigns led by Western nonprofits like the Global Polio Eradication Initiative (GPEI), a consortium including the WHO and the U.S. Centers for Disease Control and Prevention (CDC), aimed at eradicating polio worldwide (with a particular focus on Nigeria where more than 40 percent of the 677 new polio cases worldwide were recorded in 2002). Tensions culminated in a 2003 Muslim leader-led boycott of GPEI-led polio mass vaccination campaigns in five Muslim northern states in Nigeria. In interviews explaining support for the boycott, respondents explicitly cited the Pfizer drug trials. The boycotts continued for over a year and ended only after federal government officials worked with local religious leaders to demonstrate the safety of the vaccine. The boycott also led to a 30 percent increase in polio prevalence, setting back global polio eradication efforts by over a decade, with Nigeria becoming one of the last countries in the world to be declared polio-free in 2000. The Pfizer trials remain a point of tension among Muslims in Nigeria, with the specter of Muslim children’s deaths often referenced any time health authorities attempt to conduct mass vaccination campaigns in the country.

Effects of the trials on vaccine hesitancy and the role of education and trust

In a new working paper , we find that Muslim mothers significantly reduced their vaccinations of children born after 2000. The reduction (a magnitude of 11 percent to 27 percent relative to the pre-Washington Post news vaccination rate) included routine childhood vaccines for diseases such as tuberculosis, diphtheria, pertussis, and tetanus, polio, and measles—vaccines that have been known to be safe and effective for decades.

The reductions were concentrated among educated Muslim mothers who had access to more information, were literate, and hence were more likely to have read the news and be informed of health practices. The reduction effect was also stronger for Muslim mothers residing in Muslim-minority neighborhoods, where Muslims made up less than 50 percent of the neighborhood’s demographic. This pattern aligns with research showing that religious individuals may cleave more strongly to religious networks in areas where they are the minority. We find that Muslims residing in minority-Muslim neighborhoods tend to be more religious (i.e., attend mosque more frequently) and more trusting of their religious leaders, supporting the explanation that they would have been more exposed to and more receptive of their religious leaders’ anti-vaccine campaigns.

While Pfizer settled out of court for $75 million, how do these costs compare to the costs of reduced child vaccination in the country? Being unvaccinated increases an individual’s risk of infection from disease. The significant costs to treat these illnesses can incur large financial burdens on households . We conduct simple back-of-the-envelope calculations on the potential costs of treatment from an increased number of unvaccinated Muslim children as a result of the negative news about the Pfizer drug trials. Using our most conservative estimates of direct medical costs of treatment only, and without factoring in any potential deaths from disease, the reduced vaccination of Muslim children in the aftermath of the disclosure of the Pfizer drug trials incurred a total potential cost of treatment of over $94 million over the counterfactual scenario. This cost is more than $19 million higher than the Pfizer settlement to the Nigerian government of $75 million.

Researchers are increasingly recognizing the importance of public trust for the effectiveness of vaccination campaigns aimed at reducing the spread of disease during epidemics. The results from our paper show that negative news about vaccination can significantly increase vaccine hesitancy and local trust networks can be key drivers of vaccine hesitancy, especially among minority populations within regions with potentially stronger own-group cleavage. So, policymakers aiming to increase vaccination in the aftermath of epidemics must work to build and leverage trust within these local networks to enhance vaccine uptake. The findings also highlight the importance of careful, ethical, and transparent practices in vaccination efforts and institutional and local community network trust in vaccine compliance.

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“Right-to-Try” experimental drugs: an overview

Vijay mahant.

MediLite Diagnostika, Inc, 12364 Carmel Country Rd, San Diego, CA 92130 USA

Associated Data

Data sharing is not applicable to this article because no data sets were generated and/or analyzed for the study.

The “Right-to-Try” experimental drugs act passed by Donald Trump in 2018 provides an opportunity of early access to experimental drugs for the treatment of life-threatening diseases and a potential boon to many young and under-capitalized biotechnology or pharmaceutical companies. The pros and cons of experimental drugs, including a number of “cutting edge” scientific, clinical, and a number of synergistic approaches such as artificial intelligence, machine learning, big data, data refineries, electronic health records, data driven clinical decisions and risk mitigation are reviewed.

Over a century ago, most medications were the “wild west” with alleged therapeutic benefits. Most such medications sold to the public offered negligible or no evidence-based therapeutic efficacy and safety to the patient at large, except the “placebo benefit”—and hope—at the best. The drugs were unregulated and sold to the public in the USA and many parts of the world. To protect the public against the sale of misbranded, mislabeled and/or adulterated foods and drugs, the US in 1906 enacted [ 1 ] the “Pure Food and Drug Act” and this resulted in the establishment of the federal agency, the Food and Drug Administration (FDA).

Historical overview

The “Right-to-Try” experimental drugs, however, originated [ 2 – 4 ] from the Abigail Alliance for Better Access to Developmental Drugs versus von Eschenbach. Due to Abigail’s high expression of EGFR, her oncologist recommended Abigail for her terminal head and neck cancer to try an investigational EGFR-targeted drug, C222 (Erbitux), which was then undergoing clinical trial for the treatment of colorectal cancer. Due to her ineligibility to participate in the clinical trials and denial by the FDA, Abigail’s father, Frank Burroughs sued the FDA in 2003 for access to the experimental drug, Erbitux, on the pretext that an investigational drug by terminally ill patients after phase I approval was a constitutional right. Abigail’s tragic story was one of the primary precursors and a “catalyst” that inspired patients and non-patients, including advocacy groups for access to unapproved therapies by the FDA.

In May 2018, President Donald Trump signed the “Right-to-Try” Act [ 5 ]. The legislation overcame many of the regulatory barriers, limited the risks to the sponsor while implementation of the act inherently burdened the sponsor. The “Right-to-Try” legislation is in essence a derivative of the Expanded Access Programs (EAPs). Advocates such as patients, families, friends and advocacy groups of the “Right-to-Try” legislation argue that the legislation is in line within the pre-existing framework of EAPs and that the legislation: (i) provides a “streamlined” avenue for making eligible drugs available to eligible patients with no other options; (ii) it increases patient’s engagement; (iii) it is a patient’s journey of self-actualization; (iv) it empowers the patient about his or her own health, well-being and quality of life; (v) it provides optimism and access to novel interventions with potential therapeutic benefits that may prolong life and improve quality of life; and (vi) the patient can be treated in the USA with valuable family time, more comfort and fewer risks than being treated overseas. The critics, on the other hand, argue: (i) there is an inherent safety risk that may potentially cause more harm to the patient or even death than the benefit because the experimental drug did not undergo rigorous testing; (ii) there is a lack of oversight by the FDA, except posting of the consolidated annual summary report; (iii) the patient in most cases has limited understanding of the informed consent due to complexity and confusion of the medical terminology used in the consent form; (iv) there are therapeutic misconceptions combined with high expectations and optimism by the patient; (v) there is potentially a considerable financial burden by the patient or the patient’s family because payors currently do not provide coverage and deny hospice care; (vi) there is a potential loss of trust in the regulatory agency, the sponsor and the health care provider; and (vii) there is a liability “immunity” for the health-care provider, including the drug sponsor for potential negative outcomes of the treatment unless the medical provider and the sponsor were engaged in “gross negligence, reckless or “wilful misconduct.”

Some of the major inherent limitations and often overlooked about the “Right-to-Try” experimental drugs are: (i) patient’s vulnerability due to lack of oversight by the FDA; (ii) there is a lack of clinical study protocol, including the lack of sufficient statistical power to detect the intended effect(s); (iii) the information is collected in a “piece-meal”; and (iv) a lack of systematic reporting about efficacy and the safety of the experimental drug that may potentially result in limited information for the health and safety of the public. Some of these issues may be addressed and resolved by utilizing EHR systems. EHR systems are maintained by health care providers and health care organizations for delivering patient care. EHR systems can thus easily lend themselves for integrating real-time electronic health care information about the patient across multiple health care providers.

One of the most important considerations and occasionally overlooked is comorbidity; it is quite common among cancer patients and it can potentially affect the treatment outcome, worsen the adverse effects due to polypharmacy and may even shorten the life. The prognosis of patients with comorbidity is often poor survival combined with poor quality of life and higher financial costs. The use of experimental drugs in patients with morbidity may thus be risky or limited unless the experimental drug has gone through further rigorous testing and/or the experimental drug is paired synergistically with an FDA-approved drug and appropriate tools are employed for monitoring efficacy and safety of the therapy. Treatment of metastatic cancer patients with comorbidity using experimental drugs would be even more challenging and riskier with many implications that may warrant further considerations that are in the best interest of the patient’s health, well-being and life, including additional financial burden.

The “landscape, the ecosystem and the dynamics”

The implications of ethics, law, regulations, government policies, constitutional rights by terminal ill patients, patient advocacy groups, including stakeholders about the pros and cons echoed through the “ecosystem” of early access to investigational drugs. Under the “Right-to-Try” legislation, the eligibility to participate include: (i) the patient must have been diagnosed with a debilitating or life-threatening disease; (ii) the patient must have failed all standard of care treatments; (iii) the experimental or the investigational drug must have completed at least phase 1 trial; (iv) the patient must have signed an informed consent [ 6 ]; and (vi) the pharmaceutical company must be able to provide the experimental drug to the patient. Due to the potentially negative outcome about the therapeutic efficacy combined with the safety issues, most sponsors developing medications for life-threatening diseases have had reservations about participating in expanded access or the “Right-to-Try” programs. To de-risk the potential negative outcomes and the implications combined with an opportunity to target a much larger number of patients than to a few eligible patients under the early access programs, the sponsors’ primary goal has been to have full FDA approval of the drug. The drug approval process, of course, is lengthy and highly risky due to potential clinical trial failures along each step of the approval process. It is an expensive process—currently, estimated to be between US$ 1.9–2.5 billion [ 7 , 8 ].

On the other hand, China for almost two decades approved a number of experimental drugs. From 2003 to 2005, the SFDA approved H101, experimental oncolytic viral therapy for head and neck cancer, an angiogenic Endostar inhibitor for treating non-small cell lung cancer and Gendicine for treating head and neck cancer [ 9 – 11 ]. However, in December, 2019, the Drug Administration Law (DAL) by the SFDA came into effect [ 12 ]. The DAL is likely to have an impact on experimental drugs because it addresses several issues such as public health concerns, drug innovation, drug safety and drug accessibility. In the “wake” of the recent epidemics such as Ebola, MERS caused by coronavirus (MERS-CoV) and more recently the outbreak of the coronavirus, SARS-CoV2 in 2019–2020, the use of “emergency drugs and compassionate use of experiential drugs” may warrant further considerations and the options available in an epidemic or a pandemic. Gilead Sciences’ experimental drug (at the time of writing), remdesivir, is one of the most promising drug candidates that may be effective against SARS-CoV2. The drug exhibits broad-spectrum antiviral activity against a number of RNA viruses including the Ebola virus by interfering with the viral polymerase enzyme. Remdesivir is currently being used as an “emergency experimental drug” on compassionate basis while randomized controlled studies are underway [ 13 ].

The risks and benefits of phase 1 oncology trials from 1991 to 2002 have been reviewed [ 14 ] involving a total of 460 trials and 11,935 participants. The participants were tested for toxicity and 10,402 participants were assessed for therapeutic efficacy. The overall response rate was reported to be 10.6% with considerable variations among trials. The classic phase 1 trials using single investigational chemotherapeutic drug represented 20% of the trials with a response rate of 4.4%. On the other hand, the trials that included at least one FDA-approved anticancer drug consisted of 46.3% of the trials and the response rate was 17.8%. The overall death due to toxicity was found to be 0.49%. The above study demonstrated the value and merits such as higher efficacy and safety due to a lower death rate if the investigational drug is combined with at least one FDA-approved anticancer drug. Some of the most recently phase 1/II completed studies (at the time of writing) are exemplified in Table  1 [ 15 ] and the drugs are potential experimental drug candidates.

Table 1

Example of anti-cancer drugs phase I/II completed studies

Integrative synergistic approaches

Some of the most emerging and promising tools being developed and increasingly being used in the health care-related sectors include data warehouse, that is a repository of historical data from data warehouses to data refineries for refining the crude data dubbed as the “oil of the digital era” into valuable data all the way from research to clinical use [ 16 , 17 ]. Because the data in the raw form is enormous, complex, lacks structure and standardization combined with interoperability issues, compliance issues and ethical challenges, the data refineries are envisioned to bridge the gap for refining and distilling the data on its journey from research to clinical utility for the benefits of the patients, including the stakeholders.

To navigate the costly and complex landscape of therapeutic drugs from basic research to clinical use hinges on integrating multi-disciplinary approaches. Because of different goals of the stakeholders, it has been historically challenging to strike a common chord that resonates across the whole ecosystem. Over the last few years, there has been a paradigm shift due to many factors such as the high cost of drug development, lengthy approval process, closer collaborations between academia and industries, integration of emerging technologies such as digital health, telehealth and wearables, gene editing, including big data, funding, education, and changes in government policies. The health benefits of panomics (genomics, proteomics, transcriptomics, metabolomics, epigenomics, ionomics and microbiomics) and the increasing use of panomics in personalizing medicine are emerging and promising in the treatment of diseases such as cancer, cardiovascular and gastrointestinal disorders [ 18 , 19 ]. The integral role of “gut” microbiome in health and in treating many diseases, including cancer is beginning to emerge as demonstrated by immune checkpoint inhibitor therapy [ 20 , 21 ]. While panomics addresses many of the precision medicine treatment benefits, it falls short in addressing issues such as the multi-morbidity, impact of the disease on the patients’ lives, their adaptability to the disease or other existing diseases, their family, their social life and their community life. Personomics is thus envisioned to bridge the gap between panomics and the patients’ personal or an individual’s circumstances [ 22 ]. This “echoes” with the words of Sir William Osler: “the good physician treats the disease; the great physician treats the patient who has the disease” [ 23 ].

The Precision Medicine Initiative (PMI) launched in 2015 [ 24 ] has been building to a “crescendo” and its impact on drug development, clinical trials and in personalizing the treatment for therapeutic efficacy, maximum safety, higher durable response, longevity and higher quality of life is emerging. Over the last few years, the FDA has emphasized the use of real-world data (RWD) and real-world evidence (RWE) to modernize clinical trials, an advancement made possible by the 21st Century Cures Act [ 25 , 26 ]. With real-world data and real-evidence, researchers will be able to go beyond the scope of traditional trials, transition to a “hybrid” trial that is dynamic, providing insights from information collected in clinical care. As an example, the FDA in April 2019 approved a supplemental New Drug Application based on data extracted from EHR and post-marketing reports of the real-world use of Pfizer’s drug, IBRANCE (Palbociclib) to expand the indication for in combination with Fulvestrant to include men with hormone receptor positive (HR+), human EGFR 2 negative (HER2−) advanced or metastatic breast cancer, for the treatment of breast cancer in men [ 27 , 28 ]. The former FDA Commissioner, Dr. Scott Gottlieb stated [ 29 ]: “the EHRs and other data sources, paired with advances in machine learning, will be crucial for architecting the next generation of successful clinical trials.

To address many of the challenges of implementing genomics medicine for routine use, the NIH funded IGNITE Network with the goals of integrating genomic data into EHR [ 30 ]. The IGNITE Network deploys plethoric “tools” for “Point-of-Care Decisions”, genetic markers for disease risk prediction including prevention, tools about family history data, pharmacogenomics data and refinement of disease diagnosis. Similarly, IBM Watson Health in collaboration with Brigham and Women Hospital and Vanderbilt University Medical Center has been pursuing the use of artificial intelligence for supporting precision medicine, to enhance patient safety, to nurture health equity, to expand and improve EHR usability [ 31 ]. Furthermore, the Watson Studio and Watson Knowledge Catalog has the data refinery tool for processing and transforming large amounts of raw data into valuable and clinical useful information for analytics. Several governments across the world, organizations, academia and institutes have created open access networks such as the Cancer Biomedical Informatics Grid (caBIG) and the Cancer Translational Research Informatics Grid (caTrip) for the caBIG project with a focus and a mission about driving translational research and improving the patient outcome by linking network of researchers, patients and physicians [ 32 ]. Similarly government and non-government sponsored programs have been established and they have been mushrooming globally such as the ICPerMed and the ECMC in the UK that support biotech and pharmaceutical companies to develop drugs in oncology through strategic partnerships [ 33 ]. Examples of programs in the USA include: the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH), the NCI-MATCH, a precision medicine cancer treatment clinical trial that is co-led by National Cancer Institute (NCI) and the ECOG-ACRIN Cancer Research Group. In the NCI-MATCH trial, patients received therapy based on the genetic changes found in their tumor as exemplified by the results from Arm H of the study demonstrated that treatment with a “cocktail” of dabrafenib and trametinib, designed to target cancers that have specific BRAF gene mutations, was effective in a trial of 35 patients having 17 distinct tumor types [ 34 ]. Most recently, the studies [ 35 ] published by the Pan-cancer Analysis of Whole Genome (PCAWG) consortium involving whole genome sequencing of 2658 cancer genomes demonstrated new information about cancer drivers from 38 tumor types and identified potentially new targets for precision medicine.

The exploitation of such tools for the “Right-to-Try” experimental drugs in treating life threatening diseases such as cancer will most likely favor the outcome and mitigate the negative outcomes associated with the clinical use of experimental drugs. The outcome using experimental drug has the potential to be more favorable if combined (“cock-tail”) with an FDA-approved drug. Some of the other approaches include implementation of programs and policies that incorporate the interests of patients such as education, understanding of risks, second opinion about the therapy, expectations and costs due to potential complications, education of physicians about precision medicine and emerging tools, dosing, the use of EHR, systematic reporting of results that may be important for public health and safety. The sponsor should provide transparency and immediate notifications to the physician including the FDA about safety issues during the drug development stage and any manufacturing or supply issues. Due to the complexity of the informed consent form and lack of oversight by the FDA, it is important that an independent or a neutral body such as an IRB or an ethics committee is engaged in reviewing the consent procedures. The positive outcome of the treatment results will thus be a potential boon to young biotech and pharmaceutical companies facing the “valley of death” syndrome, struggling to raise funding or looking for partnerships or trying to build trust and credibility. Furthermore, a positive outcome has the potential to spawn new ventures or opportunities such as veterinary oncology and “outpatient” clinics.

It is envisioned that the use of new tools encompassing electronic medical records, personalized medicine, data refineries, artificial intelligence and machine learning, further testing of drugs, including adjuvant therapies or “cocktail” of drugs will favor the outcome of experimental drugs and may pave the way for indication expansion as exemplified by IBRANCE. Furthermore, the use of such tools are expected to: (i) accelerate drug development time; (ii) reduce drug development cost; (iii) lower the cost of drugs; (iv) improve the durable response; (v) reduce adverse effects such as hepato-and cardio-toxicity; (vi) improve longevity and quality of life of the patient.

The progress made on several fronts in healthcare and the concerted efforts by the stakeholders, including the integral role of agencies such as World Health Organization (WHO) and Global Health Council (GHC) over the last few decades for the treatment of diseases, patient and public engagements, the role of healthcare practitioners, the role of education, data ownership, data sharing, transparency, privacy, ethics, standardization across the multi-industries, regulations, compliance, funding of programs, payment by medical insurance companies, including global policy development and implementation currently present limited opportunities and many challenges for the “Right-to-Try” experimental drugs for the treatment of life-threatening diseases. The “Right-to-Try” experimental drug is nevertheless a major “milestone” along the journey and its full impact on treating life-threatening diseases such as cancer and infectious diseases such as COVID-19 remain to be seen. One of the biggest impacts of emergency use of experimental drugs and compassionate drugs or “repurposing” of drugs is unfolding during the current coronavirus pandemic crisis.

Acknowledgements

The author of the article is acting individually and independently.

Abbreviations

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• Weill Cornell Medicine

Common Terms You Should Know When Enrolling in a Clinical Trial

Clinical trials, also known as clinical studies or clinical research, are studies that explore whether a medical strategy, treatment, or device is safe and effective for humans. When deciding whether to enroll in a clinical trial, you will likely encounter many terms related to clinical research and what the specific trial entails. Some terms are fairly standard across trials, regardless of the type of trial or what is being evaluated. When evaluating trial options, it’s important to understand what is involved with the clinical trial. This is also required before consenting to enroll on a trial (a term called “informed consent”). To help you navigate through the process, we’ve outlined common clinical trial terms that you should know. 

Adverse Event: Any undesirable experience associated with a drug or procedure, also sometimes described as a side effect or negative reaction. Adverse events can range from mild to severe. Serious adverse events are those that can cause temporary or permanent disability and may result in hospitalization or death.

Baseline Characteristics: Data collected at the beginning of a clinical study for all participants and for each arm or comparison group. These data include demographics, such as age, race, and gender, and any study-specific measures (e.g. systolic blood pressure, prior antidepressant treatment).

Blinding or Masking:  When those involved in the trial are not aware of the treatment assignments. There can be many different types of blinding. “Single Blind” means that the study participants do not know to which treatment group they have been assigned. “Double Blind” means that both the study participants and the investigators don’t know who has been assigned to each treatment group.

Compassionate Use: A method of providing experimental therapeutics prior to final regulatory agency (FDA) approval for use in humans. This procedure is used with very sick individuals who have no other treatment options available. Often, case-by-case approval must be obtained by the patient’s physician from the regulatory agency for “compassionate use” of an experimental drug or therapy. 

Confidentiality: This refers to the practice of maintaining private information related to clinical trial participants, including their personal identity and all personal medical information. Results from the study will usually be presented in terms of trends or overall findings and will not mention any participant names or reveal any identifying information without obtaining additional consent.

Control Group: The group of participants that receives standard of care treatment. The control group may also be comprised of healthy volunteers.

Eligibility Criteria: This refers to the factors or restrictions that determine who can participate in the clinical trial. This is different for every trial and can sometimes be referred to as the Inclusion Criteria and Exclusion Criteria.

Experimental Group: The group of participants in a study that receive the experimental treatment or study intervention.

First-In-Human Study: A clinical trial where a medical procedure or medicinal product that has been previously developed and assessed through laboratory model or animal testing is tested on human subjects for the first time.

Food and Drug Administration (FDA): An agency within the U.S. Department of Health and Human Services. The FDA is responsible for protecting the public health by making sure that human and veterinary drugs, vaccines and other biological products, medical devices, the Nation's food supply, cosmetics, dietary supplements, and products that give off radiation are safe and effective.

Informed Consent: When a participant provides informed consent, it means that he or she has learned the key facts about a research study, including the possible risks and benefits, and agrees to take part in it.

Intervention: The treatment, drug or procedure that is being studied in the clinical trial. This term is typically used when compared to a control or standard of care treatment arm. An “Interventional” trial is a term used to describe clinical trials studying a treatment, drug or procedure. This is different from an “Observational” study (see definition below).

Observational Study: In an observational study, investigators assess health outcomes in groups of participants according to a research plan or protocol. Participants may receive diagnostic or other types of interventions as part of their routine medical care, but the investigator does not assign participants to specific interventions or treatments.

Outcome Measure: A planned measurement described in the protocol that is used to determine the effect of interventions on participants in a clinical trial. For observational studies, a measurement or observation is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment.  

Phase: The categories that each clinical trial can fall into based on what properties of the treatment are being studied in the trial and how many participants are involved. There are typically four phases of a clinical trial. Phase I is the administration of a drug or device to a small group to identify possible side effects and determine proper dose. Phase II is done to gauge whether the treatment is effective while continuing to evaluate safety. Phase III compares a new drug or device against the current standard of care. Phase III trials have the potential to lead to Food and Drug Administration (FDA) approvals. Finally, phase IV trials are done after FDA approvals. Sometimes the FDA will require additional safety information to be collected after approval. Phase IV trials are often referred to as “post-market surveillance,” which look to identify problems that were not observed or recognized before approval.

Placebo: A substance that does not contain active ingredients and is made to be physically indistinguishable from the actual drug being studied.

Protocol: The written description of the clinical trial.

Principal Investigator (PI): A medical professional who leads the conduct of a clinical trial at a study site. This person is the lead researcher for the project. The phrase is also often used as a synonym for “head of the laboratory” or “research group leader.”

Sponsor: The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data. Often, the sponsor will also provide financial support for the trial.

Subject: Any participant in a study.

Treatment Arm: A group or subgroup of participants in a clinical trial. Each group receives a specific intervention, study drug dose, or sometimes no intervention, according to the study protocol.

Randomization: The process in which study participants are randomly assigned to different treatment groups. This is to ensure that everybody has an equal chance of being a part of each treatment or control group.

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Psychedelics Are Challenging the Scientific Gold Standard

How do you study mind-altering drugs when every clinical-trial participant knows they’re tripping?

Listen to this article

Produced by ElevenLabs and News Over Audio (NOA) using AI narration.

Tomorrow, a Food and Drug Administration advisory committee will meet to discuss whether the United States should approve its first psychedelic drug. The fate of the treatment—MDMA-assisted therapy for post-traumatic stress disorder—will turn on how the FDA interprets data from two clinical trials that, on their face, are promising. Long-suffering patients who took the drug while undergoing intensive talk therapy were about twice as likely to recover from PTSD as patients who got the placebo with therapy.

If the treatment is approved this summer, it could bring relief to some of the approximately 13 million Americans with PTSD. It could also serve as a model for other psychedelics to meet the FDA’s regulatory bar. But there’s a conundrum at the core of these two clinical trials, one that has plagued virtually all efforts to study psychedelics.

In clinical trials, participants (and the researchers studying them) generally aren’t supposed to know whether they’re getting the actual drug or a placebo, to avoid allowing people’s expectations about a treatment to shape their response to it. Blinding, as this practice is called, is a key component of a randomized controlled clinical trial, or RCT—medicine’s gold standard for demonstrating that a drug actually works. But virtually no one can take a psychedelic drug and not know it.

Some experts believe that unblinding threatens to undermine the entire field of psychedelic research because it means researchers can’t know whether the drugs’ early promise in clinical trials is real or a mirage, driven by the placebo effect and outsize expectations about the power of these drugs. But others argue that RCTs themselves are at fault. To them, psychedelics are exposing long-ignored cracks in our gold standard, especially for testing drugs that act on our minds.

Read: What it’s like to trip on the most potent magic mushroom

When randomized controlled trials are well designed, “there is no substitute,” Boris Heifets, a neuroscientist at Stanford University, told me. In an RCT, participants get randomly sorted into two groups, receiving either the treatment or a placebo. Scientists have prized such trials since the 1960s for their power to rule out all the nondrug reasons people who are given a new medication might get better. Chief among those reasons is the placebo effect, in which a patient’s belief in a treatment, rather than anything about the drug or procedure itself, leads to improvement. If trial participants come in with sky-high expectations (as experts suspect is the case in many psychedelics trials), knowing that they’ve received a drug could fuel positive responses, and learning they’ve been denied it could cause them to react negatively. “We’ve gotten a ton of things wrong by trusting unblinded results,” says David Rind, the chief medical officer of the Institute for Clinical and Economic Review, a nonprofit that evaluates new medical treatments.

For all of RCTs’ advantages, “I think it’s obvious that they’re not well suited for studying psychedelics,” Heifets said. In cancer-drug trials, participants won’t know the difference between a saline IV drip and medicine; to test new surgical procedures, control groups sometimes get cut into and sewed up without the actual treatment. But psychedelics like psilocybin or LSD launch people into hallucinatory states that bend space and time. MDMA, known to many as ecstasy, is less extreme, but still sparks expansive feelings of love and empathy. “Participants will know within half an hour whether they’ve been assigned to the experimental or placebo condition,” Michiel van Elk, a cognitive psychologist at Leiden University, told me. In the MDMA clinical trials, run by the pharmaceutical company Lykos Therapeutics, nearly all participants correctly guessed which group they were in.

Many scientists want to get around this problem by designing better blinds. Some labs have tried to keep patients in the dark by administering drugs under anesthesia or using mind-altering pills like methamphetamines as a placebo. Others are trying to engineer new psychedelics that skip the trip entirely . But to other scientists, clever attempts to stuff psychedelics into the RCT framework ignore the possibility that psychedelics’ benefits aren’t reducible to the biochemical action of the drug itself. Since the 1960s, psychedelic researchers have known that the beliefs and expectations a person brings to a trip can influence whether it’s healing or nightmarish. (That’s why most psychedelic-therapy protocols include several psychotherapy sessions before, during, and after treatment.) By striving to cleave the drug’s effects from the context in which it’s given—to a patient by a therapist, both of whom are hoping for healing—blinded studies may fail to capture the full picture.

Read: Psychedelics open your brain. You might not like what falls in.

From this perspective, high proportions of unblinding in positive psychedelic trials don’t necessarily mean that the results are invalid. “It’s how people engage with those effects and their therapist that’s contributing to the improvement,” Eduardo Schenberg, a neuroscientist at Instituto Phaneros, a nonprofit psychedelic-research center in Brazil, told me. Recent research backs this up. One small study found that among chronic PTSD patients who got MDMA-assisted therapy, the strength of the bond between therapist and patient—something the drug helps forge with its empathy-inducing effects— predicted treatment success . Given the importance of context, even the most perfectly designed RCTs may fail to capture how helpful these drugs are outside trials, Schenberg said.

Such failure, if it exists, might extend beyond psychedelics to several kinds of psychoactive drugs. For instance, a 2022 analysis found that many antidepressant trials fail to effectively blind participants, in part because of side effects. “We know that 80 percent of the treatment response from antidepressants can be attributed to the placebo response,” Amelia Scott, a clinical psychologist at Macquarie University who co-wrote that study, told me. Yet in practice, antidepressants are effective for many people, suggesting that RCTs aren’t quite capturing what these drugs can offer—and that limiting ourselves to treatments that can be perfectly blinded could mean ignoring helpful mental-health interventions. “We shouldn’t be afraid to question the gold standard,” Schenberg told me. “For different kinds of diseases and treatments, we may need slightly different standards.”

RCTs likely won’t lose their perch as the gold standard anytime soon, for evaluating psychedelics or anything else. But they could be supplemented with other kinds of studies that would broaden our understanding of how psychedelics work, Matt Butler, a neuroscientist at King’s College London, told me. Scientists are already trying open-label trials, where participants know which treatment they’re getting, and measuring expectations along with treatment effects. Descriptive studies, which track how treatments are working in actual clinics, could provide a richer picture of what therapeutic contexts work best. “These levels of evidence aren’t as good as RCTs,” Butler said, but they could help deepen our understanding of when therapies that don’t conform to RCTs could be most helpful.

Read: What if psychedelics’ hallucinations are just a side effect?

None of this is to say that Lykos’s flawed RCT data will be enough to convince the FDA’s advisers that Americans with PTSD should be offered MDMA. Several groups, including the American Psychiatric Association, have expressed concern about the trials ahead of the advisory meeting. In addition to the unblinding issue, claims that therapists encouraged participants to report favorable results and hide adverse events prompted the Institute for Clinical and Economic Review to release a report casting doubt on the studies. Lykos CEO Amy Emerson pushed back in a statement, saying, “We stand by the quality and integrity of our research and development program.” Still, some researchers remain worried. “If this sets a precedent that these trials are acceptable data, what does that mean for the future?” Suresh Muthukumaraswamy, a neuropharmacologist at the University of Auckland, told me.

The recent past suggests that blinding may not be a deal-breaker for the FDA. In 2019, the agency approved Spravato esketamine nasal spray —a version of ketamine—for the treatment of depression despite concerns about unblinding in the drug’s clinical trials. And the FDA worked with Lykos to design the MDMA-therapy trials after designating it a breakthrough treatment in 2017. In an email, an FDA spokesperson told me that blinded RCTs provide the most rigorous level of evidence, but “unblinded studies can still be considered adequate and well-controlled as long as there is a valid comparison with a control.” In such cases, the spokesperson said, regulators can take into account things like the size of the treatment effect in deciding whether the treatment performed significantly better than the placebo.

Read: Placebo effect of the heart

Even if the FDA is on board, rolling out psychedelic therapies before scientists fully understand the interplay among expectation, therapy, and drugs could mean missing an opportunity to force companies to provide data that would meaningfully advance the study of these drugs, Muthukumaraswamy said. It also risks undermining these treatments in the long run. If sky-high expectations are ultimately fueling the positive results we see now, the FDA could end up approving a treatment that becomes less effective as its novelty wears off. That’s especially true if we’re missing key components of what makes these treatments work, or what puts people at risk for bad experiences. To better answer those questions—for psychedelics and other psychoactive drugs—we may need studies that go beyond the gold standard.

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• Published: 26 May 2020

When research goes wrong: the importance of clinical trials methodology

• Eleanor J. Molloy 1 , 2 , 3 , 4 , 5 &
• Cynthia F. Bearer   ORCID: orcid.org/0000-0003-4809-2250 6 , 7  

Pediatric Research volume  88 ,  pages 518–519 ( 2020 ) Cite this article

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New clinical trials methodology

Clinical trials methodology is constantly being developed and refined. Consensus statements from the CONSORT (CONsolidated Standards Of Reporting Trials) guidelines on clinical trial reporting and the registering of study protocols online (e.g., clinical trials.gov) has become a standard practice. This transparency and ethical reviews of clinical trial protocols should protect participants in these trials but needs constant revision and refinement. Therefore, careful adherence is needed to evolving clinical research methodology as exemplified in the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) network. EQUATOR is an international initiative that aims to improve the value and reliability of health research literature by promoting accurate and transparent reporting ( https://www.equator-network.org/ ). It provides links to the reporting guidelines for the main study types, for example, CONSORT (for randomized controlled trials; https://www.equator-network.org/reporting-guidelines/consort/ ) and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses; https://www.equator-network.org/reporting-guidelines/prisma/ ). These reporting guidelines are also highlighted in the instructions for authors of Pediatric Research because they are vital for future research synthesis.

In this issue of Pediatric Research , the importance of clearly defining control participants in studies to allow accurate comparisons is highlighted. Zaslawski et al. 1 in this issue of the journal also highlight the need for rigorous reporting of controls. They demonstrate the utility of the existing reporting tool (TIDieR; Template for Intervention Description and Replication), which they had modified. This tool includes 12 items: name that describes the arm, procedures, references for justification, materials, specific training provided, a description of who provided the intervention, locations of the intervention, route of delivery, number of delivered interventions, and description of personalization or modification if any occurred. This use of this modified TIDieR tool aims to improve the reproducibility and implementation of clinical trials in children.

In addition, the development of the SPIRIT (Standard Protocol Items for RandomIzed Trials) ( https://www.spirit-statement.org/about-spirit/ ) guidelines is to help improve the completeness and quality of trial protocols. The evidence-based SPIRIT recommendations were developed using systematic, transparent methodology and broad consultation with 115 experts representing diverse stakeholders involved in the design, funding, conduct, review, and publication of trial protocols. These recommendations have recently been expanded to include children as the SPIRIT-C guidelines. The evidence synthesis has been completed, the Delphi survey and international consensus have been finished, and the checklists have been finalized for SPIRIT-C 2 ( https://lab.research.sickkids.ca/enrich/research-projects/spirit-c/ ). This information will improve standardization of the way clinical trials in children are conducted using SPIRIT-C and aims to improve the impact and benefit of clinical research for children. 2

Why is this so important: lessons from the past

As an example of what can happen if correct methodology is not used is the continued perception that vaccines, specifically the measles, mumps, and rubella (MMR), causes autism. The proposed mechanism was that intestinal inflammation occurred following the vaccine which allowed intestinal peptides to enter the blood stream and impair brain development. The original observation, published in The Lancet , 3 reported on 8 children who developed autism within a month of vaccination. This study was critically flawed by the methodology used: there was no control arm (children vaccinated who did not develop autism), and the intestinal symptoms occurred after the symptoms of autism, not before ( https://www.chop.edu/centers-programs/vaccine-education-center/vaccines-and-other-conditions/vaccines-autism ).

In a second publication attempting to link autism with the measles virus, the authors studied 91 patients with autism and found 75 of them had measles virus fusion and hemagglutinin genes in their intestinal tissue by reverse transcription–polymerase chain reaction (RT-PCR) and Nucleocapsid gene by RT in situ PCR, which the authors interpreted as suggesting an association between the presence of measles virus and autism. 4 This study too had critical flaws in methodology. Measles vaccine virus is live and attenuated. It is plausible that, following the MMR, a child may have this measles form in intestinal tissue. The control arm for this study, children without autism, was not matched to the children with autism in terms of immunization status (did or did not get the vaccine) and the length of time between being vaccinated and having intestinal samples taken. Therefore, the specificity of this finding for autism was not shown. The authors also failed to distinguish between natural measles virus and the attenuated form used in vaccines, so the conclusion that the virus in the intestinal tissue came from the vaccine is unsupported. The RT-PCR method to detect virus is very sensitive and would be expected to produce false positives, but how this was avoided in the study was not described. And no mention is made if the person doing the assays was blinded ( https://www.chop.edu/centers-programs/vaccine-education-center/vaccines-and-other-conditions/vaccines-autism ). Thus we have two studies failing to meet methodologic standards that have perpetuated the lay public’s fear of vaccines, to the detriment of children.

Future directions

Should all medical students learn about these studies to ensure these mistakes are never repeated? This example makes us look at our research practice, which continues to change and may be judged negatively in the future using a different lens. In this study, inadequate study design to include appropriate controls has led to long held public beliefs. The loss of trust in medical research communities as a result of this study may have negatively affected vulnerable populations as they may not receive vaccinations. 5

As pediatricians and child health researchers, we represent some of the most vulnerable and socioeconomically deprived members of society who, in addition, have no vote, a fact that adds additional responsibility to us to develop the highest standards of collaborative research. 6 These tools are vital to protect families and researchers as they strive together to improve health outcomes.

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Acknowledgements

This study was supported by the National Children’s Research Centre, Crumlin, Dublin, Ireland and Health Research Board Ireland (to E.J.M.) and NIH/NICHD P01HD085928 (to C.F.B.).

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Molloy, E.J., Bearer, C.F. When research goes wrong: the importance of clinical trials methodology. Pediatr Res 88 , 518–519 (2020). https://doi.org/10.1038/s41390-020-0984-5

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Double blind's pollyanna mcintosh on claustrophobic thriller & the walking dead's future.

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Every Movie Coming To Theaters In February 2024

Lenore zann breaks down rogue's emotional journey in x-men '97 & hints at season 2 storylines, winter spring summer or fall director tiffany paulsen on jenna ortega’s first romance.

• Double Blind is a thrilling single-location film with a diverse cast and a tight script about an experimental drug trial gone wrong.
• Pollyanna McIntosh was intrigued by the movie's single-location storytelling and the compassionate nature of her character, Dr. Burke.
• McIntosh is also excited about her Walking Dead return in The Ones Who Live , and is hopeful for a future beyond the upcoming spinoff.

Pollyanna McIntosh returns to the world of single-location storytelling with Double Blind . The thriller revolves around a group of young adults who sign up for a drug experiment revolving around a new pharmaceutical keeping people awake, though it devolves into madness as the group learns of the dark truth behind the drug.

The Queen's Gambit alum Millie Brady leads the ensemble Double Blind cast alongside McIntosh, Diarmuid Noyes, Akshay Kumar, Brenock O'Connor, Abby Fitz, Shonagh Mare, and Frank Blake. Taking a similarly claustrophobic and paranoid approach to that of the cult classic Cube and McIntosh's own prior movie Exam , Ian Hunt-Duffy's project is a fast-paced and terrifying affair.

February 2024 will see the release of an action movie starring Henry Cavill, a Marvel movie from Sony's universe, the story of Bob Marley, and more.

In anticipation of the movie's release, Screen Rant interviewed star Pollyanna McIntosh to discuss Double Blind , her love of single-location stories, how the production design lent to the overall atmosphere of the movie, her Walking Dead future and upcoming return to the director's chair.

Pollyanna McIntosh Talks Double Blind, The Walking Dead & More

Screen Rant: I gotta say, Double Blind is awesome, I was just blown away. I didn't know what to expect. What about it really sparked your initial interest to want to be a part of it?

Pollyanna McIntosh: I thought it was such a tight script, I'm really glad you enjoyed it. It's really fun for me to be doing this press stuff, because I'm finally speaking to other people who've seen the film, so I'm being super geeky with everyone like, "What did you think? Who's your favorite?" [Chuckles] It was a really tight script, and for a single location piece, I just thought there was so much going on to keep the audience interested. The characters were all specific, and different from each other. A truly diverse group of characters, I felt. I love the underdog element to it, I love the kind of Carpenter-esque ask, f--k the system. And I thought that Dr. Burke was a really fun character. So, I then kind of looked at Ian Hunt-Duffy's work before to see his other shorts and whatnot, and spoke to a friend of mine who had done a film with him. It all just came back really positive, so I was like, "Yeah, let's do it."

I love that, and I love that you mentioned Carpenter, because that was one of the feelings I had. It was him, and it was Cube .

Pollyanna McIntosh: I did another single location movie years ago, a British indie that was nominated for a BAFTA called Exam. It's a really interesting film, it's actually one of Gemma Chan's first movies, which is kind of interesting in itself. But it's Colin Salmon, as well, and it's all about an exam for a job interview in which there is only one question to answer, and if you screw up, you get thrown out of the exam, and it's kind of that people turning on each other stuff. But, often, people compared it to Cube, so you might be one for Exam, as well.

It's been on my watch list for a while, I actually forgot Gemma Chan was in it, so I'm going to have to look into that! So, you talked about the single location. How much did you feel that helped with the atmosphere of you getting into that character and being in that tense environment?

Pollyanna McIntosh: Well, I was very lucky in that, I didn't have to go through what the wonderful cast playing subjects have to go through with this awful kind of, "if you sleep you die." First of all, what a great hook, I should have mentioned that, the script is superb in that regard, as well. So, I didn't have to sort of suffer the way an actress suffers when they're probably going into that headspace. It was a very communal vibe on the film set, so we had our lunch in that building, we had makeup done in that building, we had the production office in there. And, there was a door — don't tell anyone, but it's not real — there was a door, and we could go outside and enjoy the sun, but I think when you're in the role, when you're playing her, and we were running down those corridors, literally to save our own lives [chuckles], it really helps to have those endless white corridors and that endless single stripe. It felt very wonderfully claustrophobic in that way.

It feels more claustrophobic and hypnotic, in a way.

Pollyanna McIntosh: Yeah, I think the way it's handled — I mean, the whole crew, from the writer to the director of the production designer, and cinematographer, and then, of course, everything else combined, as well. But the way in which that set is handled, and the way in which the dreamscape elements come in, I just think it's masterful. And then, of course, Die Haxen's music adds to that extraordinary sense of calamity and internment.

The music reminded me a lot of The Shining in that haunting sort of ambient noise, I loved it. I love Dr. Burke, in that for a lot of people who know your work of recent, they're used to Jadis on The Walking Dead and her villainous kind of streak. But with Dr. Burke, it feels so different from the typical sci-fi genre doctor, where they're straight evil, she feels compassionate. What was it like trying to find that thread for her in comparison to some of your prior works?

Pollyanna McIntosh: Yeah, I think I approach every character in a similar way as in —I don't want to go on about actor-ly stuff because I think it's either a bit wanky for people who don't do it, and I think sometimes it takes away the magic of the experience when you're watching stuff. But with her, I'll say this, when you're playing a kind of "bad guy", you obviously don't want to be judgmental of your character, and you want to live through their experience of things. Sometimes, when those "bad guys" know that they're doing something awful, it's a really hard thing to carry around. With Dr. Burke, she feels things, and you can hopefully see that, and she has concerns, but she's got such an armory around her that I think has served her in coming up the ranks as a woman, as in the position she's gotten to. It's not the kind of person I want to be. [Chuckles] But that sort of protective field that she has about what she's doing, and how complicit she is, at least allowed me as an actor to not judge her, and be able to escape her when I needed to.

Did you and the director talk at all about what her backstory might have actually been, given how sort of ambiguous it kind of leaves everything?

Pollyanna McIntosh: You know, that's a really good question. We didn't, and generally speaking, I would be going there with the director, and with the writer, hopefully. But it felt really clear to me. I think this script is just really well-written, and it felt really clear to me what my role was. We had a little bit of rehearsal, which was really nice, because that's not so common anymore, and that was fun, because you get to see how the director plays, as well, you know, and he's quite specific about what he wanted. But we still played around with stuff, like I was maybe going to do Dr. Burke with a Scottish accent, for instance, because she's Burke. Burke, I think, is an Irish name, but when I think of Burke, I think of Burke & Hare, which is all set in Scotland, and I am Scottish, so why not? But we ended up with this sort of, as I call it, my headmistress voice, you know? More English than anything. [Chuckles]

It fits the mystery nature of her, so it worked!

Pollyanna McIntosh: Yeah, I didn't want to mustache twirl too much. Hopefully it turned out well.

So, actually, speaking of the headmistress nature of her, I really liked her look, it's a very striking appearance, whether it's the hair, the way she presents herself. How did you go about working with the Wardrobe and the Makeup and everything to really hone in on that look?

Pollyanna McIntosh: Our Wardrobe Designer was so great. I really enjoyed our fittings, because she had her down, man, she had it down, and there was varying degrees of that sort of slightly wipeable fabrics, to sort of clean the dirt off yourself, get the blood off yourself, go home to your nice life. I love that she wasn't stylish, she wasn't fabulous in any way, she wasn't, again, that sort of mustache-twirling villain — we need to come up with a term for women that isn't mustache twirling, not that we don't occasionally have a bit of a 'tache, but that sort of Evil Queen thing. She wasn't sexy in any way, so yeah, it was really down to the wardrobe designer, she was fantastic, and her team were lovely as well. And the shoes, I mean, the shoes are like my absolute bugbear of those kinds of shoes, so it worked really, really well. And hair and makeup were amazing. I actually used Roisin Condon from makeup on a short film I made recent in the year called Quicksand, an Irish film that I just directed and played a role in, and she's fantastic. And then Madonna Bambino — isn't that the best name in the world — Madonna Bambino is our head of the Makeup Department, and you can see how adept she is with blood and gore, and that's a real pleasure to work with as well. So yeah, they were very collaborative, but it really was down to them. All of her look, it just happened that everybody doing their job on this was doing it very, very well.

Well, that's what you love about an indie production is just everybody comes in wanting to make the best thing possible. So, when did you get to see the final product for this movie?

Pollyanna McIntosh: Oh, that's a good question, because I was sneaky. I had some ADR to do, so I had some additional dialogue recording to do on it, and I said, "I'd really like to see the film to make sure that when I'm doing the ADR, I know the whole vibe of it, so that I can make sure it all works really well." And someone — I don't remember who — was like, "I'm not supposed to send this to you," and they did. So, I got to see it quite early on before all the special effects were finished on it, so that wonderful scene where Millie Brady's character is flying up into the air — and that's not a spoiler, and it's not sci-fi, but it's part of the dreamscape of the film — I got to see some of that before the ropes had been taken out. It was such a delight to see Millie do that movement, I thought she was absolutely fantastic. So, yeah, it was around ADR time when they were almost finished with it, and I was thrilled to see it. I knew watching the monitor, during the making of that, they were making something really special, and I was not disappointed when I watched it. And then seeing it in the cinema in Galway at the Galway Film Fleadh, which is a big Irish Film Festival, it was really cool to see it with an audience, because then you felt that it wasn't just me. It's hard to be objective when you've been in something, of course, entirely objective, so it was great watching you have an audience because they were just like, "Oh. Whoa! Ah!" [Laughs]

It's a pretty visceral movie, when the first character dies, even I was like, "Whoa, that's a lot." It establishes the stakes for the rest of the movie.

Pollyanna McIntosh: Yeah, and you really care about her. I think she's probably the most lovable character in the whole thing, she played it so well. Abby, I'd seen her in The Cellar, I'd actually been at The Cellar premiere — it's worth a watch — it's a horror, and Abby played an American young woman in it, and she was brilliant. So, when I saw that she was attached, I was really thrilled, and then when I got to meet her, at first, I was like, "You were so brilliant in The Cellar!" She's like, "What?!" I'm like, "You're Irish? This is crazy!" So, yeah, I thought she did a wonderful job of making us fall in love with her and then, 'way you go.

She played it so well. What was one of the big scenes that really surprised you how well it played on the big screen when you saw it in theaters?

Pollyanna McIntosh: I think it was — oh, yeah, I can feel it now, I think it was Millie's character in the dark, and her starting to hear her mother's voice. It felt really disorienting, and really scary, and I think we've all experienced that. No matter great or big we are, we've been in a very, very dark room, we don't know which way is up, and it's just a wee bit scary, and I thought that did that so well. But you have, of course, the added high stakes of what else is going on. I love that arc with her and her feelings about her mom. But yeah, that scene, it's just the use of light and music and sound and great acting, great everything, but it's kind of really simple and really effective. I didn't think that piece of it was going to be as exciting to watch as it was.

If you like that piece, I recommend two movies called Last Shift and Malum , which was a remake of Last Shift by the same director, and there's a scene very much like that where it's all dark and music and noise, and it's haunting! So, we've talked about Double Blind a bit, I did want to ask you a little bit about Walking Dead , because I have loved Jadis' arc throughout this whole show. I'm excited that you're coming back for The Ones Who Live . What can you tell me about how much she's transformed since the last time we saw her on the mainline show and her story coming up in the new one?

Pollyanna McIntosh: Well, there's very little I can tell you, because The Walking Dead is such a wonderful show to watch, because everyone has different opinions of what's going to happen. Even when it happens, there's different interpretations. I think that's one of the pleasures for the fans, so we like to keep as many secrets as possible. But, if you haven't seen me Jadis in The World Beyond, you might not know where she's going in this, and I can certainly say that from The World Beyond, you see that she's quite high up in the Civic Republic Military, she's very committed to the cause of the CR and the CRM, and she truly believes that they are the last light of the world, and the work they're doing is going to save humanity. Which is why I suggested that ridiculous Joan of Arc haircut for The World Beyond, but I didn't really think about the fact that, a year or so later, I'd have to probably get it again for this, so I haven't been able to grow my hair for like three years or something at this point. [Laughs] So yeah, Jadis has always been a bit of a chameleon, and an ever-evolving creature, like I hope we all are, and she has found her place in this other realm, and she feels very strongly about a commitment to it. I'll say that.

I love that. I really can't wait to see what comes with that then.

Pollyanna McIntosh: I can't wait to see it too, and I'm so excited. I was supposed to be at the premiere next week, but I have to be away on another show, so I'm feeling a little bit sad that I'm not gonna get to see my peeps, if I'm honest, my wee Walking Dead family, you know? I shouldn't say that on an interview, because there's always a hope and a chance that it could still happen. But it doesn't look likely at the moment with the schedule we've got on what I'm working on, so yeah. I got a beautiful message from Andy the other day saying lovely things, so that was very nice to hear from him, and we'll see each other again. I just want to be there to celebrate, this show has been a long time coming. Four-and-a-half years, we've been waiting for people to see this thing since Jadis and Rick went off in the helicopter, and I'm so excited to see Michonne on the screen, and kicking a--, because she does it better than anyone.

She really does. Every time I watched the show, I would go, "She could just take out the apocalypse herself."

Pollyanna McIntosh: [Laughs] Yeah, no pressure, Michonne, no pressure.

So, we have you coming back in The Ones Who Live . I obviously don't know what happens in that show, but do you think there is a future for Jadis beyond that show, whether it be another season of The World Beyond or her own story?

Pollyanna McIntosh: I'm told very much that The World Beyond is done and completed. But with The Walking Dead universe, you never know, because I think Scott's been really inventive in the creations that have come since their flagship ended. You just never know, we could have all sorts of fun. I could make myself a Zimmer frame from the older bits of the junkyard, and just keep going.

That would be fun to see! Before I let you go, you mentioned that you just got to direct a short film, and I've been a big fan of your work behind the camera on The Woman trilogy. How is it looking for you possibly stepping back into the director's chair on a full feature?

Pollyanna McIntosh: Thank you. Yeah, I actually have a feature coming out shooting in Ireland called BrideSsquad. It's a big departure from Darlin', my first feature, but it's very much where I'm at home, as well. It's a comedy, and it's three women on a road trip, one of whom has been left at the altar by her fellow, and they're on a mission. It's really fun, and it's all to be shot around Ireland and in Galway, and it's just going to be beautiful. We're casting at the moment, actually, but we've already got Mary Elizabeth Ellis attached, and she's wonderful. I adore her as a person. We did Lodge 49 together, and I've always admired her talent. I was totally nerding out on her when I saw that we got to work together on Lodge 49. So yeah, it's gonna be a comedy, and it's going to be a lot of fun. And then Quicksand, the one that I made here last year, that's doing the festival circuit at the moment, it's a 22-minute short right now. It's done quite a few festivals, won the best cinematography at Louth here, we opened at Galway, which is great, it's had a great response. But I'm thinking I might cut it into a feature, I think there's something there that I might mess with it while I'm away working on this job, and cut it into a feature. So that's my plan, so that more people can see it. That'd be exciting. It's about a woman who is in love wanting a family, but is also a sex addict, and it's quite dark. I didn't write this one, it was Siobhán Callahan, who also plays the lead, and she is an actor that was on Vikings: Valhalla with me. She's so talented, and she showed me the script she'd written, and I was like, "This should be made." So, we made it.

I feel like so many actors see so many scripts that they start to pick up ways to tell their stories themselves. I'm going to keep my eyes out for more updates on Quicksand , as well as... You said Bride Smash ?

Pollyanna McIntosh: Bride Squad, but I like Bride Smash! [Laughs] Bride Squad, yeah, it's based on an Irish book by Lisa Carey and Caroline Grace-Cassidy. It was a really successful book, they wrote the script, and I've had a wee pass on it. That's fun as well, that collaboration piece, but it's their story, and I'll be directing, and we'll have a lot of fun.

About Double Blind

Filmed completely on location in Limerick, Ireland, Double Blind begins as an experimental drug trial goes horribly wrong, and seven young test subjects must face the terrifying side effect of the drug –if you fall asleep you die. Trapped in an isolated medical facility, they must find a way to escape, and somehow manage to stay awake.

Double Blind hits select theaters on February 9, followed by digital platforms on February 13 and Blu-ray on March 26.

Source: Screen Rant Plus

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What the data says about gun deaths in the U.S.

More Americans died of gun-related injuries in 2021 than in any other year on record, according to the latest available statistics from the Centers for Disease Control and Prevention (CDC). That included record numbers of both gun murders and gun suicides. Despite the increase in such fatalities, the rate of gun deaths – a statistic that accounts for the nation’s growing population – remained below the levels of earlier decades.

Here’s a closer look at gun deaths in the United States, based on a Pew Research Center analysis of data from the CDC, the FBI and other sources. You can also read key public opinion findings about U.S. gun violence and gun policy .

This Pew Research Center analysis examines the changing number and rate of gun deaths in the United States. It is based primarily on data from the Centers for Disease Control and Prevention (CDC) and the Federal Bureau of Investigation (FBI). The CDC’s statistics are based on information contained in official death certificates, while the FBI’s figures are based on information voluntarily submitted by thousands of police departments around the country.

For the number and rate of gun deaths over time, we relied on mortality statistics in the CDC’s WONDER database covering four distinct time periods:  1968 to 1978 ,  1979 to 1998 ,  1999 to 2020 , and 2021 . While these statistics are mostly comparable for the full 1968-2021 period, gun murders and suicides between 1968 and 1978 are classified by the CDC as involving firearms  and  explosives; those between 1979 and 2021 are classified as involving firearms only. Similarly, gun deaths involving law enforcement between 1968 and 1978 exclude those caused by “operations of war”; those between 1979 and 2021 include that category, which refers to gun deaths among military personnel or civilians  due to war or civil insurrection in the U.S . All CDC gun death estimates in this analysis are adjusted to account for age differences over time and across states.

The FBI’s statistics about the types of firearms used in gun murders in 2020 come from the bureau’s  Crime Data Explorer website . Specifically, they are drawn from the expanded homicide tables of the agency’s  2020 Crime in the United States report . The FBI’s statistics include murders and non-negligent manslaughters involving firearms.

How many people die from gun-related injuries in the U.S. each year?

In 2021, the most recent year for which complete data is available, 48,830 people died from gun-related injuries in the U.S., according to the CDC. That figure includes gun murders and gun suicides, along with three less common types of gun-related deaths tracked by the CDC: those that were accidental, those that involved law enforcement and those whose circumstances could not be determined. The total excludes deaths in which gunshot injuries played a contributing, but not principal, role. (CDC fatality statistics are based on information contained in official death certificates, which identify a single cause of death.)

What share of U.S. gun deaths are murders and what share are suicides?

Though they tend to get less public attention than gun-related murders, suicides have long accounted for the majority of U.S. gun deaths . In 2021, 54% of all gun-related deaths in the U.S. were suicides (26,328), while 43% were murders (20,958), according to the CDC. The remaining gun deaths that year were accidental (549), involved law enforcement (537) or had undetermined circumstances (458).

What share of all murders and suicides in the U.S. involve a gun?

About eight-in-ten U.S. murders in 2021 – 20,958 out of 26,031, or 81% – involved a firearm. That marked the highest percentage since at least 1968, the earliest year for which the CDC has online records. More than half of all suicides in 2021 – 26,328 out of 48,183, or 55% – also involved a gun, the highest percentage since 2001.

How has the number of U.S. gun deaths changed over time?

The record 48,830 total gun deaths in 2021 reflect a 23% increase since 2019, before the onset of the coronavirus pandemic .

Gun murders, in particular, have climbed sharply during the pandemic, increasing 45% between 2019 and 2021, while the number of gun suicides rose 10% during that span.

The overall increase in U.S. gun deaths since the beginning of the pandemic includes an especially stark rise in such fatalities among children and teens under the age of 18. Gun deaths among children and teens rose 50% in just two years , from 1,732 in 2019 to 2,590 in 2021.

How has the rate of U.S. gun deaths changed over time?

While 2021 saw the highest total number of gun deaths in the U.S., this statistic does not take into account the nation’s growing population. On a per capita basis, there were 14.6 gun deaths per 100,000 people in 2021 – the highest rate since the early 1990s, but still well below the peak of 16.3 gun deaths per 100,000 people in 1974.

The gun murder rate in the U.S. remains below its peak level despite rising sharply during the pandemic. There were 6.7 gun murders per 100,000 people in 2021, below the 7.2 recorded in 1974.

The gun suicide rate, on the other hand, is now on par with its historical peak. There were 7.5 gun suicides per 100,000 people in 2021, statistically similar to the 7.7 measured in 1977. (One caveat when considering the 1970s figures: In the CDC’s database, gun murders and gun suicides between 1968 and 1978 are classified as those caused by firearms and explosives. In subsequent years, they are classified as deaths involving firearms only.)

Which states have the highest and lowest gun death rates in the U.S.?

The rate of gun fatalities varies widely from state to state. In 2021, the states with the highest total rates of gun-related deaths – counting murders, suicides and all other categories tracked by the CDC – included Mississippi (33.9 per 100,000 people), Louisiana (29.1), New Mexico (27.8), Alabama (26.4) and Wyoming (26.1). The states with the lowest total rates included Massachusetts (3.4), Hawaii (4.8), New Jersey (5.2), New York (5.4) and Rhode Island (5.6).

The results are somewhat different when looking at gun murder and gun suicide rates separately. The places with the highest gun murder rates in 2021 included the District of Columbia (22.3 per 100,000 people), Mississippi (21.2), Louisiana (18.4), Alabama (13.9) and New Mexico (11.7). Those with the lowest gun murder rates included Massachusetts (1.5), Idaho (1.5), Hawaii (1.6), Utah (2.1) and Iowa (2.2). Rate estimates are not available for Maine, New Hampshire, Vermont or Wyoming.

The states with the highest gun suicide rates in 2021 included Wyoming (22.8 per 100,000 people), Montana (21.1), Alaska (19.9), New Mexico (13.9) and Oklahoma (13.7). The states with the lowest gun suicide rates were Massachusetts (1.7), New Jersey (1.9), New York (2.0), Hawaii (2.8) and Connecticut (2.9). Rate estimates are not available for the District of Columbia.

How does the gun death rate in the U.S. compare with other countries?

The gun death rate in the U.S. is much higher than in most other nations, particularly developed nations. But it is still far below the rates in several Latin American countries, according to a 2018 study of 195 countries and territories by researchers at the Institute for Health Metrics and Evaluation at the University of Washington.

The U.S. gun death rate was 10.6 per 100,000 people in 2016, the most recent year in the study, which used a somewhat different methodology from the CDC. That was far higher than in countries such as Canada (2.1 per 100,000) and Australia (1.0), as well as European nations such as France (2.7), Germany (0.9) and Spain (0.6). But the rate in the U.S. was much lower than in El Salvador (39.2 per 100,000 people), Venezuela (38.7), Guatemala (32.3), Colombia (25.9) and Honduras (22.5), the study found. Overall, the U.S. ranked 20th in its gun fatality rate that year .

How many people are killed in mass shootings in the U.S. every year?

This is a difficult question to answer because there is no single, agreed-upon definition of the term “mass shooting.” Definitions can vary depending on factors including the number of victims and the circumstances of the shooting.

The FBI collects data on “active shooter incidents,” which it defines as “one or more individuals actively engaged in killing or attempting to kill people in a populated area.” Using the FBI’s definition, 103 people – excluding the shooters – died in such incidents in 2021 .

The Gun Violence Archive, an online database of gun violence incidents in the U.S., defines mass shootings as incidents in which four or more people are shot, even if no one was killed (again excluding the shooters). Using this definition, 706 people died in these incidents in 2021 .

Regardless of the definition being used, fatalities in mass shooting incidents in the U.S. account for a small fraction of all gun murders that occur nationwide each year.

How has the number of mass shootings in the U.S. changed over time?

The same definitional issue that makes it challenging to calculate mass shooting fatalities comes into play when trying to determine the frequency of U.S. mass shootings over time. The unpredictability of these incidents also complicates matters: As Rand Corp. noted in a research brief , “Chance variability in the annual number of mass shooting incidents makes it challenging to discern a clear trend, and trend estimates will be sensitive to outliers and to the time frame chosen for analysis.”

The FBI found an increase in active shooter incidents between 2000 and 2021. There were three such incidents in 2000. By 2021, that figure had increased to 61.

Which types of firearms are most commonly used in gun murders in the U.S.?

In 2020, the most recent year for which the FBI has published data, handguns were involved in 59% of the 13,620 U.S. gun murders and non-negligent manslaughters for which data is available. Rifles – the category that includes guns sometimes referred to as “assault weapons” – were involved in 3% of firearm murders. Shotguns were involved in 1%. The remainder of gun homicides and non-negligent manslaughters (36%) involved other kinds of firearms or those classified as “type not stated.”

It’s important to note that the FBI’s statistics do not capture the details on all gun murders in the U.S. each year. The FBI’s data is based on information voluntarily submitted by police departments around the country, and not all agencies participate or provide complete information each year.

Note: This is an update of a post originally published on Aug. 16, 2019.

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John Gramlich is an associate director at Pew Research Center .

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