Scientist tests pharmaceutical drug before approval

How Big Pharma Controls Drug Research

In our last article, we covered the numerous methods pharmaceutical manufacturers employ to buy the support of health care professionals, doctors and teaching hospitals. Drug companies frequently hire physicians to give speeches promoting specific medications to other doctors. They pay for meals, accommodations and spa visits. More often than not, these financial relationships are entirely legal.

Sometimes, drug companies step over the line, and violate laws by compensating physicians for prescribing, or promoting, drugs for uses not approved by the FDA. We used GlaxoSmithKline, manufacturer of the anti-nausea drug Zofran, as an example, and detailed federal allegations that GSK had unlawfully attempted to influence physicians by promoting Zofran as a safe treatment for morning sickness, without ever conducting clinical trials that included pregnant women.

But in that article, we only reviewed the work that Big Pharma’s money does after a drug’s approval, once a product has been released onto the market and physicians are allowed to prescribe it for either approved or unapproved uses. As we’ll describe here, the pre-approval process isn’t independent of industry money, either.

In fact, it wouldn’t be too much to say that drug companies are the true “actors” behind their own products’ scientific review and approval.

Science For Sale: Big Pharma’s Surprising Control Over Clinical Research

Scientist tests pharmaceutical drug before approvalAccording to Ben Goldacre, a physician and investigative journalist, pharmaceutical companies exert surprising amounts of control over the course of scientific research.

Goldacre’s 2012 book, Bad Pharma: How Drug Companies Mislead Doctors & Harm Patients, focuses specifically on clinical trials, which form the basis upon which any drug is approved or denied approval by a country’s regulatory authority.

Goldacre outlines how these trials are funded, managed and ultimately “gamed” by pharmaceutical companies.

Drug Companies Direct The Course Of Clinical Trials, Design Them To Result In “Good” Findings

Clinical trials are studies involving human subjects, and their aim is to determine a drug’s “safety and efficacy.” These tests answer two fundamental questions:

  • “what side effects can this drug cause in people?”
  • “does this drug actually treat the indications that it’s manufacturer wants to market and sell it for?”

As the FDA has stated, clinical trials are the most expensive and lengthy requirement of the drug approval process. All drugs must be subjected to rigorous clinical trials before being lawfully sold in the US.

But clinical trials are also funded almost exclusively by pharmaceutical manufacturers, the same companies for whom a successful trial result means the difference between incredible profits and millions of wasted dollars. In fact, Goldacre has found that upwards of 90% of all clinical trials are directly funded by the drug makers whose products are under investigation.

That might not seem surprising. Clinical trials can cost up to $800 million each, and take on average 12 years. With numbers like those, who would assume the risk to conduct one in the first place other than the company that expects to profit from its results? And experts at the FDA review clinical trial data rigorously to determine its accuracy. After all that stringent review, the data should be clean. Right?

According to Goldacre, the problem with this system is that pharmaceutical companies don’t play fair. In Big Pharma’s introduction, he puts it succinctly:

“drugs are tested by the people who manufacture them, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques which are flawed by design, in such a way that they exaggerate the benefits of treatments. Unsurprisingly, these trials tend to produce results that favour the manufacturer.”

Studies have been conducted to support this claim. A 2007 review that looked at every published trial on statins, a class of drugs used to treat high blood pressure, found that trials funded by the pharmaceutical industry were 20 times more likely to conclude that statins were effective.

It’s not difficult to see why. Drugs that don’t fare well in clinical trials, ones that are demonstrated to be unsafe or ineffective, are unlikely to be approved. And without approval, they can’t be marketed and sold in the US. That’s a huge problem for pharmaceutical manufacturers.

“Bad” Trial Results Are Routinely Hidden, Even From Doctors Who Need Them To Make Prescribing Decisions

But of course, clinical researchers aren’t completely controlled by the companies who support their research financially. And sometimes, they end up with study results that seem to contradict a drug’s safety or efficacy. According to Goldacre, when that happens, pharmaceutical companies “are perfectly entitled to hide [the results] from doctors and patients.”

Bad Pharma provides several examples of physicians and academics who, after requesting the results of clinical trials, were sent “page after page” of censored material.

Recent instances have involved doctors requesting clinical data on drugs, and receiving hundreds of pages in which even basic sections critical to prescribing decisions, like “Adverse Events,” which would normally detail the side effects and complications experienced by patients taking a drug, are followed by row upon row of blacked-out information. If there’s anything a physician can learn from this desire to conceal data, it’s that pharmaceutical companies don’t want them to understand the drugs they prescribe.

There are even companies that allow pharmaceutical manufacturers to outsource their secrecy. Contact Synchrogenix and their experts will take your study results and “produce[…] redacted clinical documents” that you can submit to the FDA.

Balancing Protection & Transparency

There’s certainly a healthy amount of concealment in these circumstances. Information that would be able to identify patients shouldn’t necessarily be available to the public, or regulatory agencies for that matter. But pharmaceutical companies are also allowed to withhold what they consider “confidential business information.” As we’ve seen, that category seems to include “Adverse Events,” evidence of new side effects and complications.

But are the side effects a drug can cause in patients really examples of “confidential business information”? Or are they essential facts that doctors need to make the best decisions for their patients?

The FDA Conceals Evidence Of Fraudulent Clinical Trials From The Public & Medical Community

Usually, it’s not pharmaceutical companies who deny doctors these results. It’s the FDA, acting under provisions of federal law. After receiving a public request for clinical results, the FDA is required to consult first with a drug’s manufacturer about what data can be made public, and what data can be labeled “confidential business information,” and by that logic, concealed.

But the FDA also censors its own findings, even the results of investigations into clinical trial conduct. Charles Siefe, a professor of journalism at New York University, has been instrumental in uncovering what he calls the FDA’s “pattern of burying the details of misconduct.

When the FDA fields allegations that a clinical trial is being performed improperly, the agency sends federal investigators to the study site to determine whether or not the research is being conducted according to protocol. Siefe writes that “when there are problems, the FDA generates a lot of paperwork – what are called form 483s, Establishment Inspection Reports, and in the worst cases, what are known as Warning Letters.”

But Siefe notes that if you’re lucky enough to find any of this paperwork in the first place, “you’ll see that, most of the time, key portions are redacted: information that describes what drug the researcher was studying, the name of the study, and precisely how the misconduct affected the quality of the data are all blacked out.” As a result, it’s impossible for journalists, medical researchers and the public to learn which studies are “tainted” by fraudulent clinical trial results, and which should be considered truly objective demonstrations of a drug’s safety and efficacy.

Redacted Clinical Trial Results From FDA

Between 1998 and 2013, Siefe found 78 published papers that had used findings from clinical trials cited by the FDA for falsifying data, inadequately reporting adverse events, violating federal protocols or failing to protect patient safety. Only 4% of those published papers made any mention of the violations.

After Approval, Drug Companies Support Studies That Find Benefits In Off-Label Use

Goldacre has shown us how pharmaceutical companies control clinical research, and how after that research is completed, they can hide the results if they’re unflattering.

Studies performed after a drug is approved are no different. In fact, many post-marketing trials funded directly by drug companies go further, and come to support “off-label” uses, ones that have not been approved by the FDA.

GlaxoSmithKline: One Of Many Companies Accused Of Producing Misleading Data, Using It To Market Drugs For Unapproved Use

As we’ve mentioned elsewhere, the federal government filed a battery of criminal and civil charges against GlaxoSmithKline in 2012. The Department of Justice’s allegations included claims that the company had promoted Zofran to doctors as a safe and effective morning sickness treatment, a use for which the drug had never been approved. Glaxo continues to deny the allegations surrounding Zofran.

Nor has the company admitted any wrongdoing in the promotion of its asthma medication Advair. But federal allegations paint a different picture, one in which Glaxo conducted unsatisfactory clinical trials and then distorted their results to promote Advair for unapproved use.

GlaxoSmithKline & Trial SAS30017: Twisting Data For Profit

Advair is an asthma medication approved for use in certain patients under specific circumstances. It is not approved as a “first-line” treatment for mild cases of asthma. In fact, the FDA considers Advair “potentially unsafe” for patients with mild or non-persistent asthma. Before the drug’s approval, GlaxoSmithKline agreed on this point, and consented to labeling language that restricted Advair’s indication as a first-line treatment to patients “whose disease severity warrants treatment with 2 maintenance therapies.”

But according to internal corporate documents obtained by federal prosecutors, executives at Glaxo were never interested in restricting the drug’s promotional push to the indications for which it had been approved. At Glaxo’s launch party for Advair, a “lavish event attended by thousands of sales representatives” in April 2001, David Stout, GlaxoSmithKline’s then-President of Pharmaceutical Operations, told the sales team: “You’ve got to make Advair the 1st choice, 1st line, for the treatment of Asthma.”

Two years later, Glaxo returned to the FDA with new clinical trial results, drawn from studies funded and managed by the company. Glaxo wanted to remove the limitation on “first-line” usage, and argued that its new trial results demonstrated Advair’s safety and efficacy in patients with mild asthma. The FDA’s experts disagreed, and rejected Glaxo’s new application. In its rejection letter, the FDA stated: “we do not believe that you have provided sufficient evidence of efficacy to support this broadened indication for Advair […] in addition, this supplement did not provide adequate assurance of the relative safety of [Advair for patients with mild forms of asthma].”

The FDA noted one clinical trial in particular, a study that the Department of Justice called “pivotal” to the agency’s decision. Trial SAS30017 “failed to demonstrate the superiority of the combination product Advair Diskus to the single component fluticasone propionate,” which at the time was the industry-standard and FDA approved first-line treatment for mild asthma. Then the FDA sent Glaxo a warning: if you market Advair for unapproved use on the basis of these trial results, it “could cause the drug to be considered ‘misbranded’ under the United States Food, Drug and Cosmetic Act.” As the Department of Justice would eventually claim, this warning was not heeded.

In 2003, Glaxo terminated an ongoing clinical trial of Advair, after “a statistically significant number [of] patients […] died from asthma-related causes.” Upon review of the trial’s existing data, the FDA placed a black box warning on Advair’s label, and then strengthened the labeling further to discourage Advair’s prescription as a first-line treatment for asthma, unless a patient’s “disease severity clearly warrant[ed]” its use. The next seven years would only see the FDA’s warnings increase, as further research repeatedly demonstrated Advair’s risks in patients with mild asthma.

But at a meeting in March 2004, Stan Hull, Senior Vice President of Glaxo’s United States Pharmaceuticals operation told shareholders, “one of our strategies this year, or objectives, will be focusing on this category the mild asthmatic […] So our objective in simple terms this year is to persuade a physician to start their patients on Advair” [emphasis added].

Advair marketing presentation slide

In late 2004, GlaxoSmithKline’s Director of Asthma Marketing gave a PowerPoint presentation to his sales team, instructing them to promote Advair as a “first-line” treatment for all forms of asthma.

Over the next six years, GlaxoSmithKline’s top management would repeat this message time and time again, that, despite the limitations of the FDA’s initial approval, and despite the agency’s explicit rejection of Advair as a first-line treatment for mild asthma, the drug should be promoted to physicians for that use.

At the core of Glaxo’s marketing efforts sat Study SAS30017, a trial the FDA had already dismissed as insufficient. Rather than accept the study’s actual results, and its failure to demonstrate Advair’s efficacy in treating milder forms of asthma, Glaxo twisted it into a new form. By modifying the study’s method of statistical analysis, Glaxo researchers calibrated its results to highlight Advair’s benefits and downplay its safety risks. With the study’s manipulated conclusions in hand, Glaxo sales representatives returned to doctors’ offices nationwide, proclaiming “If it’s Asthma, it’s Advair.”

Avandia’s Vanishing Safety Results

While the company denies any wrongdoing in the promotion of Advair, Glaxo did plead guilty to three of the government’s criminal charges. In one case, Glaxo’s unlawful conduct speaks to the significant power pharmaceutical companies exert over clinical trial results.

The government claimed that Glaxo had failed to report new safety information about the drug Avandia, including the results of several post-marketing studies conducted after Avandia’s approval for the treatment of type 2 diabetes.

For example, Glaxo conducted studies on Avandia’s competitors and, according to federal prosecutors, hid the results. In a study funded by Glaxo, the diabetes drug Actos was found to create a better lipid profile than Avandia. In a settlement agreement, the Justice Department wrote that Glaxo “did not publish this scientific data […] because it was unhelpful to GSK’s marketing message on lipids.”

Internal company documents revealed that a Glaxo Vice President had “directed that the results of this Actos study not be published, stating that the trial was done ‘way under the radar’ and that ‘per [a Senior Management] request, these data should not see the light of day to anyone outside of GSK.’ “

In another post-marketing trial, researchers compared Avandia’s effects to two of its main competitors, and found Avandia the most effective in treating type 2 diabetes. The study was published in the New England Journal of Medicine (NEJM), quite possibly the world’s most prestigious medical publication, but one that frequently accepts “articles over which pharmaceutical companies and their employees can exert significant influence.”

A Washington Post investigation conducted between August 2011 and August 2012 found that of 73 articles on new drugs, NEJM had published 60 “funded by a pharmaceutical company, 50 [of which had been] co-written by drug company employees and 37 [of which] had a lead author, typically an academic, who had previously accepted outside compensation from the sponsoring drug company in the form of consultant pay, grants or speaker fees.”

The Journal’s Avandia article was no different. The Post found that “the trial had been funded by GlaxoSmithKline, and each of the 11 authors had received money from the company. Four were employees and held company stock. The other seven were academic experts who had received grants or consultant fees from the firm.” And while the study concluded that Avandia was an effective treatment for diabetes, researchers failed to report on its more important implications: Avandia raises the risk of heart attacks.

Early clinical trials demonstrated that Avandia increased the risk for congestive heart failure, and the drug bore a black box warning to that effect. But Glaxo’s sales representatives continued to promote the drug based on claims that it could actually reduce cardiovascular risks, even with what the Department of Justice called a total lack of “adequate scientific support.” In 2012, an expert from the FDA estimated that Avandia had been associated with more than 80,000 heart attacks and deaths.

When studies like the one published by NEJM fail to note evidence of increased risks, it’s no wonder why so many critics have charged that pharmaceutical companies “shape[…] their research to obscure […] dangerous side effects.”

Governmental Oversight & Academic Journals: Potential Antidotes To A Broken System?

It’s clear that pharmaceutical manufacturers command significant control over the scientific understanding of their own products, both pre- and post-approval. So who keeps watch for potential conflicts of interest? Goldacre says its not the regulatory agencies you would expect:

“Regulators see most of the trial data, but only from early in a drug’s life, and even then they don’t give this data to doctors or patients, or even to other parts of the government. This distorted evidence is then communicated and applied in a distorted fashion.”

Academic journals could serve as an alternative watchdog, but Goldacre writes that “academic papers, which everyone thinks of as objective, are often covertly planned and written by people who work directly for the companies, without disclosure. Sometimes whole academic journals are even owned outright by one drug company.”

In 1997, the Journal of the American Medical Association sent a survey to 3,394 science faculty members, although only 2,167 returned a completed questionnaire. When asked whether or not the publication of their research results had been delayed more than 6 months by a pharmaceutical manufacturer, 20% said yes, and many explicitly said that “slow[ing] the dissemination of undesired results” was a cause of the delay.

Goldacre says that journals are routinely sent papers for publication that have been drafted by pharmaceutical company representatives, rather than the “independent” researchers listed as authors. Journals that ultimately publish papers demonstrating the benefits of a specific drug are often rewarded, too. As the Guardian summarized, a drug’s manufacturer “might buy up hundreds of thousands worth of reprints (glossy versions of the published paper) to distribute to doctors to encourage them to prescribe the drug.”

Outsourcing Research To For-Profit Companies, Pharma Contracts Keep Data Under Lock & Key

In recent years, the pharmaceutical industry has turned away from academia entirely.

In 2001, a group of thirteen medical journal editors published a blistering critique in the Canadian Medical Association Journal. After noting that “until recently, academic, independent clinical investigators were key players in design, patient recruitment and data interpretation in clinical trials,” they described the industry’s new way of doing business. Rather than hand clinical work over to academic institutions, pharmaceutical companies now employ “contract research organizations,” private, for-profit research groups who “can do the job for less money and with fewer hassles.” CROs have captured the clinical research market: “CROs received 60% of the research grants from pharmaceutical companies, as compared with only 40% for academic trialists.”

The editors don’t take issue with lowering costs or increased competition within the pharmaceutical research industry; they understand that this is a business. Their problem is with the culture of secrecy that these contract research organizations create. Once a pharmaceutical company has contracted with a CRO, it’s likely that a contractual agreement will “deny [outside] investigators the right to examine the data independently.”

More often than not, CROs are tethered to a drug company’s will. Many aren’t allowed “to submit a manuscript for publication without first obtaining the consent of [its] sponsor.” As a result, even academic journals become “party to potential misrepresentation, since the published manuscript may not reveal the extent to which the authors were powerless to control the conduct of a study that bears their names.”

Does The US Government Keep Accurate Clinical Trial Records?

In response to similar claims made in Bad Pharma, the Association of the British Pharmaceutical Industry released an official statement saying that the book’s illustrating examples are old, that the pharmaceutical industry has cleaned itself up, and that new federal regulations ensure that drug companies publicly report the results, good or bad, of their clinical trials.

But Bad Pharma had already anticipated, and refuted, this argument. Moving on from British legislation, Goldacre notes that several US laws now require all clinical trials to be registered with the National Institutes of Health, no matter who funds the research. But Goldacre points out that after initial registration, no one from the NIH checks up on the study results.

We wanted to check Goldacre’s allegation for ourselves, so we headed over to ClinicalTrials.gov and performed a search for all clinical trials with “ondansetron” and “pregnancy” in the brief title. Our search returned 7 applicable trials, most of which involved women receiving ondansetron as a treatment for post-operative nausea after cesarean section, rather than for morning sickness.

Regardless, out of those seven studies, we found:

  • A trial submitted to the database on May 10, 2011 that was listed as “completed.” The trial’s status had been updated last on June 7, 2013, but read “no study results posted.”

We found the study’s results published in the June 2014 issue of Antimicrobial Agents & Chemotherapy.

  • A trial submitted on May 3, 2009 read: “the recruitment status of this study is unknown because the information has not been verified recently.” The record had not been updated since 2009.

We found its results published in the April 2011 edition of Supportive Care In Cancer.

  • Two studies, submitted by the same researcher from Stanford University in January of 2013, were listed as “completed.” The records had last been updated on May 14, 2014, but had “no study results posted.”

We found a paper that drew data from both trials published in Clinical Pharmacology & Therapeutics on December 4, 2014.

  • One study that had been submitted on August 15, 2012 and last updated September 11, 2013 as “completed.” The record on ClinicalTrials.gov reads “no study results posted,” but scroll down and you’ll find that a paper based on the trial’s results had been published in October 2014, and “automatically indexed” to the page.

For most of these trials, researchers are required by US law to report their results within one year of completing a study. If our findings are any indication, this isn’t happening and the administrators of ClinicalTrials.gov certainly aren’t checking up on the results of studies, either.

In the UK, regulators are having trouble getting their hands on study results, too. In 2014, an investigation led by members of the British parliament suggested that pharmaceutical manufacturers were only reporting the results of around 50% of completed clinical trials to regulatory authorities.