Tag Archives: Pharma

03/23/21

The Trickery of Drug Approval

© Andriy Popov | 123rf.com

From all that the public is hearing and seeing about the COVID vaccines, both the pharmaceutical companies and the FDA have done an amazing job bringing the first two vaccines to market. In order to alleviate public mistrust of the “warp speed” development process, Dr. Anthony Fauci and NIH director Francis Collins publicly received their first dose of the Moderna vaccine. Dr Fauci said it was remarkable to be receiving it less than a year after the virus it treated was discovered. “What we’re seeing now is the culmination of years of research which have led to a phenomenon that has truly been unprecedented.” But will the pharmaceutical companies continue this standard of fast, safe and effective drug development?

In January 2020, just before the emergence of the pandemic, Harvard Medical School researchers published a study in JAMA that found the FDA is approving new drugs more quickly than ever before and using less stringent standards to determine if the drugs actually work. The lead author of the study told NPR “There has been a gradual erosion of the evidence that’s required for FDA approval.” As a result, patients and doctors “should not expect the new drugs will be dramatically better than older ones.” The use of expedited programs (Accelerated Approval, Fast-Track, and Priority Review) for new drugs increased over time, with 81% of new drugs benefiting from at least one such program in 2018. NPR reported the study found the median review time for standard drug applications was just over 10 months in 2018 compared to 2.8 years for standard and priority applications from 1986 through 1992.

The proportion of new approvals supported by at least 2 pivotal trials decreased from 80.6% in 1995-1997 to 52.8% in 2015-2017, based on 124 and 106 approvals, respectively, while the median number of patients studied did not change significantly (774 vs 816). FDA drug review times declined from more than 3 years in 1983 to less than 1 year in 2017. But total time from the authorization of clinical testing to approval has remained at approximately 8 years over that period.

Drug makers began to pay FDA fees to fund the review process as a result of AIDS activists protesting the slowness of the agency in the 1980s. In 1993, the first year after Congress passed the Prescription Drug User Fee Act, the FDA collected $29 million in fees. That amount rose to $908 million in 2018. The industry fees amounted to around 80% of the money spent on FDA employee salaries for drug reviews that year. The lead author of the JAMA study said: “There is some concern about the incentives that this created within the FDA … And whether it has created a culture in the FDA where the primary client is no longer viewed as the patient, but the industry.”

The Pharma Marketing Blog tracked the relationship of fees paid to the FDA by the pharmaceutical industry and the push for less rigorous scientific proof in clinical trials (and therefore faster drug approvals). He noted that there was a negative correlation between the rise in user fees and a drop in the number of warning letters sent out by the FDA to companies. There was also a positive correlation between drug user fees and adverse event reports, which track drug safety. See the following graphs taken from the Pharma Marketing Blog.

This hasn’t been the only recent evidence of how the pharmaceutical industry seems to be replacing patients as the FDA’s primary clients. Researchers published a study of the “Association between FDA and EMA [European Medicines Agency] expedited approval programs and therapeutic value of new medicines” in the October 2020 issue of the BMJ. The study sought to characterize the therapeutic value of new drugs approved by the FDA and EMA and how these ratings were associated with the regulatory approval process of the expedited programs of the FDA and EMA.

Over the past few decades both agencies have established programs to expedite drug development for serious conditions. The four main expedited programs of the FDA are: fast track (introduced in 1987), accelerated approval (1992), priority review (1992), and breakthrough therapy (2012). Emergency use authorization, under which the COVID-19 vaccines have been expedited, technically isn’t an FDA approval of the drug, but it authorizes the FDA to facilitate an unapproved product during a declared state of emergency. Its latest update occurred in 2017. The EMA has two expedited programs, accelerated assessment (2005) and conditional marketing authorization (2006). The EMA instituted a third program, PRIME, the priority medicines scheme, in 2016.

These expedited programs were intended to prioritize the most important medicines for faster access to patients, and are increasingly the route by which new medicines are approved. For example, the FDA approved 60% of new drugs through at least one expedited program in 2019, while only 34% of drug approvals in 2000 were expedited. The FDA and EMA guidance indicated that an expedited program should be reserved for drugs that are expected to show an improvement over the available therapies. “However, neither the FDA nor the EMA specifically requires data on, or makes regulatory approval contingent on, comparative effectiveness; most new drugs are approved on the basis of placebo-controlled trials or single arm studies.”

This means the therapeutic value of medicines that benefitted from the FDA and EMA expedited programs is uncertain. Using ratings of therapeutic value published by health authorities in four countries and an independent non-profit organization, the researchers “evaluated the association between expedited programs and ratings of therapeutic value for all new drugs approved by the FDA and EMA from 2007 through 2017.”

We found that less than a third of all new drugs approved by the FDA and EMA were rated by any of five independent organizations as having high therapeutic value—that is, providing moderate or better improvement in clinical outcomes for patients. Most of the increase in the number of new drug approvals over the past decade was driven by drugs rated as having low therapeutic value, which calls into question the common practice of using simple counts of new drug approvals as a measure of innovation. Rather, a more nuanced view of innovation is needed that takes into account the clinical benefits and relevance to patients of new medicines.

The study’s findings suggest that after FDA regulatory approval, there is a widening gap between the drug’s approval and the clinical and public health priorities of health systems, payers and patients in drug safety and efficacy. Contributing to this gap is the varying quality of clinical evidence available at the time of approval. This leads to uncertainty around the extent of clinical benefit of the respective drug. The study’s data emphasizes the importance of robust post marketing evaluation for expedited drugs. “Such an evaluation would confirm early evidence of efficacy and help to elucidate findings from several previous studies suggesting that accelerated approval, priority review, and fast track drugs were associated with increased safety related reports or labeling changes.”

The researchers suggested one step leading to greater assurance of timely completion of post marketing study requirements for expedited drugs could be to require that certain mandated studies enroll patients before the FDA or EMA grants approval. They also suggested that regulatory agencies explore whether additional explanations were necessary. These explanations could include elaboration in product labeling, press releases, or approval documents. They could provide more realistic expectations of benefit for expedited drug approvals by patients and clinicians. Their findings also had implications for the controversy around drug prices.

In the US, the largest public payers are required by law to cover most (Medicaid) or a substantial number (Medicare) of drugs approved by the FDA, regardless of the quality of the evidence supporting their approval or their therapeutic value. Previous studies of cancer drugs have found no association between clinical benefit and drug prices and reimbursement.

In conclusion, the researchers said while the FDA and EMA are increasingly using expedited programs to facilitate drug development, the absolute value of highly rated drugs approved by the FDA and EMA over the past decade was low. Policy makers could explore implementing therapeutic value ratings more widely for new drug approvals. This would align the evidentiary needs of regulatory approval and reimbursement decisions with informing patients and doctors about the benefits and risks of new drugs, particularly those approved by expedited programs.

It’s not so surprising, then, that so many Americans are hesitant to say they plan to get a coronavirus vaccine. It seems that the above discussed results of research into new drug development by the pharmaceutical companies is at least partly to blame. Many people do not trust the claims drug companies make about their products.

The Pew Research Center conducted a survey of Americans at the end of November 2020. Sixty percent said they would definitely or probably get a vaccine for the coronavirus, which was up from 51% in September. Thirty-nine percent say they will definitely or probably not get a coronavirus vaccine. About half of this group, 18%, said it’s possible they would decide to get vaccinated once people start getting vaccinated and there is more information available. “Yet, 21% of U.S. adults do not intend to get vaccinated and are ‘pretty certain’ more information will not change their mind.”

While public intent to get a vaccine and confidence in the vaccine development process are up, there’s considerable wariness about being among the first to get a vaccine: 62% of the public says they would be uncomfortable doing this. Just 37% would be comfortable.

Public confidence has increased since September that the research and development process will yield a safe and effective vaccine for COVID-19. Seventy-five percent of individuals now have a great deal or fair amount of confidence in the R&D process. However, one of the factors influencing whether someone intends to get a vaccine for COVID-19 is mistrust of the vaccine development process. Sixteen percent of Americans do not have much confidence in the process; 8% have no confidence that the R&D process will produce a safe and effective vaccine for COVID-19. Confidence in scientists remains slightly higher than before the pandemic.

With scientists and their work in the spotlight, 39% of Americans say they have a great deal of confidence in scientists to act in the public’s best interest, an uptick from 35% who said this before the pandemic took hold. Most Americans have at least a fair amount of confidence in scientists. However, ratings of scientists are now more partisan than at any point since Pew Research Center first asked this question in 2016: 55% of Democrats now say they have a great deal of confidence in scientists, compared with just 22% of Republicans who say the same.

Pharmaceutical companies have an opportunity when they resume the research and development process for new drug applications after the pandemic. Will they continue to use external committees of scientists vetting the data for new drug applications and produce truly independent recommendations and rejections? If pharmaceutical companies can maintain an open and transparent R&D process and develop drugs with a truly high therapeutic value, the confidence level of patients and their doctors would be higher than ever. For more on COVID, see “Learning from COVID Drug Development.”

11/19/19

A Shot Across the Bow of Pharma

© John Tansey | christourhopeministries.com

Ending a four year-long federal investigation, Avanir Pharmaceuticals agreed to pay an estimated $116 million in criminal penalties and civil damages in a settlement reached with the Department of Justice (DOJ) on September 26, 2019. According to FiercePharma, the company also agreed to assist in the prosecution against former employees and a top prescriber of its bestselling drug, Nuedexta. As a part of the deal, Avanir agreed to a five-year Corporate Integrity Agreement with the Department of Health and Human Services (HHS). Avanir CEO Wa’el Hashad said the “company takes its responsibilities to patients, their families and caregivers, and healthcare providers very seriously. . . . Avanir is deeply committed to regulatory and legal compliance, integrity and ethical behavior, and the health and safety of patients.”

The DOJ reported Avanir agreed to pay over $95 million to resolve civil False Claims Act allegations that the company paid kickbacks to a physician to prescribe Nuedexta, and that it made false and misleading marketing claims about Nuedexta to long-term care facilities. Allegedly the false claims were targeted to influence providers to prescribe Nuedexta as an alternative to antipsychotic drugs. The federal government was trying to limit the use of antipsychotics as “chemical restraints” used to manage behaviors commonly associated with dementia patients.

Avanir has agreed to pay $95,972,017 to the United States to resolve allegations under the False Claims Act related to its marketing of Nuedexta. The government alleged that between October 29, 2010, and December 31, 2016, Avanir provided remuneration in the form of money, honoraria, travel, and food to certain physicians and other health care professionals to induce them to write prescriptions for Nuedexta. One form of remuneration included Avanir’s payment to certain health care professionals to give talks (commonly known as “speaker’s programs”) about Nuedexta based on their willingness to prescribe Nuedexta. These events were primarily social, with no educational value.

Nuedexta is only approved as a treatment for a rare condition called pseudobulbar affect (PBA) that causes uncontrollable laughing or crying that is not connected to a person’s mood. PBA is extremely rare in dementia patients, affecting less than 5%. It is most commonly associated with people who have multiple sclerosis (MS) or Lou Gehrig’s disease, ALS. Doctors were found to be inappropriately diagnosing PBA to justify using Nuedexta to treat difficult to manage elderly patients. There was a CNN investigation in 2017 that  indicated between 2012 and 2016 Nuedexta sales jumped 400%; more than half of which had gone to long-term care facilities. For more on this, see: “Conjuring Diagnoses For the Elderly.”

According to a recent CNN report, whistleblowers alleged that from the drug’s early years Avanir illegally directed salespeople to market Nuedexta in nursing homes as an alternative to antipsychotic drugs specifically for “use in controlling the behavior of patients prone to disruptive outbursts.” They also claimed salespeople coached doctors on how to describe patients’ conditions in order to guarantee approval, and even forged physician signatures on paperwork for insurers. One lawsuit stated, “At least one Avanir (salesperson) went so far as to dress in scrubs, review patients’ files at the nurses’ station in nursing homes, and write the diagnosis for PBA in the medical files of patients.” These tactics were allegedly praised by an executive on a national sales call. Government data indicated Medicare Part D spent around $225 million on Nuedexta in 2017, a 700% increase since 2012.

Assistant Attorney Jody Hunt of the DOJ said kickbacks can corrupt a provider’s medical judgment. “And it is particularly concerning when a pharmaceutical company uses kickbacks to drive up sales in connection with a vulnerable population, such as elderly patients in nursing care facilities.” The government alleged Avanir sought to take advantage of efforts by the Centers for Medicare and Medicaid Services to reduce the use of antipsychotics with dementia patients. Avanir instructed its sales force to initiate discussions in long-term care (LTC) facilities about antipsychotic use and how Nuedexta could be used to reduce their reliance on antipsychotics.

Avanir’s own studies demonstrated that the actual population of patients with PBA is limited. In order to counter the objection by certain physicians that they had few, if any, patients that exhibited signs of PBA in their facilities, Avanir instructed sales representatives to provide false and misleading information that PBA patients could be exhibiting a wide variety of “behaviors” such as crying without tears, moaning, or making other inarticulate sounds, when, in fact, those symptoms are commonly observed in patients who have dementia but do not have a diagnosis of PBA. This strategy worked, and Nuedexta utilization in LTC facilities increased.

The DOJ reported the civil settlement resolved lawsuits by three whistleblowers, who were all former employees of Avanir. Under the whistleblower provisions of the False Claims Act, private citizens are permitted to sue on behalf of the government for false claims and to share in any recovery.

The Employment Law Group® law firm reported Kevin Manieri was the first person to report the company’s activities to authorities. A biopharmaceuticals executive with decades of experience, he was fired only months after joining Avanir in 2014 when he complained to an Avanir vice president about the company using “speaker fees” to reward doctors for writing unnecessary prescriptions for Nuedexta. Many of Avanir’s speaking engagements were small, sparsely attended gatherings at local restaurants. The speakers tended to be individuals willing to diagnose PBA “based upon a bare minimum of symptoms,” according to Kevin Manieri’s complaint. A press release issued by the U.S. Attorney’s Office for the northern District of Ohio said many of the Nuedexta speaking engagements had “little to no educational value.”

According to the complaint filed by Mr. Manieri, whom the drug company hired to oversee Nuedexta sales to physicians in the northern U.S., Avanir pushed its reps to focus on a few high-volume prescribers who were willing to recommend Nuedexta to patients who likely didn’t need the drug. He cited a vivid example in the complaint: A Cleveland-area neurologist who wrote twice as many Nuedexta prescriptions as any other doctor in the U.S. — and who also was Avanir’s highest-paid speaker, with 42 engagements in 12 months yielding more than $56,000 in payments.

Sadly, Avanir’s marketing strategy is not unusual in the world of pharmaceutical companies. According to Dr. Marcia Angell in The Truth About Drug Companies, Parke-Davis paid academic experts to put their names on flimsy research papers that supposedly showed Neurontin (gabapentin) was effective for certain off-label conditions. The result was Neurontin becoming a blockbuster drug, with over 2 billion in sales for 2003. “About 80 percent of prescriptions that year were for unapproved uses—conditions like bipolar disorder, post-traumatic stress disorder, insomnia, restless legs syndrome, hot flashes, migraines, and tension headaches.” In fact, Neurontin became an all-purpose restorative for chronic discomfort. An internal company e-mail described Neurontin as “the ‘snake oil’ of the twentieth century.”

In May of 2004, Warner-Lambert, of which Parke-Davis was then a division, agreed to pay $430 million to resolve criminal charges and civil liabilities related to its “illegal and fraudulent promotion of unapproved uses” for Neurontin. See the Department of Justice announcement here. Also see “Twentieth Century Snake Oil” for more on this.

The larger issue is that we can no longer trust much of the clinical research that is published. Among the concerns are reportedly selective publication of clinical trials, rigging the outcomes of those trials, publication bias and industry payments to medical journals and their editors. Richard Horton, and editor in chief of The Lancet said: “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue.” Marcia Angell, a former editor in chief of the New England Medical Journal (NEJM) said: “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor.” See “Corrupted Clinical Trials” for more on this.

So, the actions of whistle blowers like Kevin Manieri are not simply the acts of disgruntled ex-pharmaceutical employees in the long run. What happened to a relatively small pharmaceutical company, Avanir, and its attempts to expand the marketing reach of its featured drug, Nuedexta, are hopefully a warning shot across the bow of Pharma. Marketing rhetoric disguised as “treatment” or “evidence-based medicine” will not be tolerated. And there will be individuals and firms like The Employment Law Group® ready to hold you accountable for your actions. For more on Avanir and Nuedexta, also see “A Reason to Cry Uncontrollably.”

09/14/18

Machiavellian Drug Approval

photo by JoJan; Creative Commons Attribution 3.0 Unported license.

ProPublica noted that when the FDA’s responsibilities expanded in the 1970s, the review times for new drug approvals began to lag to more than 35 months on the average. The AIDS crisis came soon after, leading activists to accuse the FDA of holding back cures and then press the agency for faster drug approval times. One of the then activists, now an assistant professor of epidemiology at Yale, said they were desperate back then and naively thought there were drugs behind the FDA approval curtain being held back by its slow process. “Thirty years of our rash thinking has led us to a place where we know less and less about the drugs that we pay more and more for.”

The activists’ protests helped bring about the Prescription Drug User Fee Act in 1992, which began drug industry contributions to fund FDA salaries. In return, the FDA promised to speed up review times for drugs—within 12 months for normal applications, and 6 months for priority cases. You can probably guess what happened. The more the FDA relied upon industry fees to pay for drug reviews, the greater was its tendency towards approval. “The virginity was lost in ’92,” according to Jerry Avorn, who is a professor at Harvard Medical School. “Once you have that paying relationship, it creates a dynamic that’s not a healthy one.”

In 1993 Pharma funded 27% of the FDA’s scientific review budgets for branded and generic drugs. In 2017, that had increased to 75% or $905 million. Staffers know you don’t get promoted if you aren’t pro-industry. A former FDA medical team leader said: “You don’t survive as a senior official at the FDA unless you’re pro-industry.” He added the FDA has to pay attention to what Congress says, and the industry will lobby to replace you if they don’t like you. The attitude at the agency is: “Keep Congress off your back and make your life easier.”

The FDA’s Center for Drug Evaluation and Research gives internal awards annually to review teams. Former FDA employees said they never saw an award granted to a team that rejected a drug application. Congratulatory emails are sent to review teams by higher-up administrators when a drug is approved. “Nobody gets congratulated for turning a drug down, but you get seriously questioned.” FDA rejections of all drug applications have fallen over 50% since 2008. See the following graph from the above linked article in ProPublica.

Over the past thirty years Congress authorized the FDA to implement at least four major routes to faster approvals. Initially, these pathways were supposed to be the exception to the rule, but now they seem to have become the rule.  In 1988 Congress authorized the FDA to create “fast track” regulations. In 1992 the Prescription Drug User Fee Act formalized “accelerated approval” and “priority review.” Then when the law was reauthorized in 1997, the goal for review times was lowered to ten months. Finally, in 2012, the designation of “breakthrough therapy” enabled the FDA to waive normal procedures for drugs “that showed substantial improvement over available treatments.”

Sixty-eight percent of novel drugs approved by the FDA between 2014 and 2016 qualified for one or more of these accelerated pathways, Kesselheim and his colleagues have found. Once described by Rachel Sherman, now FDA principal deputy commissioner, as a program for “knock your socks off, home run” treatments, the “breakthrough therapy” label was doled out to 28 percent of drugs approved from 2014 to 2016.

The industry’s lobbying group, Pharmaceutical Research and Manufacturers of America (PhRMA), is pressing for even faster approvals. A policy memo on its website warns of “needless delays in drug review and approval that lead to longer developmental times.” Aaron Kesselheim, an associate professor at Harvard Medical School said he thought it was reasonable to want to move drugs faster, particularly for “an extremely promising new product, which treats a serious or life-threatening disease.” When you do that, he said the key factor “is that you’ve got to make sure you closely follow the drug in a thoughtful way and unfortunately, too often we don’t do that in the U.S.” FDA approvals of novel drug applications have nearly doubled since 2008. See the following graph from the above linked article in ProPublica.

Nuplazid, a drug for hallucinations and delusions associated with Parkinson’s disease, was an example of the potential consequences from this accelerated approval process in Caroline Chen’s article for ProPublica. The drug was created in 2001 by a chemist at Acadia Pharmaceuticals. In 2009 it failed to prove its benefit over a placebo in the first of two Phase 3 clinical trials; two successful Phase 3 trials are required. The company halted the second trial and asked the FDA for permission to revise the scale used to measure benefit. They argued the original scale was typically used for schizophrenia assessments and thus wasn’t appropriate for Parkinson’s-related psychosis.

Given that Acadia didn’t raise this issue with the FDA until after its failed clinical trial, their objection seems like sour grapes to me. Why didn’t they use the revised scale from the beginning? Nevertheless, the FDA agreed to this new scale—even though it had never been used before in a study for drug approval! Then, since there were no treatments approved for Parkinson’s-related psychosis, the FDA granted Acadia’s request for break-through therapy status, meaning Nuplazid now only needed one positive Phase 3 clinical instead of two for approval. “In 2012, Acadia finally got the positive trial results it had hoped for. In a study of 199 patients, Nuplazid showed a small but statistically significant advantage over a placebo.”

An FDA medical reviewer was skeptical of Nuplazid. In analyzing all of the drug’s trial results, he calculated you would have to treat 91 patients to get seven who would receive the full benefit. Five of those 91 would suffer “serious adverse events,” including one death. He recommended against approval, citing “an unacceptably increased, drug-related, safety risk of mortality and serious morbidity.” So the FDA convened an advisory committee to help it decide. That committee eventually voted 12-2 to recommend accelerated approval.

Fifteen members of the public testified at its hearing. Three were physicians who were paid consultants for Acadia. Four worked with Parkinson’s advocacy organizations funded by Acadia. The company paid for the travel of three other witnesses who were relatives of Parkinson’s patients, and made videos shown to the committee of two other caregivers. Two speakers, the daughter and granddaughter of a woman who suffered from Parkinson’s, said they had no financial relationship with Acadia. However, the granddaughter is now a paid “brand ambassador” for Nuplazid. All begged the FDA to approve Nuplazid. . . . The only speaker who urged the FDA to reject the drug was a scientist at the National Center for Health Research who has never had any financial relationship with Acadia.

Since Nuplazid was approved in 2016, Acadia raised its price twice from the original base price of $24,000 to more than $33,000. “There have been 6,800 reports of adverse events for patients on the drug, including 887 deaths” as of March 31st of 2018. In more than 400 instances Nuplazid was associated with worsening hallucinations—“one of the very symptoms it was supposed to treat.” After a CNN report about adverse events related to Nuplazid in April of 2018, the FDA began an evaluation. There are more examples of drugs-gone-bad after approval in the article.

Although the FDA expedites drug approvals, it will wait ten years or more for the post-marketing studies manufacturers agree to do when their drug is approved. Studies on Nuplazid aren’t expected until 2021. One of the reasons post-marketing studies take so long to complete is the fact it’s harder to recruit patients to risk being given a placebo when the drug is available on the market. In addition, the manufacturer no longer has a financial incentive to study its impact since the drug is on the market and could lose money if the results are negative. “Of post-marketing studies agreed to by manufacturers in 2009 and 2010, 20 percent had not started five years later, and another 25 percent were still ongoing.”

The FDA has the authority to issue fines or pull a drug from the market if a manufacturer doesn’t meet its post-marketing requirements. “Yet the agency has never fined a company for missing a deadline.”  The agency would have the burden to show the company was dragging its feet, which could be difficult to prove. “It’d be an administrative thing that companies could contest,” according to the FDA director of the Center for Drug Evaluation and Research.

Michael Carome, the director of the health research group for Public Citizen, a nonprofit advocacy organization, said instead of a regulator and a regulated industry, we now have a partnership. “That relationship has tilted the agency away from a public health perspective to an industry friendly perspective.”

In “FDA’s revolving door,” Charles Piller pointed out how many former FDA employees end up working or consulting for the drug makers they previously regulated. There are safeguards that are supposed to prevent the prospect of industry employment from affecting an employee’s decisions while at the agency. And there are others to discourage them from exploiting relationships with former colleagues after they leave. But the reality seems to be somewhat different. Piller cited a 2016 BMJ article that found 15 of 26 FDA employees who had conducted reviews over a 9-year time period in the hematology oncology field later worked or consulted for the biopharmaceutical industry.

Science has discovered that 11 of 16 FDA medical examiners who worked on 28 drug approvals and then left the agency for new jobs are now employed by or consult for the companies they recently regulated. This can create at least the appearance of conflicts of interest.

The co-author of the 2016 BMJ study thought that weak federal restrictions and the expectation of future employment inevitably biases how FDA staffers conduct drug reviews. “When your No. 1 major employer after you leave your job is sitting across the table from you, you’re not going to be a hard-ass when you regulate. That’s just human nature.” No, that’s not human nature, it’s just plain Machiavellian behavior—whether you’re doing whatever it takes to get your drugs on the market or whether you’re trying to position yourself for a future job with Pharma as you regulate their drugs.

07/13/18

Pharma Problems Defy Solutions

© ironstealth | stockfresh.com

In January 2017, President-elect Donald Trump said the pharmaceutical industry’s practices were disastrous and suggested the federal government should negotiate drug prices. He characterized the industry with getting away with murder. He said: “Pharma has a lot of lobbies, a lot of lobbyists, a lot of power. And there’s very little bidding on drugs.” The response from the industry’s top trade group, the Pharmaceutical Research and Manufacturers of America (PhRMA), was to increase its lobbying expenditures from $20 million in 2016 to $25.4 million in 2017. The biggest jump occurred in the first quarter of 2017. Only the U.S. Chamber of Commerce and the National Association of Realtors outspent PhRMA lobbying in 2017.

Writing for The Hill in January of 2018, Jessie Hellmann commented that despite the president’s tough talk, “his administration has yet to take action toward lowering drug prices, and some of his policies have even been viewed as being favorable to the industry.” Danit Felber noted the same thing in the first article of her two part series for Vision Magazine. She added how President Trump selected a former Eli Lilly executive as his Secretary of Health and Human Services. “There’s no doubt that the pharmaceutical industry is growing rapidly, as are its donations to political campaigns.”

Between the years 1997 to 2016, the U.S. population grew by 21% but the number of prescriptions (to both adults and children) grew by 85%. One in every six Americans takes a psychiatric drug (antidepressants, anxiety relievers, antipsychotics, etc.) – many of the conditions treated with these drugs can be treated in whole or in part by lifestyle changes and/or therapy. And in 2014, close to 1.3 million people went to the emergency room for adverse drug effects and about 124,000 of those died (U.S. government data cited by Consumer Reports).

An infographic linked by Vision Magazine reported in 2012, 46% of American adults took prescription drugs. 11.5% of American adults take 3 or more prescription drugs; 6.5% take 4 or more. There were 4.2 billion prescriptions written in 2011—an average of 13 per average American. The amount of money spent on prescription drugs increased from $208 billion in 2001, to $234 billion in 2008, to %325 billion in 2012. Among older adults, 46% above 55 are on a prescription drug; 12.6% above 65 take 4 or more prescription drugs.

Danit Felber noted how the U.S.  is only one of two countries globally that permits direct-to-consumer advertising for prescription drugs. She also pointed out that Congress passed a bill restricting the DEA from addressing the black market prescription drug trade the same way they go after the illicit drug trade. See “Head of a Snake” for more information on this. Tom Marino withdrew his name from consideration as the “drug czar” for the Trump administration when it was revealed he had spearheaded efforts to get that legislation through Congress.

The drug companies may be full of brilliant medical researchers and lawyers but it doesn’t take much brilliance to see that the American public is being exploited so pharmaceutical executives and politicians can get rich. It’s no exaggeration to say that human lives are at stake and it’s time the people understand our own place in this billion-dollar industry.

In part 2 of her series for Vision Magazine, Danit Felber reported that nine out of ten members of the U.S. House of Representatives received campaign contributions from pharmaceutical companies; as did all but three of U.S. senators. She referenced an October 2017 article in The Guardian that called out lobbying efforts of Pharma in 2016, which spent $152 million attempting to influence legislation that year; $20 million went directly to political campaigns. Reportedly, about 60% went to Republicans. Paul Ryan received $228,670. Pfizer gave $1 million towards President Trump’s inauguration.

Scores of attempts by some members of Congress to introduce legislation to bring down the price of prescription medicines or to let people buy them from Canada, where they are often cheaper, have failed to make it out of committee.

Bloomberg reported the industry’s lobbying trend continued into 2018. PhRMA spent $9.96 million on federal lobbying in the first quarter of 2018, an increase of almost $2 million from the same quarter in 2017. Several pharmaceutical companies, including Bayer Corp., AbbVie Inc, Sanofi US and Novo Nordisk all had new highs for their lobbying expenditures. PhRMA successfully stopped legislation that would have permitted generic-drug companies to study patented pharmaceutical products in order to bring low cost alternatives to market.

Bayer spent $3.45 million, AbbVie $2.89 million, Sanofi $2.03 million, Celgene $1.22 million and Novo Nordisk $1.46 million. In addition to the records, Pfizer Inc. spent $4.65 million, up from $3.79 a year earlier. Merck & Co. spent $3.31 million, nearly double its spending in the first quarter of 2017. Eli Lilly & Co. spent $1.34 million, down from $1.39 million a year earlier. Abbott Laboratories spent $790,000 in the first quarter, the same as it had in the same period in 2017.

Polls indicate high drug prices are one of Americans top health care concerns. During the 2016 presidential campaign both Hillary Clinton and Donald Trump attacked drug makers, so pharmaceutical companies stepped up their lobbying and nervously waited to see what action the President would take. One lobbyist said: “Anyone who thought the industry is fine because Hillary Clinton lost is naïve.” Companies, he thought, will want to talk with him, “particularly since his words have such an immediate impact on stock prices.”

So it was with some trepidation that Pharma faced the President’s announced plan to put “American Patients First” on May 11, 2018. In a speech given in the Rose Garden, he said:  “Everyone involved in the broken system — the drug makers, insurance companies, distributors, pharmacy benefit managers and many others — contribute to the problem.”  The President added that government—under previous leaders—was part of the problem by turning a blind eye to the abuse. “But under this administration we are putting American patients first.”

However, The New York Times quoted a securities analyst who said the president’s speech was “very, very positive to pharma. . . . We have not seen anything about that speech which should concern investors.” As a matter of fact,

Shares of several major drug and biotech companies rose immediately after the speech. Drugmakers’ stocks jumped immediately after the speech, as did the stocks of pharmacy benefit managers, the “middlemen” who Mr. Trump said had gotten “very, very rich.”Rather than take aim at the pharmaceutical makers, Mr. Trump said his administration would cut out the middleman, provide new tools to private benefits managers in Medicare’s prescription drug program to negotiate lower prices, stop limiting pharmacists from helping patients save money and speed up approval of over-the-counter medicines so that fewer will require prescriptions.

The Washington Post pointed out “American Patients First” suggested a number of policy ideas without a specific timeline for implementations. It excluded an idea Trump had previously proposed: “allowing the government to negotiate drug prices on behalf of the Medicare program.” It was silent about allowing Americans to import low-cost prescriptions from other countries like Canada. There was also evidence that some of the ideas spread by the pharmaceutical lobby took root. “Over the past year, drug companies have sought to deflect criticisms of their prices by blaming a secretive tier of middleman industries, such as pharmacy benefit managers that negotiate drug prices, for the role they play in prices.”

In addition to turning away from drug companies to condemn the “middleman” of PBMs—pharmacy-benefit managers—President Trump said he would make it a priority to stop foreign countries from getting drastically lower prices than in the U.S. Yet there isn’t a clear path to see that an increase in foreign prices would offset U.S. drug prices. Allan Coukell from the Pew Charitable Trusts commented: “I haven’t seen so far any manufacturers stepping forward to say how much they would lower prices in the U.S. if the U.K. and Germany paid more.” Rachel Sachs, an associate professor of law at Washington University School of Law, said: “With all the buildup the administration has given it, the president’s speech was deeply underwhelming. There is very little new in the administration’s plan, and little if anything that will make a difference in the near future, as the president has promised.” Gerard Anderson, a professor at John Hopkins Bloomberg School of Public Health, said: “He diagnosed the problems very well, and just didn’t have a solution.”

06/22/18

Corrupted Clinical Trials

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Dr. Jason Fung opened his article, “The Corruption of Evidence Based Medicine—Killing for Profit” with the following: “The idea of Evidence Based Medicine (EBM) is great. The reality, though, not so much.” He said if the evidence base was false or corrupted, then evidence-based medicine was completely worthless. “It’s like building a wooden house knowing the wood is termite infested.” He’s not alone in this opinion and he quoted three current or former editors of the two most prestigious medical journals in the world who corroborated his statement.

Richard Horton, editor in chief of The Lancet said: “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue.”

Dr. Marcia Angell, former editor in chief of the New England Medical Journal (NEJM) said: “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor.”

Dr. Arnold Relman, the former editor of the NEJM, said: “The medical profession is being bought by the pharmaceutical industry, not only in terms of the practice of medicine, but also in terms of teaching and research. The academic institutions of this country are allowing themselves to be the paid agents of the pharmaceutical industry. I think it’s disgraceful.”

Dr Fung said: “Physicians and universities have allowed themselves to be bribed.” He went on to say the examples in medicine are everywhere. For instance, medical research is typically paid for by pharmaceutical companies. “Trials run by industry are 70% more likely than government funded trials to show a positive result.” Among the issues he described were: the selective publication of clinical trials, rigging the outcomes of those trials, publication bias and industry payments to medical journals and their editors.

Clinical trials with negative results are likely to be suppressed. Using the company Sanofi to illustrate the problem, Dr. Fung noted the company completed 92 studies in 2008, but only published the results of 14. He acknowledged how it would be financial suicide to publish data that would harm your company. “But knowing this, why do we still believe the evidence based medicine, when the evidence base is completely biased?”

With antidepressants, a review of the published literature published in the NEMJ suggested 94% of the trials conducted were positive. Among FDA-registered trials, 31% were not published and only 51% showed positive results. The authors said:

We cannot determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both. Selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals, and patients.

Before the year 2000, pharmaceutical companies doing clinical trials did not have to declare beforehand what their primary outcomes would be. So they would “measure many different endpoints and simply figured out which one looked best and then declared the trial a success.” The government changed that requirement and after 2000, 8% of clinical trials showed good results when 57% of those before 2000 showed a positive result. Evidence of the evidence base was being corrupted by commercial interest.

If a journal publishes a positive article about a Pharma drug, the company would order several hundred thousand copies of the article to distribute to doctors in their marketing efforts. “It’s insanely profitable for journals to take money from Big Pharma.” The NEMJ gets 23% of its income from reprints; the Lancet gets 41%; and the American Medical Association gets 53%! “No wonder these journals are ready to sell their readers (ordinary physicians) down the river. It pays.” A cited study noted where 50.9% of the editors of prestigious medical journals received at least some payments from the industry, and in some cases “these payments were often large.”

We found that industry payments to journal editors are common and can be substantial. Moreover, many journals lack clear and transparent editorial conflicts of interest policies and disclosures. Given our findings, we would suggest that journals take several steps. Firstly, we would strongly argue that all journals should develop and implement a transparent, publicly accessible editorial conflicts of interest policy. Secondly, editors in chief should consider excluding those with considerable industry relations from editorial positions. While such a stance could be considered drastic, editors play a crucial role in research integrity; even an appearance of conflict can serve to undermine the clinical research enterprise.

In The Chronicle of Higher Education, Batt and Fugh-Berman noted where “Disclosing Corporate Funding Is Not Nearly Enough.” In the U.S. in 2015, industry spent $102.7 billion on health-related research, while federal agencies spent $35.9 billion. “The current administration attempted to further decrease NIH funding, but those efforts were unsuccessful.” They said reliance on industry money limits the scope of research; and “it weakens researchers’ ability to act as independent critics.” Pharmaceutical companies fund, publish and promote studies that that are favorable to their marketing goals and “suppress or attack research that threatens market share.”

Perhaps most troubling is that if the final results of a study do not support commercial goals, the full study may never be published. In general, industry-funded studies are less likely to be published than non-industry-funded ones. And contrary to expectations, the reason negative studies are unpublished is not because journals rejected them, but because they were never submitted for publication. Although many universities frown on agreements that give funders the right to suppress the publication of findings, policies regarding publishing are not uniform across colleges and universities. In any case, enforcement is nil: Colleges can’t force researchers to publish studies. Industry insiders tell us that when company representatives fail to prevent a researcher from publishing unfavorable results on a drug, they may attempt to persuade the researcher to “bury” the paper in an obscure journal. Or, under the guise of reviewing a manuscript for “accuracy,” a company may soften statements or insert subtle marketing messages into the article to mitigate harm to its marketing goals. We don’t know the extent to which industry funding distorts biomedical literature — and clinical decision-making — but a substantial body of evidence now shows that allowing industry to choose what scientific questions should be asked, and how findings should be analyzed, interpreted, and disseminated, has public-health costs. We need strategies to minimize industry influence on scientific questions, and the resulting impact on policies and medical practice.

Writing for Mad in America, Zenobia Morrill summarized a review article by three researchers, “Industry-corrupted psychiatric trials.” The authors quoted from Marcia Angell’s 2008 article for JAMA, “Industry-sponsored clinical research: A broken system,” where she said:

Over the past 2 decades, the pharmaceutical industry has gained unprecedented control over the evaluation of its own products. Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer.”

Amstersdam, McHenry and Jureidini, the authors of “Industry-corrupted psychiatric trials,” noted it was common knowledge that pharmaceutical companies “laundered” their promotional efforts through medical communications companies that “ghostwrite articles and then pay academic consultants to sign on to the fraudulent articles.”

The firms set up advisory board meetings with key opinion leaders and marketing executives in advance of the clinical trials. Once a trial is complete, the medical ghostwriter who is employed by the medical communications firm produces a draft of a manuscript – from a summary of the Final Study Report of the clinical trial – and seeks feedback from the corporate sponsor. It is at this stage in the manuscript production that misrepresentation of the trial data frequently occurs, since the medical ghostwriter is under the direction of marketing executives to “spin” the data. The medical ghostwriter then revises a number of drafts with input from the external academic “authors” and internal industry scientists, and once the corporate sponsor is satisfied that the final manuscript draft is “on message,” it is submitted by a corporate-designated lead author to a medical journal for peer review. Once the manuscript is submitted, the medical ghostwriter disappears or is acknowledged in the fine print for “editorial assistance.”

As a result, ghostwriting by the pharmaceutical industry has become a major factor in the “crisis of credibility” in academic medicine. “The integrity of science depends on the trust placed in individual clinicians and researchers and in the peer-review system which is the foundation of a reliable body of knowledge.” If academics allow their names to appear on ghostwritten articles, “they betray this basic ethical responsibility and are guilty of academic misconduct,” according to Amstersdam, McHenry and Jureidini. Ghostwriting extends to include an academic façade for research “that has been designed, conducted and analyzed by industry.” Yet the vast majority of ghostwritten publications won’t be revealed as such.

Key opinion leaders (KOLs) or “thought leaders” are academic physicians who are carefully vetted by the industry on the basis of their receptivity to the sponsor’s products. Pharmaceutical companies say they have engaged these KOLs for expert evaluation and feedback on marketing strategy. However, they essentially are highly paid “product champions” or marketers. “Few physicians and psychiatrists can resist the flattering offer by industry to become KOLs.” Medical journals are noted to be part of the problem here as well.

Medical journals are part of the problem rather than the solution to the problem. Instead of demanding rigorous peer review of a submissions and an independent analysis of the data, medical journal editors are pressured to publish favorable articles of industry-sponsored trials and rarely publish critical deconstructions of ghostwritten clinical trials. As medical journals and their owners have become dependent upon pharmaceutical revenue, the journals fail to adhere to the standards of science. Thus the publication of “positive” studies showing drug safety and effectiveness means more pharmaceutical advertising and more orders of reprints for dissemination by the sales force. In contrast, a “negative” study showing poor tolerability or ineffectiveness results in no such revenue.

“Industry-corrupted psychiatric trials” then went on to deconstruct how three studies, “SmithKline Beecham Paroxetine Study 329,” “Forest Laboratory Citalopram Study CIT-MD-18” and “SmithKline Beecham Paroxetine Study 352” all manipulated or misrepresented outcome data. The first two to support the use of the SSRI antidepressants paroxetine (Paxil) and citalopram (Celexa) for the treatment of childhood and adolescent depression. The third study, “Paroxetine Study 352,” misrepresented and manipulated outcome data in adults diagnosed with bipolar affective disorder. Morrill said: “Misconduct of this study was revealed when academics filed complaints of plagiarism and research misconduct against KOLs at medical research universities across the U.S. as well as pharmaceutical company executives.”  Read the review article for further details on how these three research studies were deconstructed to reveal how they manipulated or misrepresented outcome data.

In closing, let me remind you again of the opinion of Marcia Angell, former editor of the NEMJ:

It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. . . . Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer.

01/24/17

Herding Pharma “Cats”

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The Chinese government released a report in September of 2016 by the State Food and Drug Administration (SFDA) that found fraudulent clinical trial practices on a massive scale. The SFDA concluded that over 80% of clinical trial data was fabricated. The scandal was the result of a “breach of duty by supervision departments and malpractice by pharmaceutical companies, intermediary agents and medical staff.” More than 80% of the applications for the mass production of new medications have been cancelled, with warnings by the SFDA that further evidence of malpractice might still emerge.

Radio Free Asia also reported the SFDA indicated much of the clinical trail data was incomplete at best. But it also failed to meet basic analysis requirements or was untraceable. “Some companies were suspected of deliberately hiding or deleting records of adverse effects, and tampering with data that did not meet expectations.” Apparently, this came as no surprise to industry insiders. “Clinical data fabrication was an open secret even before the inspection.”

Many of the new drugs were combinations of existing ones. Clinical trial outcomes were written beforehand, and their data presented so it agreed with the fabricated outcomes. A doctor at a top Chinese hospital said the problem lay with the failure to implement regulations governing clinical trial data. “Guangdong-based rights activist Mai Ke said there is an all-pervasive culture of fakery across all products made in the country.” Reporting for Pharmafile, Ben Hargreaves said:

The root of the issue is then not regulation, with regulation for clinical trials running on similar lines to Western practises, but in the lack of adherence to them. China’s generic drug industry has struggled with quality problems and therefore there is a temptation for companies to manipulate data to meet standards. The report found that many of the new drugs were found to be a combination of existing drugs, with clinical trials outcomes written beforehand and the data tweaked to fit in with the desire outcomes.

Sadly, clinical trial problems are not unique to China. An editorial published in the British journal The Lancet Psychiatry described multiple issues beginning with how subjects are recruited, moving on to determining what the control group should be, and ultimately defining meaningful outcome measures. Sometimes, trial recruits receive “care” they didn’t agree to. “Researchers and ethics review boards need to examine the ethical arguments and practical procedures from other areas of medicine where consent is problematic.” If such trials are done, regular and rigorous monitoring is essential. Patient safety and autonomy needs to be a priority.

In his discussion of the editorial, Justin Carter elaborated on one of the problems with recruiting subjects. An individual was recruited into a study on three antipsychotics while under a forced commitment order from a judge. “The psychiatrist who recruited him was in charge of the study and was his treatment provider and was also empowered to report on the patient’s progress to the judge.” The individual died by suicide during the drug trial.

The work of Irving Kirsch and others has shown the problem with inert placebos (sugar pills). The side effects from medication make it easy for participants to guess which study group they are in.

And when the trial is over and the data in, do the outcome measures really provide something meaningful for people’s lives? If the ultimate goal is for people to fell better and resume their prior level of functioning, should outcome measures by primarily patient self-reports, clinical assessment, or differences shown by imaging or the as-yet-to-be-clearly-identified biomarkers?

Given the problems running and interpreting psychiatry trials, it is essential to learn how even the most successfully tested interventions work in real clinics with the broad patient population. Implementation, uptake, and effectiveness in real-life settings must be analysed, and delivery of new innovations modified accordingly. Future research should be thought of not as a plain linear process from innovation to trial to implementation, but as a virtuous circle where research feeds into the clinic and vice versa.

Another issue pointed to by Carter was the validity and reliability of the diagnosis or classification system used to determine who to include and who to exclude from the trials. The DSM system, now in its fifth edition (DSM-5), is the current “bible” for assessing and diagnosing problems the psychiatric medications in clinical trials are supposed to “treat” in the U.S. Yet there have been questions about the reliability and validity of the DSM dating from an argument raised by Robert Spitzer and others in the 1970s that ushered in changes still embedded in the DSM-5. Rachel Cooper gave a brief history of the reliability questions with the DSM in “How Reliable is the DSM-5?” You can also refer to “Psychiatry Has No Clothes,” “Where There’s Smoke …”, and  “The Quest for Psychiatric Dragons,” Parts 1 and 2.

A few weeks before the release of the DSM-5, Thomas Insel, then the NIMH Director, announced the NIMH would be “reorienting” its research away from DSM categories. The agency’s new approach is called the Research Domain Criteria (RDoC) project. For now, RDoC is a research framework and not a clinical tool. But NIMH has high hopes for it: “RDoC is nothing less than a plan to transform clinical practice by bringing a new generation of research to inform how we diagnose and treat mental disorders.” While Tom Insel has moved on to work for Alphabet (Google), RDoC is alive and well within NIMH. You can keep up with news about RDoC on the “Science News About RDoC.”

The Science Update for February 16, 2016 noted the March 2016 issue of the journal Psychophysiology would be devoted to the RDoC initiative. Dr. Bruce Cuthbert said the special issue was a unique opportunity for researchers to engage with one another and reflect on work being done in various laboratories throughout the country. He thought it was encouraging to see many investigators already engaged in the kind of work RDoC advocates. “What this shows is that while the RDoC acronym may be new, the principles behind RDoC are certainly not new to psychiatric research.”

If the principles behind RDoC are not new to psychiatric research, how can it bring “a new generation of research to inform how we diagnose and treat mental disorders” in order to transform clinical practice? It sounds a lot like using the same deck of cards to just play a new card game. RDoC may not be the transformative framework it’s touted to become.

Added to these issues is the failure of pharmaceutical companies to publically report the results of clinical trials, as they are required by law to do. New reporting rules will take effect on January 18, 2017. But advocates for transparency in clinical research have cautioned the success of the new rules will depend upon the willingness and vigor of government enforcement of those rules. The failure to enforce the existing rules, which went into effect in 2008, led to widespread noncompliance with reporting requirements. If the FDA had fined the violators, they could have collected an estimated $25 billion.

Reporting for STAT News, Charles Piller said studies have indicated only a small fraction of trials will comply with the law. Yet there are no current plans to increase enforcement staffing at the FDA and NIH. That’s a big problem, according to Ben Goldacre, an advocate for full disclosure in clinical research. Francis Collins, the NIH director said they are serious about this and will withhold funds, if needed. “It’s hard to herd cats, but you can move their food, or take their food away.”

The legislation that created ClinicalTrials.gov emerged from numerous cases of drug manufacturers withholding negative trial results, making drugs look more effective and less harmful. Efforts to market the antidepressant Paxil for teenagers more than a decade ago stimulated the push for better reporting. A recent analysis in the journal BMJ found that GlaxoSmithKline, Paxil’s manufacturer, failed to disclose 2001 data showing the drug to be no more effective than a placebo, and was linked to increased suicide attempts by teens.

Writing for Time, Alexandra Sifferlin reported on a new study that suggested many of the medical reviewers for the FDA go to work for the drug companies they oversaw while working for the government. One of the study’s authors said: “I don’t think there is overt collusion going on, but if you know in the back of your mind that a major career opportunity after the FDA is going to work on the other side of the table, I worry it can make you less likely to put your foot down.”

Returning to the Francis Collins metaphor, it seems that the willingness to try and herd Pharma cats is dependent on whether or not you are afraid they will scratch you in the attempt.

12/2/16

Pharma and Advertising

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© Maksim Kabakou | 123rf.com

The FDA recently held public hearings on the off-label advertising of approved medications and medical devices on November 9 and 10, 2016. “FDA is engaged in a comprehensive review of its regulations and policies governing firms’ communications about unapproved uses of approved/cleared medical products, and the input from this meeting will inform FDA’s policy development in this area.” There were specific questions asked at the hearing, but the FDA was also interested in “any other pertinent information participants would like to share.” If you weren’t able to be in Maryland for the hearing, electronic or written comments will be accepted until January 9, 2017. A videotape of the hearing will be available for one year afterwards.

Your initial reaction may be one of “Boring!” That is unless you are aware of the crossroads we are approaching with regard to the off-label advertising of medications and medical devices. On March 8, 2016, the FDA made a settlement agreement with the pharmaceutical company Amarin that allows the company to promote its drug Vascepa for off-label use. What is this important breakthrough medication? Vascepa is prescription strength fish oil. This action was the outcome of a struggle between Amarin and the FDA going back several years.

Amarin wanted to widen the population for whom they could recommend Vascepa to include patients with different cardiovascular diseases—patients other than what Vascepa was initially approved to treat. But the FDA ruled against their request. Amarin’s stock price took a nosedive. Concerned with how their investors were reacting, the company fought back by suing the FDA. Then in August of 2015, a judge ruled that Amarin could market its drug to the broader population. He also ruled the company could claim that Vascepa “may reduce the risk of coronary heart disease.” This was despite the fact that the FDA had called the claim misleading, as there was “supportive but not conclusive research” to that effect.

Amarin successfully argued that it had a First Amendment right to market its drug for a broader patient group, “despite the lack of regulatory approval and the lack of evidence of an outcomes benefit for patients.” Justin Karter noted how the FDA settlement strikes at the heart of the drug regulatory system in the U.S. Amarin argued that companies should have the right to market their products consistent with what “a judge would consider to be neither false or misleading.” Be clear on what Amarin was saying. A judge, not the FDA, should rule on whether or not the marketing claims by a pharmaceutical company for their product were truthful and not misleading.

Amarin argued that this system is unconstitutional, and that companies should instead be allowed to market their products in any way that a judge would consider to be neither false nor misleading.

Commenting on the FDA settlement agreement in Amrain Pharma v. U.S. Food & Drug Administration, lawyer and mental health advocate Jim Gottstein said he thought that for all practical purposes, the FDA ban against off-label promotion of drug companies was dead. He noted that the ruling in the Amarin case was based upon a 2012 decision in Unites States v. Caronia that reversed a criminal conviction for off-label promotion.

In light of the settlement I think it is fair to ask where things stand with the FDA’s enforcement of its ban against off-label promotion and Department of Justice prosecutions of drug companies for off-label promotion leading to false claims.  I think the ban against off-label promotion is dead for all practical purposes.  The FDA could try and get a different ruling in another circuit and, if successful, ask the Supreme Court to rule, but since it didn’t ask the Supreme Court to take the case in Caronia, it doesn’t seem likely that it has any intention of trying to overturn Caronia. This will give the drug companies free rein for off-label promotion.  Of course, anything that is false or misleading is still grounds for charges, but that is a far harder case to make.

So if this is the supposed future for off-label drug advertising unless there is some radical change by Congress, let’s now take a look at the past—what has been taking place under the existing FDA rules. In his book Saving Normal, Allen Frances published a chart that he called the drug company “hall of shame.” Prepared by Melissa Raven, PhD, it listed the fines and settlements by Pharma companies for off-label promotion, marketing and fraudulent misbranding of 20 well know pharmaceuticals.

Here is a sampling of the companies and their total fines and settlements between 2004 and 2012 recorded in the Saving Normal chart. The fines and settlements listed below combine both civil and criminal cases. Johnson & Johnson ($1.44 billion); GlaxoSmithKline ($3 billion); Abbott ($1.5 billion); Novartis ($422.5 million); Forrest ($313 million); AstraZeneca ($520 million); Pfizer ($2.3 billion); Eli Lily ($1.415 billion); Bristol-Myers Squibb ($515 million); Purdue (almost $635 million). I think it’s clear why Pharma is going after the FDA. The sum total in fines and settlements from the chart was $12.06 billion in fines and settlements between 2004 and 2012.

On March 31, 2016, the nonprofit organization Public Citizen published an updated analysis of all major financial settlements and court judgments between pharmaceutical companies and the federal and state governments. The time period covered by their analysis ran from 1991 through 2015 and included 373 settlements for a total of $35.7 BILLION. Financial penalties have declined sharply since 2013. The most striking decrease occurred with criminal penalties. “For 2012 and 2013 combined, criminal penalties totaled $2.7 billion, but by 2014-2015, the total had fallen to $44 million, a decrease of more than 98%.”

From 1991 through 2015, GlaxoSmithKline and Pfizer reached the most settlements—with 31 each— and paid the most in penalties, $7.9 billion and $3.9 billion respectively. Six additional companies, Johnson & Johnson, Merck, Abbott, Eli Lilly, Teva, Schering-Plough, Novartis, and AstraZeneca paid more than $1 billion in financial penalties. Six of the above eight were listed in the top 14 pharmaceutical companies by global sales in 2014. Thirty-one companies entered repeat settlements. Pfizer (11), Merck (9), GlaxoSmithKline, Novartis, and Bristol-Myers Squibb (8 each) finalized the most federal settlements. It seems these fines were simply the cost of doing business.

Financial penalties continued to pale in comparison to company profits, with the $35.7 billion in penalties from 1991 through 2015 amounting to only 5% of the $711 billion in net profits made by the 11 largest global drug companies during just 10 of those 25 years (2003-2012). To our knowledge, a parent company has never been excluded from participation in Medicare and Medicaid for illegal activities, which endanger the public health and deplete taxpayer-funded programs. Nor has almost any senior executive been given a jail sentence for leading companies engaged in these illegal activities. Much larger penalties and successful prosecutions of company executives that oversee systemic fraud, including jail sentences if appropriate, are necessary to deter future unlawful behavior. Otherwise, these illegal but profitable activities will continue to be part of companies’ business model.

Since the U.S. approved direct-to-consumer advertising of prescription drugs in 1997, there has been a dramatic increase in spending on pharmaceuticals. A New England Journal of Medicine study by Donohue, Cevasco and Rosenthal in 2007 found that spending on pharmaceutical promotions increased from $11.4 billion in 1996 to $29.9 billion in 2005. This was a 330% increase. Promotion to physicians was still the primary marketing strategy, but spending on direct-to-consumer advertising increased both in absolute terms and as a percentage of pharmaceutical sales.

Becker and Midoun recently published an article that investigated the effects of direct-to-consumer advertising (DTCA) on patient prescription requests in the Journal of Clinical Psychiatry. Of the 989 articles they initially identified, they read full-text reviews of 69 articles, but only found four that met their inclusion criteria for investigating the consequences of these ads on prescription rates and treatment quality. They conclusion was: “Findings suggest that DTCA requests are typically accommodated, promote higher prescribing volume, and have competing effects on treatment quality.” They called for methodlogically stronger studies to increase the confidence in their conclusions.

Reporting for Mad in America on the study, Justin Karter noted where the U.S. is only one of three countries globally that allows DTCA. He said the pharmaceutical industry spent $3.83 billion on DTCA in 2013 and $4.53 billion in 2014. He also noted that the American Medical Association (here) and the American Society of Health-System Pharmacists (ASHP) (here) have called for a ban on DTCA. The AMA Board Chair, Patrice Harris, commented that physicians were concerned with the negative impact of DTCA and the role marketing costs play in fueling escalating drug prices. “Direct-to-consumer advertising also inflates demand for new and more expensive drugs, even when these drugs may not be appropriate.” The ASHP approved a new policy at their 2016 meeting that would advocated for Congress to ban DTCA for prescription drugs and medication-containing devices.

Pharmaceutical companies have whittled away at existing FDA regulations that restrict direct-to-consumer advertising. And they seem to be poised to begin an era of DTCA that will massively overshadow what has already taken place under the existing rules. Healthcare organizations representing physicians and pharmacists in the U.S. have publically voiced their opposition to DTCA. Individuals and organizations have an opportunity to voice their concern for this practice, which is implicated in the rising cost of healthcare and medications. Congress also has an opportunity to enact new legislation that would eliminate this predatory marketing practice. But it will have to overcome the horde of lobbyists—more than there are members of Congress—and the $272,000 in campaign donations Pharma spent per member of Congress in 2015.

12/31/15

Medieval Alchemy

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© algolonline | 123rf.com

Three years after the publication of the fourth edition of the DSM in 1994, the US became the only country in the world to allow direct to the consumer advertising of pharmaceuticals. Now there’s New Zealand. Soon after the approval, pharmaceutical advertising was everywhere in the US. Over the next decade, from 1997 to 2007, drug companies tripled their spending on marketing. Everyday problems were being portrayed as unrecognized psychiatric disorders. The chair of the DSM-IV, Allen Frances, admitted they had failed to anticipate how easily their manual could be utilized to promote pharmaceutical sales. They were not able to stem the flood of “false demand” instigated by the marketing done by drug companies. “Within a few years, it was clear the drug companies had won and we had lost.”

We should have been far more active in educating the field and prospective patients about the risks of overdiagnosis. There should have been prominent cautions in DSM-IV warning about overdiagnosis and providing tips on how to avoid it. We should have organized professional and public conferences and educational campaigns to counteract drug company propaganda. None of this occurred to anyone at the time. No one dreamed that drug company advertising would explode three years after the publication of the DSM-IV or that there would be the huge epidemics of ADHD, autism, and bipolar disorder—and therefore no one felt any urgency to prevent them. . . . We missed the boat. (Allen Frances, Saving Normal, p. 74)

Frances said the evidence for this diagnostic inflation is clear. There has been a fortyfold increase in childhood bipolar disorder. Autism diagnoses have increased twentyfold. “Attention deficit/hyperactivity has tripled; and adult bipolar disorder doubled.” The result has been huge profits for the drug companies.

At the very top of the Pharma hit parade are the antipsychotics at a resounding $18 billion a year. Antidepressants produce a hardy $12 billion a year, despite the fact that many are now off  patent and sold in cheaper generic versions. Fifteen years ago, stimulants were a rounding error in drug company sales at a measly $59 million a year. Now with direct-to-consumer advertising and heavy marketing to doctors, sales have been juiced up to a hefty $8 billion a year. And because primary care doctors love to prescribe them, antianxiety agents are eight in sales among drug classes—even though they probably do much more harm than good. (Saving Normal, p. 105)

Patients regularly misdiagnosed themselves and asked their doctor for “the magic pill that would correct their chemical imbalance,” just as the advertisements suggested. And as requested, doctors prescribed the medications. “Patients who requested a drug they had seen advertised were seventeen times more likely to walk out of the office with a prescription.” Primary care physicians (PCPs), such as general practitioners, obstetrician-gynecologists and pediatricians, now prescribe most of the psychiatric drugs in the US.

Using data from August 2006 to July 2007, Ryan DuBosar noted in “Psychotropic drug prescriptions by medical specialty” that 59% of the psychotropic prescriptions were written by PCPs. Breaking down the drug by class, PCPs prescribed 37% of the antipsychotics, 52% of the stimulants, 62% of the antidepressants and 65% of the anxiolytics (anti-anxiety meds). Frances said: “Too often, drugs are used promiscuously in a way that approximates the quackish practice of medieval alchemists.”

On November 17, 2015, the American Medical Association (AMA) adopted a new policy that calls for a ban on direct to the consumer advertising of prescription drugs. The new policy calls for a physician task force and launching an advocacy campaign to promote prescription drug affordability.

The AMA Board Chair-elect, Patrice Harris, said the vote reflects concerns among physicians about Pharma’s commercially-driven promotions and the impact of marketing costs in escalating drug prices. She said direct-to-consumer advertising also created a demand for new and more expensive drugs, even when these drugs may not be appropriate. “Patient care can be compromised and delayed when prescription drugs are unaffordable and subject to coverage limitations by the patient’s health plan. In a worst-case scenario, patients forego necessary treatments when drugs are too expensive.”

Reporting for Reuters, Susan Kelly noted that the AMA did not say how the ban could be overturned. There have been a series of court decisions determining that the ads are a form of commercial speech protected by the U.S. Constitution. PhRMA, the largest trade group for the pharmaceutical industry in the US, said the ads increase consumer awareness of available treatments for diseases. PhRMa spokesperson, Tine Stow said: “Providing scientifically accurate information to patients so that they are better informed about their health care and treatment options is the goal of direct-to-consumer pharmaceutical advertising about prescription medicines.” REALLY?

Allen Frances said that Big Pharma seems to feel it is above the law. “Almost all of the companies have absorbed huge fines and even criminal penalties as punishment for their illegal sales practices. He published a chart in Saving Normal that he referred to as the drug company hall of shame. It contained information on fines and settlements by Pharma for off-label promotion (which is illegal at this time) as well as shady marketing and fraudulent misbranding. The sum total of the fines between 2004 and 2012 was $12.06 billion.

Yet a Pharma company has been in court attempting to assert that it has “a constitutional right to share certain information about its products with doctors.” The drug companies have been increasing their pressure on the FDA to relax its guidelines around off-label marketing. See “Pharma Goes to Court” for more on this issue.

Frances said it is our fault that we allowed drug companies to prey on our weakness. “Diagnostic questions should be decided by what is best for the patient, not what is best for the doctor or the APA [American Psychiatric Association] or Pharma or the consumer group.” All this could be reversed if we had the political will to do so. He proposed fourteen ways to tame Pharma. The top six were:

  • No more direct-to-consumer advertising on TV, in magazines, or on the internet.
  • No more drug company-sponsored junkets, dinners, promotional gifts, or continuing medical education for doctors or medical students.
  • No more financial support for medical professional organizations.
  •  No more beautiful salespeople congregating in the doctors’ waiting room.
  • No more free samples.
  • No more off-label marketing.

These changes strike at the heart of Pharma’s marketing strategy, so it won’t be easy to get Congress to approve the changes. Pharma outspends all other industries in its lobbying efforts. Since 1998, the pharmaceutical industry has spent $3,716,474,293 lobbying Congress. In 2017 Pharma has spent $209,395,967. Annually they outspend all other industries. See OpenSecrets.org for more information on this issue. The OpenSecrets data was updated to reflect spending since this article was originally published in 2015.

07/29/15

Pharma Goes to Court

© Satori | 123RF.com

© Satori | 123RF.com

Okay, stay with me on this one. I want to talk about some jousting going on in the court system between Pharma and regulatory agencies, like the FDA. Amarin Corporation is suing the FDA, saying that the FDA violated its first amendment rights to free speech. The company argued that it has “a constitutional right to share certain information about its products with doctors.” Lawyers for the company believed this was the first time a manufacturer has sued the agency before the FDA ruled against them. The future “blockbuster” at the center of this fight is an omega-3 fatty acid product derived from fish called Vascepa. That’s right prescription strength fish oil.

As a matter of fact, according to Katie Thomas of The New York Times, Vascepa is the only existing product for Amarin. The FDA approved Vascepa for patients with extremely high levels of triglycerides, which are linked to heart disease. When the company sought to expand the drug’s approved reach to individuals with severe levels of triglycerides, the FDA denied its request. Lawyers for the company claim the company is not trying to market Vascepa to a wider population of patients than it was approved for, which is illegal. Amarin merely wants to make statements about its product that manufacturers of fish-oil supplements make—namely that there is “supportive but not conclusive research” that shows fish oil products like Vascepa may reduce the risk of coronary hear disease.

A lawyer for Amarin pointed out where doctors are already prescribing Vascepa off-label, which is legal for doctors to do once the FDA approves a drug for any purpose. “Those doctors who are already prescribing off-label need more information, not less, about what their treatment options are.” John Sullivan said on Drug and Device Law, that the content of Amarin’s supporting brief was convincing. In addition to the “truthful, non-misleading statements it wants to provide to healthcare workers, it wants to provide the results of its ANCHOR clinical trial and other peer-reviewed articles on the connection between the active ingredient in Vascepa and coronary risk.

But is all this legal dancing around just about the right of a relatively small biopharmaceutical company to make the same claims about its prescription drug that dietary supplement companies can make about their fish oil products?

Toni Clarke, writing for Reuters, noted where drug companies have been increasing their efforts to pressure the FDA to relax its guidelines since a 2012 decision  (2-1) from the Second Court of Appeals overturned the conviction of a sales representative for Orphan Medical, who was caught talking to physicians about off-label uses for the narcolepsy drug, Xyrem. The court said truthful and non-misleading off-label “speech” was protected by the First Amendment. “Pharmaceutical companies are citing the Caronia and similar rulings to pressure the FDA to let them talk more freely about off-label use.”

A coalition of pharmaceutical companies known as the Medical Information Working Group has petitioned the FDA to “’adequately justify and appropriately tailor its regulatory regime in light of Caronia and similar rulings.” This coalition includes Pfizer, Sanofi, Novartis AG, Johnson & Johnson, Eli Lily and Co., GlaxoSmithKline, Purdue Pharma, and Bayer Healthcare Pharaceuticals. What’s at stake is the right of manufacturers to attempt to persuade physicians to use their products for unapproved uses. This would be a potentially serious weakening of the FDA’s regulatory authority. Oh, and it could mean billions of dollars in potential sales for Pharma.

The FDA sent a letter to Amarin, essentially saying that it did not have concerns with most of the information Amarin proposed to communicate to doctors. The FDA pointed to existing guidance documents that indicated Amarin could distribute the results of its ANCHOR clinical trial results through peer-reviewed articles. Further, it said Amarin could communicate summaries of those trail results, but not in marketing materials or through sales reps.

Then on June 23, 2015, the FDA filed its brief in response to Amarin’s Motion for Preliminary Injunction. The brief called the lawsuit a frontal assault on the framework for new drug approval, rather than a narrower as-applied constitutional challenge. Lisa Baird, writing for ReedSmith, further noted where the FDA felt that if successful, the Amarin litigation “has the potential to establish precedent that would return the country to the pre-1962 era when companies were not required to prove that their drugs were safe and effective for each of their intended uses.”

At the heart of the matter is the distinction made by the FDA between drugs and dietary supplements. The FDA brief noted that Amarin ignored “the critical reality that drugs present markedly different considerations from dietary supplements.” After citing several legal rulings in support of this claim, the FDA said that Amarin wanted to market Vascepa as a drug intended to treat patients who are already being treated with statins, but continue to be at risk for cardiovascular disease. “Yet, FDA has found on multiple occasions that the heart disease claim did not meet the statutory standard of significant scientific agreement as the claim is based on ‘less persuasive studies.’” The potential harm posed by drugs is presumably much greater than that posed by dietary supplements.

These considerations amply justify a more cautious approach to drug approval and promotion, and the applicable statutory scheme recognizes this necessity. Unlike drugs, there is no statutory requirement of premarket approval for dietary supplements to be distributed. See 21 U.S.C. § 301 et seq. In addition, as a result of Pearson, claims about dietary supplements are held to a much lower standard (credible evidence) than the robust evidentiary requirement for drugs (substantial evidence) or the intermediate standard that FDA applies to reprints. See 21 U.S.C. § 355(d) & (e); Woodcock Decl. ¶¶ 31-32. Unlike for drug claims, qualified health claims “can be made [for dietary supplements and foods] under some circumstances even when the weight of the scientific evidence is against the claim, provided there is some credible evidence supporting it.” Woodcock D ecl. ¶ 33. Indeed, the June 5 Letter advised Amarin that if it “were to repackage and re-label [its] product as a dietary supplement” and ensure that other relevant conditions were met, “FDA would not object to your inclusion on that dietary supplement of the” heart disease claim. June 5 Letter at 10. Plaintiffs thus conflate two separate regulatory regimes and seek to make Amarin subject only to the aspects of each regime that it finds convenient—an approach that is unsupported by law and contrary to logic and sound public health policy.

This is an important and potentially a serious game changer in FDA attempts to protect the public from the growing evidence of the harmful marketing tactics of Pharma. This jousting between Amarin and the FDA is taking place in the context of the recent approval of “The 21st Century Cures Act,” which was unanimously approved by the House Energy and Commerce Committee on May 21, 2015. Toni Clarke reported that language in the bill adds pressure on the FDA to relax its guidelines.

Allen Frances, in his book Saving Normal, published a chart that he called the drug company “hall of shame.” Prepared by Melissa Raven, PhD, it listed the fines and settlements by Pharma companies for off-label promotion, marketing and fraudulent misbranding of 20 well know pharmaceuticals. Most of the companies noted above who are part of the Medical information Working Group were listed there. Here are the companies and their total fines and settlements between 2004 and 2012 recorded in the table in Saving Normal. The fines and settlements combine both civil and criminal cases. Johnson & Johnson ($1.44 billion); GlaxoSmithKline ($3 billion); Abbott ($1.5 billion); Novartis ($422.5 million); Forrest ($313 million); AstraZeneca ($520 million); Pfizer ($2.3 billion); Eli Lily ($1.415 billion); Bristol-Myers Squibb ($515 million); Purdue (almost $635 million). I think it’s clear why Pharma is going after the FDA. The sum total in fines and settlements from the chart was $12.06 billion between 2004 and 2012.

The FDA announced that it plans to hold a public meeting this summer to address drug company concerns with restrictions on what they can say about off-label use of drugs. But as of the beginning of July, I could find no indication of a set date and time for the public meeting. Perhaps the FDA decided to delay scheduling the meeting until there was an indication what would happen with the 21st Century Cures Act. They may also want to see further reaction to its June 23, 2015 brief filed in response to Amarin’s Motion for Preliminary Injunction.

If I wanted to build case law precedents to justify my constitutional right to share certain information about my pharmaceutical products with doctors, I think I’d first try to have the courts rule in favor of a product like pharmaceutical grade fish oil. It’s already sold as a dietary supplement and there are hardly any known side effects. If successful, I’d build on it and the Caronia case by filing additional litigation in an attempt to cut off the FDA regulations against off-label promotion and marketing of pharmaceuticals at the knees.