In the following piece, Max Fenrir details FDA failures to regulate opioid manufacturers, a lack and adequate and well-controlled clinical trials, and poor management of conflicts of interest between FDA staff and industry.

A country ruined by lack of oversight.
Photo: APO

THE OPIOID CRISIS

In the United States, opioid use disorder (OUD) and opioid overdose were once rare. But over the past 25 years, the number of Americans suffering from OUD increased exponentially and in parallel with an unprecedented increase in opioid prescribing.¹

OUD become a serious problem just a few years ago, especially in patients with chronic pain treated with opioid analgesics,¹. Opioid overdose was the leading cause of accidental death.²

The high prevalence of OUD led to an array of health and social problems. The United States saw record high rates of neonatal opioid withdrawal syndrome, more children entering foster care,³ rising heroin and fentanyl use,⁴ outbreaks of injection-related infectious diseases,⁵ and a decline in workforce participation in areas with relatively high rates of opioid prescribing.⁶

The Centers for Disease Control and Prevention (CDC) aptly described the crisis as the “worst drug overdose epidemic in [US] history.”¹

Using the term ‘epidemic’ to describe the sharp increase in OUD and overdose deaths is appropriate. However, unlike communicable disease outbreaks, the opioid crisis was not caused by a pathogen.

As a federal judge presiding over hundreds of county and state cases against opioid manufacturers and distributors found during his investigations: “It is accurate to describe the opioid epidemic as a man-made plague, 20 years in the making.”⁷

Much of the responsibility for the opioid crisis rested with the pharmaceutical industry’s promotion of aggressive opioid prescribing.

In a first-of-its-kind trial against opioid manufacturers, a state court in Oklahoma in 2019 found that the “exponentially increasing rates of addiction,” “overdose deaths,” and babies born exposed to opioids were caused by “false, misleading, and dangerous marketing campaigns” for medications.⁸

But the fact that opioid manufacturers disseminated false claims regarding the risks and benefits of opioids for the past 25 years points to a dereliction of duty by the US Food and Drug Administration (FDA)—the federal agency charged with regulating pharmaceutical companies.

Until these past mistakes are understood and corrected, the United States remains vulnerable to a real health crises via means of pharma deception — caused by inadequate regulation of companies.

NO ENFORCEMENT OF MARKET REGULATIONS

The Food, Drug, and Cosmetic Act requires drug manufacturers to demonstrate that their products are both “safe and effective” before they are marketed.¹³ The benefits of a drug must outweigh potential risks for specific indications listed on an FDA-approved label.¹³

However, the FDA’s regulatory failures with respect to opioids paints a very different picture.

In 2017, the President’s Commission on Combatting Drug Addiction and the Opioid Crisis found that the opioid crisis was caused in part by “inadequate oversight by the Food and Drug Administration,” and the National Academy of Sciences (NAS) publicly called on the FDA to overhaul its opioid policies.^9, 10

The agency has adopted a defensive posture and sought to shift blame for the crisis for years.

In response to a critical letter from Senator Maggie Hassan of New Hampshire, the FDA’s top official at the Center for Drug Evaluation and Research offered a blanket defence of their handling, claiming that the agency has properly enforced the Food, Drug, and Cosmetic Act.¹²

However, FDA did not properly enforce the Food, Drug, and Cosmetic Act when it approved Purdue Pharma’s new drug application for extended-release (ER) oxycodone in 1995.

Had it done so, ER oxycodone’s label would have had a narrow indication for the specific conditions for which the benefits of ER oxycodone outweigh the risks, such as relief from severe pain from a life-limiting illness.

Instead, the label on ER oxycodone featured a broad indication,¹⁴ allowing Purdue to promote the drug’s use for common conditions for which opioids are more likely to harm than help, such as low-back pain and fibromyalgia.

As Purdue earned billions of dollars from sales of oxycodone, other drug companies took note.¹⁵

They introduced their own opioids and joined Purdue in funding a brilliant, multifaceted campaign that changed the culture of opioid prescribing in the United States.

Clinicians who previously understood that opioids are addictive, that development of tolerance results in dose escalation, and that dependence would make discontinuation difficult began hearing from spokesmen for opioid manufacturers that addiction was rare and that long-term use was safe and effective.1^{, 6, 7, 8, 9, 10, 11, 12, 13, 15}

Risks were minimized, benefits were exaggerated, and opioid prescribing surged.

In 2002, faced with evidence that opioid prescribing had risen beyond levels that could be clinically warranted, the FDA convened an advisory committee meeting of 10 outside experts and asked if the broad indication on opioid labels should be narrowed to prohibit marketing for common chronic pain conditions.¹⁶

Eight of these experts had financial ties to pharmaceutical companies, including Purdue,¹⁶ and advised the FDA against narrowing the indication.¹⁷ An opportunity to reign in overprescribing early in the crisis was lost, and, by 2013, enough opioids were prescribed to provide every adult in the country with a full pill bottle.¹⁸

A former FDA Commissioner rebuked the agency he had previously led, saying that the FDA was wrong to allow promotion of opioid use for chronic pain.¹¹

Despite this mounting criticism, FDA policies for approving and labelling opioids remain largely unchanged. The FDA has not undertaken a root cause analysis of its regulatory errors that contributed to this public health catastrophe, let alone instituted any major reforms.¹¹

DID NOT OBTAIN EVIDENCE OF LONG-TERM SAFETY AND EFFECTIVENESS

Marketing opioids as safe for long-term use is at odds with a growing body of medical literature, dating from the 1950s,¹⁹ which demonstrates serious dose-dependent risks, including addiction, respiratory depression, neuroendocrine dysfunction, and other medical problems.²⁰

Even in safety trials for opioid drugs approved by the FDA, serious adverse events—including respiratory depression, death, and drug diversion—are common.^21, 22

And, despite evidence that as many as 41% of patients on long-term opioids meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for OUD,²³ drug companies are not required to assess clinical trial subjects for development of OUD at the conclusion of a study.

Here is where things get concerning.

The Food, Drug, and Cosmetic Act requires “adequate and well-controlled studies” before products can be approved and promoted as safe and effective.¹³

The FDA generally requires at least 2 randomized controlled trials demonstrating clear efficacy for a proposed indication.²⁴ Yet, it approved extended release oxycodone based on only one adequate and well-controlled study. This was a 2-week clinical trial in osteoarthritis patients.²⁵

No long-term effects studied.

The FDA’s failure to obtain adequate evidence of effectiveness was not limited to oxycodone.

Over the past 25 years, despite mounting evidence that a surge in opioid consumption was resulting in adverse public health consequences, the FDA continued to approve new opioid formulations for chronic pain based on efficacy trials utilizing a controversial methodology called enriched enrolment randomized withdrawal (EERW).²⁶

Since its 2006 approval of oxymorphone, the FDA has relied on EERW as evidence of opioid efficacy for chronic pain.²⁷ EERW trials differ from traditional double-blind, randomized, controlled studies.

In an EERW trial, prior to randomization for a double-blind phase, all subjects are made physiologically dependent on the opioid in a 4-to-6 week open-label phase.

Then, only the patients who tolerated the opioid and found it helpful during the open-label phase are ‘randomized’ to remain on the opioid or switch to a placebo.

Critics of EERW have correctly described this methodology as “cooking the books” for 2 reasons.²⁸

First, because only patients who tolerated the opioid and found it helpful are allowed to proceed to randomization, the study is not representative of the general population, and the results cannot be generalized to clinical practice.

Second, because daily use of opioids causes physiological dependence, efficacy results are skewed in favor of the subjects who remain on the opioid.

This is because opioid-dependent subjects who are switched to placebo experience opioid withdrawal symptoms, including increased sensitivity to pain. Moreover, switching opioid-dependent subjects to placebo renders the study not truly double-blind.

The FDA’s decision to rely on EERW trial methodology is a consequence of the agency’s close ties to industry. In fact, the FDA’s decision to use EERW for analgesics was based on discussions at private meetings between FDA officials and pharmaceutical company executives hosted by an organization called Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT).²⁹

Drug companies paid up to $35 000 each for the opportunity to attend IMMPACT meetings and interact with FDA staff.²⁹

Yet, despite the uproar that followed public disclosure of the IMMPACT meetings, the FDA continues to rely on EERW trials as evidence that opioids are effective for chronic pain.²⁶

FAILURE TO MANAGE CONFLICTS OF INTEREST

The FDA has never been held to account for its improper handling of the opioid crisis.

But the FDA’s conduct is all the more troubling in light of the close relationship between the agency officials responsible for opioid oversight and opioid manufacturers.

For example, the 2 principal FDA reviewers who originally approved Purdue’s oxycodone application both took positions at Purdue after leaving the agency.¹¹

Over the past 20 years, several other FDA staff involved in opioid approvals also left the FDA to work for opioid makers.

In 2019, the head of the FDA’s analgesic division retired from the FDA to start her own consulting business, which promises drug makers “help” to “successfully and efficiently bring your products to market” with “more than 30 years of experience at the FDA.”³⁰

All a business in motion.

To be clear, the revolving door between the FDA and the pharmaceutical industry is not limited to opioids.

A 2018 study found that 11 of 16 FDA medical reviewers involved in approving 28 products now work for the companies whose products they regulated.³¹

Without appropriate limits on employment after leaving the FDA, staff might be tempted to put the interests of future employers, whose favour they wish to gain, ahead of public health.

This is where we need to examine the current vaccine rollout for coronavirus.

HISTORY REPEATING?

Does all of this sound a little too familiar to you?

A lack of long-term analysis of effectiveness or impact?

‘Cooking the books’ for short-term safety and efficacy studies?

Conflicts of interest between manufacturers and board members?

The world is rejoicing at the fact the U.S. Food and Drug Administration has finally approved the Pfizer-BioNTech coronavirus vaccine for use in people 16 and older on Aug. 23.

Describing FDA approval as “the gold standard,” U.S. President Joe Biden, heralded the moment as “a key milestone in our nation’s fight against COVID.”

Scott Gottlieb, who served as the 23rd Commissioner of the FDA from 2017 until April 2019 — at the height of the opioid crisis — joined the board of Pfizer right after his departure.

He remains a member of the board of directors during COVID-19 vaccine manufacturing.

Let that sink in for a second.

Will we see the same regulatory failures during the current ‘crisis’?

The opioid health epidemic — just barely out of the minds of millions in the United States — should be a stark reminder to always question the motives and agenda of the FDA behind the scenes.

As history has shown us, their words can barely be trusted.

By Max Fenrir

Max is a retired medical researcher from Columbia University School of Public Health.

Max has a new Twitter account here.

REFERENCES

The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction.
View Article – PubMed – Google Scholar
National Safety Council Injury Facts. Preventable deaths: odds of dying.
https://injuryfacts.nsc.org/all-injuries/preventable-death-overview/odds-of-dying/data-details/.
Trends in infants reported to child welfare with neonatal abstinence syndrome (NAS).
View Article – Google Scholar
Trends in deaths involving heroin and synthetic opioids excluding methadone, and law enforcement drug product reports, by census region—United States, 2006-2015.
View Article – PubMed – Google Scholar
Injection drug use, HIV/HCV, and related services in nonurban areas of the United States: a systematic review. View Article – PubMed – Google Scholar
Where have all the workers gone? An inquiry into the decline of the US labor force participation rate. Brookings Papers on Economic Activity Conference draft.
https://www.brookings.edu/wp-content/uploads/2017/09/1_krueger.pdf.
Feeley J. Opioid-industry claims proceed as judge cites “man-made plague.” Bloomberg News.
https://www.bloomberg.com/news/articles/2018-12-20/opioid-industry-claims-proceed-as-judge-cites-man-made-plague.
Hoffman J. Johnson & Johnson ordered to pay $572 million in landmark opioid trial. New York Times.
https://www.nytimes.com/2019/08/26/health/oklahoma-opioids-johnson-and-johnson.html.
The President’s Commission on combating drug addiction and the opioid crisis.
https://www.whitehouse.gov/sites/whitehouse.gov/files/images/Final_Report_Draft_11-1-2017.pdf.
Both urgency and balance needed in addressing opioid epidemic: a report from the National Academies of Sciences, Engineering, and Medicine.
View Article – PubMed – Google Scholar
Did the FDA Ignite the Opioid Crisis? 60 Minutes. CBS television.
https://www.cbsnews.com/video/opioid-epidemic-did-the-fda-ignite-the-crisis-60-minutes/.
Woodcock J; US Food and Drug Administration. Letter to Senator Margaret Hassan, United States Congress. January 21, 2020.
Innovation, regulation, and the FDA.
View Article – PubMed – Google Scholar
Purdue Pharma statement to 60 Minutes regarding the segment on opioid medicines expected to air Sunday, February 24, 2019.
https://www.purduepharma.com/news/2019/02/22/purdue-pharma-statement-to-60-minutes-regarding-the-segment-on-opioid-medicines-expected-to-air-sunday-february-24-2019/.
Prescription drugs: OxyContin abuse and diversion and efforts to address the problem.
http://www.gao.gov/new.items/d04110.pdf.
Rising painkiller addiction shows damage from drugmakers’ role in shaping medical opinion.
https://www.washingtonpost.com/business/economy/2012/12/30/014205a6-4bc3-11e2-b709-667035ff9029_story.html.
Center for Drug Evaluation and Research, US Food and Drug Administration. Meeting of the Anesthetic and Life Support Drugs Advisory Committee, January 30, 2002; Gaithersburg, MD.
Centers for Disease Control and Prevention. CDC guideline for prescribing opioids for chronic pain. https://www.cdc.gov/drugoverdose/pdf/guidelines_at-a-glance-a.pdf.
Rayport M. Experience in the management of patients medically addicted to narcotics.
View Article – PubMed – Google Scholar
The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop.
View Article – PubMed – Google Scholar
Patients overdosed on opioids in a clinical trial. Now Virginia is suing. Washington Post.
https://www.washingtonpost.com/news/powerpost/paloma/the-health-202/2020/02/10/the-health-202-patients-overdosed-on-opioids-in-a-clinical-trial-now-virginia-is-suing/5e3e1fc288e0fa0a47d9c6a3/.
New painkiller rekindles addiction concerns. New York Times.
https://well.blogs.nytimes.com/2014/04/21/new-painkiller-rekindles-addiction-concerns/.
Opioid-use disorder among patients on long-term opioid therapy: impact of final DSM-5 diagnostic criteria on prevalence and correlates.
View Article – PubMed – Google Scholar
Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012.
View Article – PubMed – Google Scholar
Purdue Pharma. Application summary: oxycodone hydrochloride controlled release tablets (OxyContin™ tablets). December 6, 1995.
“Unsettling circularity”: clinical trial enrichment and the evidentiary politics of chronic pain.
View Article – Google Scholar
American Overdose: The Opioid Tragedy in Three Acts.
View Article – PubMed – Google Scholar
Letter to FDA Commissioner Scott Gottlieb.
https://www.hassan.senate.gov/imo/media/doc/Hassan%20Letter%20to%20FDA.pdf.
Fauber J. FDA and pharma: emails raise pay-for-play concerns.
https://www.medpagetoday.com/painmanagement/painmanagement/42103.
Sharon Hertz LinkedIn page.
https://www.linkedin.com/in/sharon-hertz-7bb28a30/.
Piller C. Is FDA’s revolving door open too wide?
View Article – PubMed – Google Scholar
Opioid prescriptions dropped 12% in 2017 as guidelines change.
https://healthitanalytics.com/news/opioid-prescriptions-dropped-12-in-2017-as-guidelines-change.
Opioid therapy for chronic pain: overview of the 2017 US Department of Veterans Affairs and US Department of Defense clinical practice guideline.
View Article – PubMed – Google Scholar
Comparative Effectiveness Review Number 229: Opioid Treatments for Chronic Pain.
Google Scholar