Year in Review: Troubling New Drug Approvals in 2016

Of the new drugs approved by the Food and Drug Administration (FDA) in 2016,[1] Public Citizen’s Health Research Group has evaluated three. We found one to be ineffective and testified against approval for the other two—both opioid pain relievers—because of a lack evidence to support the manufacturers’ claims that they are less likely to be abused.

Eteplirsen: Do Not Use

The FDA approved eteplirsen (EXONDYS 51) in September for the treatment of a severe genetic muscle disease known as Duchenne muscular dystrophy (DMD).[2] The approval was based on three very small clinical trials involving a total of 25 subjects with DMD. FDA staff agreed that there were “[m]ajor flaws in both the design and conduct” of these trials.[3] Moreover, the trials found no meaningful improvement in subjects’ physical performance and only minuscule increases in their levels of the muscle protein that is deficient in DMD and that the drug is intended to boost. As a result, a team of FDA scientific experts concluded that the trials failed to provide substantial evidence that the drug is effective—the legal standard for approving new drugs since 1962—and recommended against approval of the drug.

Despite the overwhelming opposition to the approval of eteplirsen, the director of the FDA’s Center for Drug Evaluation and Research (CDER), Dr. Janet Woodcock, supported by then-FDA Commissioner Dr. Robert Califf, overruled the FDA’s scientific experts and decided to approve the drug. Woodcock’s decision to overrule so many agency experts represents a dangerous, unprecedented capitulation to pressure from politicians and patients and a stunning disregard of scientific evidence. Her action eviscerates the FDA’s long-standing (but, under Woodcock, already declining) approval standards for new drugs, threatens public health and demonstrates that she is unfit to serve as CDER director, a position she has held for almost 20 years.

New opioids: Limited Use

From 2000 to 2015, more than half a million people died of drug overdoses in the U.S.[4] Many of these were fatal opioid overdoses, which have quadrupled in the U.S. since 1999. President Barack Obama’s administration called the opioid abuse problem an “epidemic.”[5]

The driver of the epidemic has been the dramatic increase in the prescription of opioids for pain. Opioids were originally intended primarily for short-term treatment of severe pain following major trauma or surgery and for longer-term management of pain associated with terminal conditions, such as cancer. However, the drugs have been heavily marketed to physicians, and in some cases, the marketing misleadingly downplayed the drugs’ potential to lead to addiction[6] or pushed the drugs for “off-label” uses not approved by the FDA.[7] Such extensive, often illegal marketing helped fuel the widespread use of—and addiction to—opioids in the U.S.

In the wake of the epidemic, the drug industry began developing newer formulations of opioid medicines that they claimed would be more resistant to abuse. The idea behind these newer drugs was to prevent people from getting “high” from crushing in order to snort, or dissolving in order to inject, the drugs, which are intended to be taken orally.[8] However, it is doubtful that these drugs are sufficiently resistant to such tampering (see “Extended-release oxycodone-naltrexone” below). And the drugs can still be abused through oral use, as can older forms.

In 2009, the first supposedly “abuse-deterrent” opioid, EMBEDA—a new combination of the opioid morphine with another drug, naltrexone, intended to make it abuse-deterrent—was approved by the FDA.[9] Since then, there have been six others approved, including two in 2016.[10]

Extended-release oxycodone

In April, the FDA approved a new, purportedly abuse-resistant formulation of extended-release oxycodone (XTAMPZA ER), for severe, chronic pain, for which alternative treatment options are inadequate.[11] XTAMPZA ER capsules contain microscopic spheres with inactive ingredients intended to make the medication more difficult to manipulate and abuse. In two small studies evaluating the risk of abuse with XTAMPZA ER, subjects reported that the intact, chewed or inhaled XTAMPZA ER capsules were less desirable than the crushed non-abuse-deterrent version of oxycodone.[12] Subjects were less likely to want to inhale, but no less likely to orally abuse, XTAMPZA ER again, when compared with non-abuse-deterrent oxycodone.[13] Because no studies evaluated whether subjects were actually less likely to abuse the new formulation of extended-release oxycodone in real-world conditions, it is impossible, at this point, to know whether XTAMPZA ER will be abused less than other versions of oxycodone.

Extended-release oxycodone-naltrexone

In August, the FDA approved yet another supposedly abuse-deterrent opioid, extended-release oxycodone and naltrexone (TROXYCA ER) for severe, chronic pain.[14] TROXYCA ER is intended to be resistant to abuse when taken in a way other than orally ingesting the pill intact. When crushed, the naltrexone component of the medication is activated, blocking the effect of oxycodone. Public Citizen testified against the drug’s approval because the drug could be easily manipulated and therefore abused.[15] Furthermore, as was the case with XTAMPZA ER, the company was not required to show, before approval, that the new formulation of TROXYCA ER actually resulted in lower rates of abuse. If the FDA continues to approve opioids that are considered abuse-deterrent, with minimal data to support such a designation, companies are more likely to market these drugs as lower-risk, which may consequently increase the use of these drugs—before any studies have determined whether the drugs are truly less likely to lead to dependence and addiction.

References

[1] Food and Drug Administration. Novel drug approvals for 2016. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm483775.htm. Accessed December 8, 2016.

[2] Food and Drug Administration. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. September 19, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm. Accessed December 8, 2016.

[3] Food and Drug Administration. Summary review for eteplirsen. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206488_summary%20review_Redacted.pdf. Accessed December 15, 2016.

[4] Centers for Disease Control and Prevention. Opioid basics: Understanding the epidemic. https://www.cdc.gov/drugoverdose/epidemic/. Accessed January 9, 2017.

[5] The White House. FACT SHEET: President Obama proposes $1.1 billion in new funding to address the prescription opioid abuse and heroin use epidemic. February 2, 2016. https://www.whitehouse.gov/the-press-office/2016/02/02/president-obama-proposes-11-billion-new-funding-address-prescription. Accessed December 1, 2016.

[6] Meier B. U.S. maker of OxyContin painkiller to pay $600 million in guilty plea. The New York Times. May 11, 2007. http://www.nytimes.com/2007/05/11/business/worldbusiness/11iht-oxy.1.5665287.html. Accessed December 19, 2016.

[7] Department of Justice. News release. Biopharmaceutical company, Cephalon, to pay $425 Million & enter plea to resolve allegations of off-label marketing. September 29, 2008. https://www.justice.gov/archive/opa/pr/2008/September/08-civ-860.html. Accessed December 19, 2016.

[8] Food and Drug Administration. FDA facts: Abuse-deterrent opioid medications. http://www.fda.gov/NewsEvents/Newsroom/FactSheets/ucm514939.htm. Accessed December 19, 2016.

[9] Food and Drug Administration. Approval letter for EMBEDA. August 13, 2009. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/022321s000ltr.pdf. Accessed December 19, 2016.

[10] Food and Drug Administration. FDA facts: Abuse-deterrent opioid medications. August 19, 2016. http://www.fda.gov/NewsEvents/Newsroom/FactSheets/ucm514939.htm. Accessed December 19, 2016.

[11] Food and Drug Administration. Letter of approval for new drug application for XTAMPZA ER. April 26, 2016. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/208090Orig1s000ltr.pdf. Accessed December 28, 2016.

[12] Collegium Pharmaceutical, Inc. Label: oxycodone capsule, extended release (XTAMPZA ER). December 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=b0a5ded2-8ee2-49ca-a86c-2b28ae40f60c&type=pdf&name=b0a5ded2-8ee2-49ca-a86c-2b28ae40f60c. Accessed December 28, 2016.

[13] Collegium Pharmaceutical, Inc. Label: XTAMPZA ER- oxycodone capsule, extended release. December 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b0a5ded2-8ee2-49ca-a86c-2b28ae40f60c&audience=consumer. Accessed December 28, 2016.

[14] Food and Drug Administration. Letter of approval for new drug application for TROXYCA ER. August 19, 2016. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/207621Orig1s000ltr.pdf. Accessed December 28, 2016.

[15] Public Citizen. Testimony before the FDA’s Drug Safety and Risk Management Committee and Anesthetic and Analgesic Drug Products Advisory Committee regarding ALO-02 (Oxycodone/Naltrexone). June 8, 2016. http://www.citizen.org/hrg2326. Accessed December 8, 2016.