12/3/19

The Pied Pipers of Suboxone

© Lucas Salcedo | artstation.com/artwork/JEY5D

Reckitt Benckiser, the company that brought Suboxone to market, settled allegations that the company wrongly marketed and promoted Suboxone, resulting in the improper expense to state Medicaid funds. Reckitt will pay $700 million to settle the allegations. New York State Attorney General, Letitia James, said in a release dated October 23, 2019, that no company is above the law: “Reckitt misled the public about the real impacts of Suboxone and encouraged physicians to wrongly prescribe it, while cheating New York out of tens of millions of dollars in the process.” FiercePharma reported that would bring Reckitt total settlements this year to just over $2 billion, putting its Suboxone marketing investigations behind it, once and for all.

On April 9th 2019, a federal grand jury indicted Indivior, formerly part of Reckitt Benckiser Pharmaceuticals Inc., for allegedly engaging in an illicit nationwide scheme to promote Suboxone. Reckitt Benkiser had spun off Indivior Inc., meaning the two became separate companies in December of 2014. The U.S.’s criminal trial against Indivior is scheduled to begin on May 11, 2020. Then the U.S. Department of Justice announced on July 11, 2019 that Reckitt Benckiser agreed to pay $1.4 billion to resolve potential criminal and civil liability related to a federal investigation of the marketing of Suboxone.

After the April 9, 2019 indictment against Indivior, FiercePharma reported the company said the allegations were “wholly unsupported by either the facts or the law.” Indivior’s Chairman said the company “never deliberately diverted its product.” In an open letter he claimed the company went beyond what the law required in its education campaign to doctors and by reporting multiple physicians to the appropriate authorities. He further claimed the DOJ indictment can’t be justified on any fair reading of the facts or the law. “But we will contest these charges vigorously and we are confident in our position.”

It is not clear if Indivior is as confident in its position following the DOJ announcement. “RB Group has agreed to cooperate fully with all investigations and prosecutions by the Department of Justice related, in any way, to Suboxone.” Indivior may find it is fighting against the interests of its former parent company, Reckitt Benckiser. The DOJ said:

According to the indictment, Indivior—including during the time when it was a subsidiary of RB Group—promoted the film version of Suboxone (Suboxone Film) to physicians, pharmacists, Medicaid administrators, and others across the country as less-divertible and less-abusable and safer around children, families, and communities than other buprenorphine drugs, even though such claims have never been established.The indictment further alleges that Indivior touted its “Here to Help” internet and telephone program as a resource for opioid-addicted patients. Instead, however, Indivior used the program, in part, to connect patients to doctors it knew were prescribing Suboxone and other opioids to more patients than allowed by federal law, at high doses, and in a careless and clinically unwarranted manner.The indictment also alleges that, to further its scheme, Indivior announced a “discontinuance” of its tablet form of Suboxone based on supposed “concerns regarding pediatric exposure” to tablets, despite Indivior executives’ knowledge that the primary reason for the discontinuance was to delay the Food and Drug Administration’s approval of generic tablet forms of the drug.The indictment alleges Indivior’s scheme was highly successful, fraudulently converting thousands of opioid-addicted patients over to Suboxone Film and causing state Medicaid programs to expand and maintain coverage of Suboxone Film at substantial cost to the government.

Meanwhile, as alluded to above in the above news release from the DOJ, Indivior has been fighting a legal battle to delay generic approval for Suboxone. On June 14, 2018, the FDA approved Mylan Technologies Inc. and Dr. Reddy’s Laboratories SA to market the first generic versions of buprenorphine and naloxone sublingual film (Suboxone). Then on June 15th, the U.S. District Court of New Jersey granted Indivior a temporary injunction against Dr Reddy’s, compelling it to immediately stop its launch activities with Suboxone film. According to FiercePharma, Indivior has filed patent infringement lawsuits against both Mylan and Dr Reddy’s. Indivior will have to pay Dr Reddy’s $18 million to satisfy losses or damages incurred during the temporary restraining order if the generics company is successful in its legal defense.

When the U.S. Court of Appeals found that Indivior was not likely to succeed on the claimed patent infringement and ruled the lower court’s preliminary injunction be lifted, Indivior then tried blocking the appeals court ruling by taking the issue to the Supreme Court. Chief Justice John Roberts denied Indivior’s motion to stay the appeals court mandate on February 19th, 2019, clearing the way for Dr Reddy’s to market its generic version of Suboxone as the litigation continues. Dr Reddy’s immediately began shipping its generic version, as the original injunction did not stop it from manufacturing the drug. Indivior then announced it would launch its own generic version of Suboxone in the U.S. on February 20th. Mylan, which had made a deal with Indivior, announced it will launch its generic version on February 22nd.

Then on July 12, 2019, the U.S. Federal Circuit Court of Appeals in Washington upheld lower court rulings that “Dr. Reddy’s did not infringe two Indivior patents related to Suboxone.” Two other companies, Teva and Alvogen were also found to not have infringed on Indivior patents. Writing for the majority, Circuit Judge Alan Lourie said that while Indivior’s patents should not be voided, it failed to show that they covered Dr. Reddy’s and Alvogen’s drying processes for their products. This was the day after Reckitt Benckiser agreed to pay $1.4 billion to settle a federal investigation of the marketing of Suboxone noted above. Indivior said the settlement was separate from its own case.

The above consequences have been coming for several years. And Reckitt Benckiser and Indivior are complicit in the actions taken by both companies to position themselves as the primary service provider for buprenorphine-based MAT in the U.S. But their actions to delay generic buprenorphine/naloxone didn’t just begin during the time period described above.

Reckitt Benckiser (RB) knew it only had patent exclusivity for their buprenorphine products  (Suboxone and Subutex tablets) until 2009, but they had a strategy to circumvent the pending loss. First, they acquired the rights for the sublingual film version of Suboxone in 2008. Then in October of 2008 they submitted a New Drug Application to the FDA for the film version of Suboxone, which was approved by the FDA in August of 2010.

In its 2011 annual report, Reckitt Benckiser thought generic versions of Suboxone could take up 80% of the revenue and profit from the U.S. Suboxone market. However, they expected Suboxone film would help “to mitigate the impact.” Then in September of 2012 RB announced that they were voluntarily withdrawing Suboxone tablets from the market because of data they had received from the U.S. Poison Control Centers suggesting there were higher rates of pediatric overdose on the tablet formulation than the film version. The FDA thought the study Reckitt Benckiser cited (and paid for) did not demonstrate any difference in its safety profile of abuse formulations between Suboxone tablets and film.

Public Citizen said that few, if any, companies went as far as RB to pre-emptively withdraw an off-patent drug from the market (Suboxone tablets) to make room for a newly patented successor (Suboxone film). A year before the withdrawal of the tablets from the market, RB stated in its 2011 report that its goal was to convert as many tablet users as possible to the film version.

To this end, the company initiated a marketing campaign to persuade physicians to switch patients from the tablet to film form. It also employed more direct tactics to complement the marketing push, raising the price of the tablets to levels higher than the film versions. As a result of these efforts, tablet sales fell 19 percent between August 2011 and August 2012, while sales of Suboxone film doubled during the same period. By September 2012, the film version had captured 70 percent of the Suboxone market, clearing the way for the announcement of the withdrawal of the tablets that month. See “The Opioid Buzzard” for more on this.

Whether you look at Reckitt Benckiser or Indivior you can see a pattern of systematic steps to maintain a monopoly on the buprenorphine-naloxone end of the MAT, medical-assisted treatment, market. This resulted in 2019 with over $2 billion in settlements for improper, illegal marketing tactics with Suboxone for Reckitt Benckiser. Indivior is next, as the federal government indicted it for an illicit scheme to market Suboxone. Yet Indivior still projects a rosy future for its products. It has a new buprenorphine product, monthly depot shot of buprenorphine called Sublocade, and Perseris, which is an extended release injectable of risperidone for schizophrenia that launched in February of 2019. But there are additional changes in the MAT market that contribute to Indivior’s optimism.

The first quarter financial report by Indivior for 2019 reported that U.S. net revenue grew 2% as Suboxone Film share loss was more than offset by “underlying market growth, strong initial sell-in of the Group’s authorized generic film product and net revenue from SUBLOCADE™.” Operating Highlights for the first quarter included continued growth of the U.S. buprenorphine market, driven primarily by Government channels. The share erosion since the “at risk” launch of generic buprenorphine/naloxone film products in February 2019 was lower than anticipated. Suboxone Film market share ended the quarter with a 53% market share. “Sandoz Inc. launched an Indivior authorized generic buprenorphine/naloxone film and captured the leading position among allgeneric film products” by the end of the first quarter. Shaun Thaxter, the CEO of Indivior, said their first quarter performance only strengthened their confidence that they are “putting the building blocks in place for a return to sustained growth” with Sublocade and Perseris. He looked forward to reporting progress throughout the year.

His optimism seems to rest on how the market for buprenorphine products continues to grow, benefitting from legislative changes that have expanded opioid use disorder (OUD) treatment funding and treatment capacity. This was accomplished by increasing the number of patients that physicians could treat from 100 to 275.

Recognising the foregoing factors, we are introducing FY 2019 financial guidance. A key element of guidance is of course the performance of SUBLOCADE™, our new monthly buprenorphine extended-release injection, and here we made good progress in executing our plans: Q1 net revenue of $11m puts us on track to meet our FY 2019 guidance for net revenue of $50m-$70m. We continue to believe SUBLOCADE™ to be a transformational treatment for opioid dependence and we will not be distracted in our efforts to bring this important new option to patients in the US. Separately, while not a material contributor to our full-year guidance, we are nonetheless encouraged by the initial market reception to PERSERIS™, our monthly risperidone injection for schizophrenia, which we launched towards the end of the first quarter.

Thaxter said Indivior remained “undaunted in the pursuit of our Vision to improve the lives of patients suffering from addiction and its co-occurring disorders.” Yet the above story seems to point to another Vision—sustained growth and profitability—that blinds them from seeing where they are potentially taking us. Is this self-described “leader and innovator” in OUD treatment leading towards a “treatment” strategy that increases rather than decreases the number of those who are chained to an opioid? Like in the story of the Pied Piper, are we dancing to the tune of Indivior, unaware we are being led into the river of OUD instead of being saved from it?

For more on Indivior and Sublocade, see “Opioid Epidemic Price Gouging.” For further information on Reckitt Benckiser and its attempts to prolong a market for Suboxone, see “A Double-Edged Drug.”

01/23/18

Opioid Epidemic Price Gouging

© Karen Roach | 123rf.com

The FDA recently approved Sublocade, the first once-monthly buprenorphine injection in its fight against the opioid epidemic. Indivior, the company which also sells Suboxone film, projected it would be available on the market sometime in the first quarter of 2018. Sublocade is a drug-device combination product. “It is injected by a healthcare professional (HCP) under the skin as a solution, and the delivery system form a solid deposit, or depot, containing buprenorphine.” The initial procedure will to be to start with daily stabilizing doses of Suboxone for at least seven days before the first injection of Sublocade.

After initial formation of the depot, buprenorphine is released by the breakdown (biodegradation) of the depot. In clinical trials, Sublocade provided sustained therapeutic plasma levels of buprenorphine over the one-month dosing interval.

Prescribing information for Sublocade said the recommended protocol was two monthly doses of 300 mg followed by 100 mg monthly maintenance doses. “Increasing the maintenance dose to 300 mg monthly may be considered for patients for whom the benefits outweigh the risks.” Sublocade will come in prefilled syringes of 100 mg and 300 mg. It will carry a boxed warning of the risk of serious harm or death if used intravenously.

The Indivior announcement of Sublocade’s approval indicated Sublocade will be distributed through a restricted distribution system, “which is intended to prevent the direct distribution to a patient.” This restricted release to only healthcare professionals is because of the risk of serious harm or death if someone were to attempt intravenous self-administration of Sublocade. Intriguingly, the boxed warning in the prescribing information wasn’t as clear on the intent of the restricted distribution system to prevent patients from having direct access to Sublocade. The harder it is to get a hold of Sublocade, the harder it will be to figure out a way to hack into the buprenorphine it contains.

The FDA is requiring postmarketing studies to assess four things. First, whether patients would benefit from a higher dose. Second, whether Sublocade can be safely started without a dose stabilization period of Suboxone. Third, to assess the feasibility of administering Sublocade at a longer inter-dose interval than once-monthly. Fourth, to determine a process for transitioning patients stabilized long term on Suboxone film to a monthly dose of Sublocade without the loaded dose in the first two months of treatment.

I assume the study to see if patients would benefit from a higher dose fits into the above prescribing information that maintenance doses could be increased up to 300 mg monthly. But I have this nagging question of whether Indivior felt unsure about the safety risk of maintenance doses above 100 mg. So they wanted to be safe rather than sorry, knowing there was always Suboxone film to supplement Sublocade in a pinch. And postmarketing studies could look at whether higher maintenance doses put people at risk in some way.

The procedure of having an initial “dose stabilization” period on Suboxone before injecting Sublocade helps ensure the individual has really stopped using opioids before their injection. The required postmarketing study will help evaluate whether that’s necessary. My initial thoughts are that given the significant amount of buprenorphine in the depot, clinically the dose stabilization period should remain, especially if this is done when the person is an outpatient. If the person’s pattern of use isn’t stable enough to reach a week of daily Suboxone use, they should probably try inpatient drug treatment to stabilize first before Sublocade.

Depots containing either 100 mg or 300 mg have a significant amount of buprenorphine. So I’m concerned about thoughts of assessing the feasibility of administering Sublocade at longer inter-dose intervals, which would require even higher doses. I guess the thinking behind the longer inter-dose interval study is anticipating of having/keeping Sublocade patients on the treatment for an indeterminate length of time, perhaps years.

Except for the supposed convenience of a once-monthly shot, why would someone who is stable on Suboxone film long term want to switch to Sublocade? If you have demonstrated the discipline, stability and willingness to successfully maintain opioid abstinence with Suboxone, why switch to Sublocade? I do know why Indivior would want you to switch. The average monthly cost for Suboxone is $132, while the average monthly cost for Sublocade is $1,580. The cost for Sublocade puts it in the ballpark for Vivitrol, which costs around  $1,687 per month.

STAT News quoted one addiction professional who said: “It’s potentially a game changer. . . . This could become first-line [medication] for opioid addiction.” But Sublocade is just the first injectable buprenorphine product to be approved. A similar medication, known as CAM 2038, is made by Braeburn Pharmaceuticals and it could be get FDA approval by January 19, 2018. The president and CEO of Braeburn said: “This new technology has the potential to greatly influence the way patients are treated today. . . [It can] free patients from the daily decision and reminder of the disease.” Did this guy ignore or just forget about the Warnings and Precautions on the Sublocade medication guide?

It says: “Buprenorphine can be abused in a manner similar to other opioids; Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with Sublocade.” Pain treatment should be with a non-opioid analgesic whenever possible. “If opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect.” Sublocade won’t free patients of the daily reminder of the disease, because it is the daily reminder.

STAT said long-acting buprenorphine could make future inroads within the criminal justice system. “In recent years judges, wardens, and health officials have warmed up to Vivitrol, citing fears that daily tablets of buprenorphine can be diverted or abused.” Additionally, the criminal justice system has been more receptive to Vivitrol because Alkermes has been doing targeted marketing with them to promote Vivitrol for a number of years. However, the approval of Sublocade adds a second monthly injectable alongside Vivitrol and potentially could diminish “one of the biggest competitive advantages held by Vivitrol.”

STAT also pointed to another likely financial incentive for Invidior to put Sublocade into the market. Medicaid spending on buprenorphine last year was five times higher than for Vivtrol. But those spending statistics could be partly due to the cost discrepancy between monthly Vivitrol and Suboxone and not the preference for buprenorphine. However, it is likely Invidior will be able to slice off a nice chunk of non-negotiated drug price income for Sublocade from Medicaid.

Another STAT article discussed a study published in The Lancet, Lee et al., that found both Vivitrol and Suboxone had comparable effectiveness outcomes during 24 weeks of outpatient treatment. STAT quoted Dr. Nora Volkow, director of NIDA as saying she hoped the study will change the widespread prejudice patients don’t do as well on naltrexone as they do on buprenorphine.  Apparently it didn’t. In the very same STAT article, two different doctors, not involved in the study, said the study showed buprenorphine was more effective than Vivitrol. However, the lead author of the study, Dr. Joshua Lee told STAT: “Both medications worked quite similarly and, therefore, both should be discussed as treatment options.”

The study findings pointed to by the two doctors included the following: its easier to initiate and patients stay with the treatment (buprenorphine) longer. Fewer participants successfully started Vivitrol treatment, as it required a three day period for detoxification, whereas Suboxone participants could begin as soon as the onset of withdrawal symptoms began. The differences in induction rates were 72% for Vivitrol and 94% for Suboxone.

Naltrexone (Vivitrol) is an antagonist, meaning if there were residual levels of opioids in a participant’s body they would immediately be thrown into acute withdrawal. The delay was medically necessary. Naltrexone is also not an opioid, while Suboxone (buprenorphine) is. The induction period with Vivitrol was expected by the study authors themselves to be more difficult. They didn’t get the easement of acute opioid withdrawal that the Suboxone group did—and yet, 72% were successfully inducted into the study.

Curiously one individual pointed to where many of the overdoses in the study occurred after detox, apparently indicating more occurred with Vivitrol. Yet she failed to comment on the fact that of the five fatal overdoses in the study, THREE were in the Suboxone group!

There were more relapse events (defined as 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use.) for the Vivitrol group, but “most or all of this difference [was] accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures.” The more difficult time intiating patients into Vivitrol treatment effected the over relapse rates. “However, once initiated, both medications were equally safe and effective.”

The Lee et al. study was actually the second study to demonstrate that Vivitrol was as effective as Suboxone in maintaining short-term abstinence. The previous study was a smaller Norwegian study, Tanum et al., that followed its participants for 12 weeks. The bottom line is replicated results are more difficult to rationalize away.

Diversion and abuse of Suboxone has been evident from the time it was approved by the FDA. The approval of Sublocade would hopefully nullify the diversion and abuse problems experienced with Suboxone, if you have the money or insurance for it.

Bringing buprenorphine into the realm of “a restricted delivery system” to prevent direct distribution to patients also seems to be where some justification for the added cost factor comes in. But I wonder to what extent dispensing Vivitrol and Sublocade in a medical setting can justify the high cost. Is there price gouging going on? This is now the second time that technological innovation has extended patent exclusivity for Indivior’s buprenorphine products. Read more about how Reckitt Benckiser, the parent company to Indivior and Indivior itself accomplished this in “The Opioid Buzzard.”