Endo and Opana: How a Drug Maker Creates a Dynasty

A story involving fatal stakes, secret pacts, and even betrayal between two drug makers with little but tragedy for the public.

Over the course a bizarre, eleven year odyssey, Endo International seized loopholes, paid off their competition (Impax Laboratories), and made dramatic moves to maintain a monopoly for their painkiller, Opana ER. They undertook an ever-shifting set of schemes and cunning plans to maintain their high profits before moving on to a new drug. In retrospect, the lengths they took shed light on the problems of the pharmaceutical industry and the accompanying collateral damage.

Shakespeare’s comedies involved impossible unions and changing identities. His tragedies involved the powerful brought down by their fatal flaws. This will be a story involving fatal stakes, secret pacts, conspiracy, and even betrayal– but with its principal roles played by two drug makers. While the business manoeuvres are at times absurd, the unintended consequences for the public are undeniably tragic.

The Opioid Epidemic

Opioid abuse is running rampant through America at an alarming rate. The explosion follows a common pattern - persuasive pushers and powerful cartels. But unlike the 80s, things are corporate now.

The gateway drug gets sold in pharmacies. The front-line pushers are well-heeled medical professionals, drawing on their authority to introduce patients to powerful narcotics. Behind them, large pharmaceutical companies send sales representatives to influence what the physicians prescribe.

That’s how some city and state governments are seeing it. Across the country, numerous lawsuits have sprung up with small governments attributing growing opioid abuse to actions taken by drug makers. Recently, the County of Multnomah, Oregon alleged the following in a suit against several pharmaceutical companies:

“Defendants, and each of them, committed repeated tortious acts, in concert with each other […] to create a vast population of addicts dependent on their product. […] Inherent to this scheme’s success is the imprimatur of legitimacy that comes along with doctors, pharmacists, and Fortune 500 companies saying that opioids are safe and nonaddictive.” - Multnomah Oregon Opioid Suit¹

How Endo Plays a Role

At the center of the storm lies Endo International. Just over a decade ago, they began to produce the painkiller oxymorphone under the name Opana ER. The “ER” stands for “extended-release.” Unlike other oxymorphone pills, which have to be taken every few hours, the extended-release pills lasts 12 hours. This means fewer pills for patients to take.

Opana ER was their best selling pain management medicine, with $159M in sales in 2016 ² and about $2.3 billion over the last eleven years. It’s been linked as a central component of the current opioid crisis. Earlier this year, the Food and Drug Administration (FDA) requested that Endo stop selling the drug due to fears that it was intensifying the opioid crisis. The request only cited practical concerns – the drug had already gone through FDA approval and began selling in 2006 – but the FDA made it clear that Endo had no choice but to comply.

[…] The FDA has requested that the company voluntarily remove reformulated Opana ER from the market. Should the company choose not to remove the product, the agency intends to take steps to formally require its removal by withdrawing approval. -FDA’s June 8, 2017 press release³

While the FDA action is concerning, it’s unlikely to be the last of Endo’s legal issues regarding Opana ER. Innumerable lawsuits have come forth over the past few years. That’s not too alarming on its own, pharmaceutical companies spend as much energy litigating as researching. The real shock - Endo is being sued by city and state governments for alleged abuses in marketing and promotion of addictive opioids. Given that it’s happening in the middle of an opioid epidemic, it’s an extremely damning allegation.

Before diving into the issues Endo faces, it’s helpful to get a rough overview of the pharmaceutical industry. It’s an industry where the legal innovation is as fascinating as the product innovation.

Roosevelt, Kennedy, and Reagan - Three Eras of Drug Regulation

The history of the FDA is roughly marked by three shifts occurring during the T. Roosevelt, Kennedy, and Reagan presidencies. While the key moments involved many people, specifically the members of congress who introduced the related acts⁴, the presidents who signed the bills into law serve as a useful reference point.

The Roosevelt Era

At the onset of the 20th century, life was nasty, brutish, and short. The average American could expect to live only to 49⁵. Many medicines were fake and much of the food was foul. Unscrupulous businessmen would dilute milk with water, pass off margarine as butter, and use unsafe amounts of chemical additives⁶. To combat this, Progressive Era advocates pushed for better food regulation leading to the creation of the Food and Drug Administration in 1906.

The Kennedy Era

In late 1950s Germany, Chemie Grunenthal, the predecessor of modern-day drug maker Grunenthal GmbH, discovered the drug thalidomide⁷ as a treatment for nausea. By the end of the decade, tens of thousands of pregnant women were prescribed the drug. Tragically, thalidomide caused birth defects, with more than 10,000 infants born with missing limbs worldwide.

The impact in the United States was dramatically limited thanks to Frances Oldham Kelsey⁸, a pharmacologist at the FDA who refused to approve thalidomide, despite pressure from drug companies.

The fallout led to an expansion of the FDA’s role through the 1962 Kefauver-Harris Amendment. In addition to safety concerns, drug makers now had to demonstrate efficacy, disclose side effects and seek consent from patients for their participation in clinical trials.

The Reagan Era

By the early 1980s, a complex set of problems became clear for several stakeholders: branded drug makers, generic drug makers, and consumers.

Branded drug makers are the firms that develop new drugs. The process involves massive R&D investments over many years with no guarantee that revenue will cover costs. Generic drug makers compete by selling lower-price versions of the branded drugs. They bring the costs down for consumers through competition and in-so-doing, threaten the profitability of the branded drug maker.

That’s a simplification of what has proven to be anything but a simple problem. To balance the incentives and needs of the three groups, Congress passed the Drug Price Competition and Patent Term Restoration Act, more commonly referred to as the Hatch-Waxman Act, in 1984.

The law reshaped the tension between incentives and competition with a series of significant changes that would eventually give rise to strange legal manoeuvres. Most of these manoeuvres are consequences of the law being largely viewing the situation as one of branded drug maker versus all competitors and generics versus one another. Later on, we’ll see situations where the branded firm and first generic essentially form a two-party cartel against all other generics.

Changes in the Hatch-Waxman Act

The Hatch-Waxman Act made several dramatic changes to the process of launching new drugs. It aimed to balance profit incentives and competition. It did so by granting monopolies to incentivize companies to make new drugs, but limit those monopolies so competition could eventually lower prices for consumers.

It’s a delicate task to balance a market. Each of these changes played a major role in shaping the future strategies for drug makers, as we’ll see for Endo and Impax.

Five Year Exclusivity

The FDA grants branded drug makers five years of exclusivity⁹ following approval of drugs containing a new chemical entity¹⁰. This is separate from a patent, instead exclusivity means the FDA will not approve other applications during the period¹¹. If the new drug application involves new clinical studies, but not a new chemical entity, then the exclusivity term is only three years¹².

ANDAs - Abbreviated New Drug Applications

After the five-year protection period, generic drug makers can enter the market by filing an abbreviated new drug application (“ANDA”)¹³. ANDAs accelerate the launch of generic drugs by allowing companies to submit a shorter filing if the drugs are shown to be bioequivalent to a previously approved branded drug. This means the generic drug contains the same active ingredient, targets the same condition, and affects patients in an identical manner to the original branded drug.

Patent Lawsuits, 30-Month Holds

Following the submission of an ANDA, the branded drug maker has 45 days to file a lawsuit if they believe their patents are being infringed. If the patent is found to have been violated, the generic drug maker is blocked from competing until after the patent expires. The lawsuit triggers an automatic 30-month hold, during which ANDAs cannot be approved by the FDA. This effectively extends the branded drug maker’s monopoly by two-and-a-half years¹⁴.

180-Day Generic Exclusivity

If the generic drug maker’s ANDA is approved, they are granted a 180-day Generic Exclusivity period by the FDA. During this period, they’re the only company, aside from the branded drug maker, allowed to sell the drug. The market is still far from competitive since the entrants are limited. Studies show that drug prices don’t fall much until there are two or more generic competitors¹⁵.

Drugs in Context

At this point, it’s important to clarify what a “drug” is in the context of the FDA. The FDA makes a distinction between the active ingredient and the formulation. To put it in more relatable terms, let’s look at the crack vs powder cocaine disparity. In common terms, most people think of crack cocaine and powder cocaine as the same drug. From the perspective of the FDA, they’re not bioequivalent. They would have the same active ingredient (cocaine), but are two different drugs because they have different intake methods (snorting vs smoking), absorption rates, or dosages. The FDA requires a new drug application for completely new active ingredients as well as for new formulations of an already approved active ingredient. Endo’s drug, Opana ER, was a new formulation of an existing drug.

The Mess We’re In

This brings us back to our modern-day mess. Public policy is a dynamic game. Rulemakers try to close exploits, but every rule changes the terrain, creating new opportunities for some while placing limits on others. Firms play a clever game in court, exploiting vagary or unintended loopholes in the rules. The rules and the players respond to one another, but unfortunately, firms move much more quickly than government. As a result, regulation can often have the opposite effect of what was intended.

The drug market is stuck between two counter-acting forces of incentive and competition. Manufacturers won’t develop drugs unless they can profit and so the government gives protections through FDA exclusivity. They often do anything they can to delay market entrants and extend their exclusivity. Over the life the drug, Endo would make more than $2 billion dollars by extending their effective exclusivity. In the next section, we’ll explore how far Endo went to protect the revenue stream.

Lawyers, Drugs, and Money

But at no time did Rockefeller have in mind driving all the competitors from the field: Rockefeller’s partner, Charles Pratt stated: “Competitors […] we must have. If we absorb them, be sure it will bring up another.” -Charles Pratt, Partner of John D. Rockefeller ¹⁶

Back to Endo and their painkiller, Opana ER.

The drug’s active ingredient, oxymorphone hydrochloride, was approved under the brand name Numorphan in 1959¹⁷, with an immediate-release version being sold throughout the 1960s until being discontinued in 1982.

Opana ER wasn’t a new chemical entity, however the extended-release formulation was novel. There were initial concerns about the effect of an extended-release form in patients who were new to painkillers. Further, initial reviewers stressed the need to clearly communicate the difference between the immediate-release and extended-release formulation in labeling and marketing.

[Endo’s] educational plan is comprehensive about the treatment of pain and general, appropriate opioid usage, but does not emphasize the potential risks associated with oxymorphone extended-release tablets. - Office of Surveillance and Epidemiology¹⁸

Endo was the only manufacturer of extended-release oxymorphone tablets. Rather than taking a pill every few hours, a patented gelling mechanism allows patients to take one pill every 12 hours, thanks to a special coating that slowly releases the drug over time.

Shuffling Patents to Delay Competition

“At the same time, other observers have identified the increasing acquisition of additional patents by brand-name drug makers, often of doubtful validity or applicability, in order to delay generic competition. This activity has been given the equally evocative label of ‘evergreening.’” - C. Scott Hemphill “Evergreening, Patent Challenges, and Effective Market Life in Pharmaceuticals” ¹⁹

Endo initially claimed 3 patents²⁰ applicable to the drug, but only one made it into the official listing when it was approved (patent 5,128,143; “the ‘143 patent”).

The FDA granted three years of exclusivity¹² for Opana ER, rather than the full five years, because it was new formulation of an already approved active ingredient. As a new formulation, and effectively a different drug, the extended-release tablets couldn’t be substituted for immediate-release tablets. In order to directly compete, generic drug makers would have to catch up by creating their own extended-release formulations.

The ‘143 patent was set to expire two years after approval, in September 2008²⁰. In October 2007, well-past the thirty day window for declaring relevant patents in the official register, Endo added three more patents. Most notable were two patents set to expire in 2013 (“the 2013 patents”). Unless a generic drug maker could successfully challenge the newly added patents, Endo could hold off competition until their expiration.

Corporate Cooperation

Finally, the FTC alleges that Endo willfully maintained a monopoly of extended-release oxymorphone[…]” - October 20, 2016 FTC Memorandum²¹

On December 14, 2007, Impax Laboratories announced their intention to create a generic version of Opana ER along with a legal challenge for the 2013 patents.

In its first 18 months on the market, Opana ER had made Endo $114 million in revenue. The entry of competition threatened the revenue stream.

In response, Endo sued for patent infringement, instantly triggering a 30-month stay during which Impax’s ANDA could not be approved. Impax was sidelined, unable to enter the market, effectively extending Endo’s exclusivity by 30 months.

THE 30-MONTH STAY: During the 30 month period from 2008-mid 2010, Endo added roughly half a billion dollars of revenue from Opana ER.

Nearly 30 months later, Endo and Impax announced a pair of agreements that would raise antitrust concerns from the Federal Trade Commission. While Endo claimed they were independent, the FTC viewed tham as a two steps halves of an anti-competitive plan.

The first settlement would allow Impax to begin selling generic Opana ER in January 2013, eight months before the expiration of Endo’s 2013 patents. As the first ANDA filer, Impax still retained their 180-day generic exclusivity, meaning no one else could enter the market until July 2013 at the earliest. As a result, Endo would be the only seller for another two-and-a-half years (from mid-2010 to January 2013). In addition, Endo would pay Impax $110 million if Endo created a new competing oxymorphone drug.

“In June 2010 […Endo] agreed to dismiss our suit with prejudice and Impax […] agreed to dismiss their counterclaims with prejudice.

“…[Endo has] agreed to grant Impax […] a license to the patents to sell a generic version of Opana ER on or after January 1, 2013 […] and earlier under certain circumstances, and have agreed not to sue Impax […] under such patents.” - Endo’s 2010 Annual Report²²

At the same time, Endo paid Impax $10 million as part of a partnership to develop future drugs²³.

The FTC claimed that Endo paid Impax to delay entering the market for Opana ER. In 2016, they charged both Endo and Impax for anti-competitive violations:

“The FTC alleges that both these Agreements with Impax were intended to eliminate generic competition to Opana for two and a half years […] Finally, the FTC alleges that Endo willfully maintained a monopoly of extended-release oxymorphone—including through its execution of the Impax Agreements[…]” - FTC Memorandum from October 20, 2016

The FTC further summarized on page 61 of the FTC’s October 2016 memorandum in its case against Impax: “By entering into the anti-competitive agreement, Impax shared in Endo’s additional monopoly profits at the expense of consumers.” The FTC essentially charged that the two companies took advantage of the Hatch-Waxman Act’s provisions to extend Endo’s monopoly, share the outsized profits from higher drug prices, and delay competition.

A Separate Peace - the Reformulation of Opana ER

Leveraging our pain management expertise by developing proprietary products and generic products with significant barriers to market entry. - Endo’s 2006 Annual Report²²

In early 2012, Endo began a bold plan to extend the profitability of Opana ER even further. The next year, Impax would begin selling its own generic version, followed six months later by many more generic firms. Endo had reached $384 million in annual revenue for Opana ER in 2011. At this point, they devised two cunning manoeuvres to try to extend the monopoly by three more years.

This is when Endo began “product-hopping”²⁴, or reformulating their drug, by switching to a new formulation of the same active ingredient.

Endo already had a large sales force and direct contact with physicians. Through this marketing channel, they could inform prescribers of a new, “better” drug, and draw them into the new, single-seller market, leaving generic firms to scramble and either market to prescribers or wait through another cycle of brand drug monopoly.

Thus, crush-resistant Opana ER was born.

The presence of the crush-resistant formulation created problems for the generic Opana ER market. Less than a year before generic competition would begin, Endo began to shift the market to the crush-resistant formulation, which couldn’t be substituted with Opana ER. This was a direct hit to the profit potential for Impax’s generic drug. Endo had left them the market, but not before making it a ghost town.

Endo settled the aforementioned anti-competitive case with the FTC in January 2017²⁵, but the case against Impax is still ongoing. In a pre-trial conference, Impax’s legal council described the effects of the Opana ER discontinuation and the deteriorating relationship between Impax and Endo.

“But as we stand here today, Impax is the only company selling Opana ER. In fact, Endo withdrew the drug to move to a crush-resistant formula, so right now, we are the only ones selling the drug. There is no A/B rated brand. We don’t get – you asked about writing a [prescription]. We don’t get automatically substituted. The company, after this settlement and after what Endo did – and, again, this has been a bitter battle between these two companies – the company had to go out, which is not something generic companies typically do, and detail it, convince people to write the [prescription] for Opana ER.” - legal council for Impax, during an initial pretrial conference with the FTC²⁶

“A bitter battle between these two companies” - those are harsh words considering they had multi-year cooperation agreements following their Opana ER patent challenge settlement. The council was likely influenced by a deft and daring action attempted by Endo. It wasn’t just that they abandoned the non-crush-resistant Opana ER market, Endo attempted to salt the fields behind them.

The Betrayal

An excerpt from the first page of Endo’s citizen petition asking the FDA to prohibit Opana ER’s generics. The full document can be found here.

In 2012, Endo filed a citizen petition to the FDA requesting that they prohibit sales of non-crush-resistant Opana ER – the drug that they had launched 6 years earlier – as well as any generics. The petition mentioned concern to public safety, but the effect would have been made Endo’s new formulation the only legal extended-release oxymorphone pill for at least three more years.

The FDA refused the request, rejecting Endo’s claims that their non-crush-resistant was safer than the currently available formulation. Years later, it would be discovered that the launch of new formulation would unwittingly lead to an intensification of the opioid epidemic.

Final Act

The business drama that took place in the extended-release oxymorphone didn’t occur in a vacuum or even in a noncrucial industry. It wasn’t a quarrel between Apple and Samsung over products we could survive without – it occurred in arguably America’s most important industry. Endo is being sued precisely for the unintended consequences in such a vital industry.

Unintended Consequences

The same active ingredient can have markedly different effects depending on the intake method. Pain-relief patients are instructed to swallow the pills, but opioid abusers would generally crush and snort them. By snorting rather than swallowing the pill, the oxymorphone enters the bloodstream more quickly, resulting in a stronger effect. Injecting provides an even more potent delivery path, since the drug isn’t “filtered through the lungs and/or kidneys before being absorbed into the brain” as it is when taken orally or nasally²⁷.

This is why the FDA references intake methods when distinguishing between drugs. The path from entering the body to reaching the brain has a profound influence on the effects for the user.

As a tragic unintended consequence, Endo’s switch to a crush-resistant version of Opana ER changed the patterns of drug abusers. They could no longer crush then snort the pill, leaving the choice between a weaker high from oral intake versus a riskier, but stronger high from injection. Many drug abusers chose injection. With injection, came the spread of related diseases which raised the alarm for the opioid epidemic to another level.

On March 13, the FDA and CDC held a joint meeting to discuss public safety related to Opana ER’s role in the opioid epidemic²⁸. During the meeting, a presentation by the CDC noted that abusers “in Scott County applied moderate heat to ‘brown’ [crush-resistant] Opana ER tablets to facilitate dissolution in water and reduction in gelling²⁹.” Just as drug makers respond to changes in regulation, drug abusers adapt to changes in their own landscape:

“[I was] probably 24….I snorted the Opanas. It was when the government put the formula in where you had to cook them…. It pretty much forced me to have to inject really… If there was a possible way I could snort them, I’d rather snort than shoot.” - a respondent to a CDC survey, pg 21 of the presentation²⁹

“These [crush-resistant Opana ER] you can’t. They’re like, plastic. Real hard. Well, I shot too, but I, mostly I would snort it. But, and then, when you couldn’t snort it at all. I started shooting it.” - a respondent to a CDC survey, pg 21 of the presentation²⁹

To make matter worse, the same gelling compound used to create the extended-release made it harder to isolate the desired drug. As a result, the end product was more diluted, and abusers would inject multiple times³⁰, thus increasing risk of HIV and hepatitis C transmission.

Endo’s Wish Granted

Following two days of presentations by respresentatives from Endo, the FDA, the CDC, and public advocacy groups, the FDA-CDC joint committee voted that the risks of crush-resistant Opana ER outweighed the benefits³¹.

The FDA’s decision is based on a review of all available postmarketing data, which demonstrated a significant shift in the route of abuse of Opana ER from nasal to injection following the product’s reformulation. Injection abuse of reformulated Opana ER has been associated with a serious outbreak of HIV and hepatitis C, as well as cases of a serious blood disorder (thrombotic microangiopathy). […] The FDA has requested that the company voluntarily remove reformulated Opana ER from the market. Should the company choose not to remove the product, the agency intends to take steps to formally require its removal by withdrawing approval. - FDA’s June 8, 2017 press release³

Eleven years after the Opana ER’s were first released, five years after Endo switched the market to the crush-resistant variant, the FDA asked Endo to recall the crush-resistant Opana ERs. It makes for an ironic end considering that five years earlier, Endo stopped selling the non-crush-resistant formulation and asked the FDA to disallow Opana ER’s generic competition.

Over 11 years, Endo undertook an array of clever business manoeuvres to maintain their drug’s profitability. The manoeuvres ultimately harmed the public directly by hampering lower-price competition and indirectly by tilting drug abusers towards a more dangerous path that led to HIV and hepatitis C outbreaks in several states. The outcome of those lawsuits by city and state governments remains to be seen. For now, all that’s clear is that their actions have left them on the outside, with no drug to sell, watching a market they tried to shut down³².

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1. Multnomah Oregon Opioid Suit ↩

2. Endo International US Branded Sales Breakdown from their 2016 Annual Report ↩

3. FDA’s June 8, 2017 Press Release ↩ ↩²

4. Weldon Heyburn’s 1906 Pure Food and Drug Act, Estes Kefauver and Oren Harris’ 1962 Kefauver-Harris Amendment, and Orrin Hatch and Henry Waxman’s 1984 Hatch-Waxman Act ↩

5. CDC Life Expectancy data ↩

6. FDA History link ↩

7. In 2012, the Grunenthal Group issued an apology for the thalidomide tragedy. ↩

8. Frances Oldham Kelsey. JFK awarded her the President’s Aware for Distinguished Federal Civilian service in 1962. ↩

9. “If a drug product that contains a new chemical entity was approved after September 24, 1984, in an NDA submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act, no person may submit a 505(b)(2) application or ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act for a drug product that contains the same active moiety as in the new chemical entity for a period of 5 years from the date of approval of the first approved NDA, except that the 505(b)(2) application or ANDA may be submitted after 4 years if it contains a certification of patent invalidity or noninfringement described in 314.50(i)(1)(i)(A)(4 ) or 314.94(a)(12)(i)(A)(4 ).” ↩

10. “New chemical entity means a drug that contains no active moiety that has been approved by FDA in any other NDA submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act.” from the FDA Title 21 Sec. 314.108(a) ↩

11. Patents and exclusivity are distinct. The US Patent and Trademark office issues patents, while the FDA grants exclusivity. The FDA won’t approve any generic drug applications during the exclusivity period. ↩

12. “Contained reports of new clinical investigations (other than bioavailability studies) conducted or sponsored by the applicant that were essential to approval of the application, for a period of 3 years after the date of approval of the application, the Agency will not approve a 505(b)(2) application or an ANDA for the conditions of approval of the NDA, or an ANDA submitted pursuant to an approved petition under section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act that relies on the information supporting the conditions of approval of an original NDA.” from the FDA Title 21 Sec. 314.108(b) ↩ ↩²

13. “The approval of a 505(b)(2) application or ANDA […] will occur […] unless the owner of a patent that claims the drug, the patent owner’s representative, or exclusive licensee brings suit for patent infringement against the applicant during the 1-year period beginning 48 months after the date of approval of the NDA for the new chemical entity and within 45 days after receipt of the notice described at 314.52 or 314.95, in which case, approval of the […] ANDA will occur[…].” from the FDA Title 21 Sec. 314.108(b) ↩

14. The first generic’s ANDA application is delayed by the 30-month period. Also, any additional generics can’t be approved before the first ANDA. ↩

15. Drug prices fall only 6% when the first generic appears. Prices fall an additional 44% percent with the entry of the third generic drug maker. ↩

16. Quoted from American Entrepreneur, Ch. 7 The Big Business Backlash: 1870-1920 pg224 by Larry Schweikart and Lynne Pierson Doti link ↩

17. Meeting minutes for the CDC-FDA joint committee, March 13-14, 2017 ↩

18. Office of Surveillance and Epidemiology’s review of Opana ER’s Risk Minimization Action Plan on page 38 of the FDA Patent and Exclusivity document for Opana ER. ↩

19. From C. Scott Hemphill’s ‘Evergreening, Patent Challenges, and Effective Market Life in Pharmaceuticals’ ↩

20. Initial Opana ER Patents and Exclusivity Document ↩ ↩²

21. FTC Memo from October 20, 2016 outlining case against Endo link ↩

22. Endo International’s 2016 Annual Report ↩ ↩²

23. “In June 2010, the Company [Endo] entered into a Development and Co-Promotion Agreement (the Impax Agreement) with Impax Laboratories, Inc. (Impax), whereby the Company was granted a royalty-free license for the co-exclusive rights to co-promote a next generation Parkinson’s disease product. Under the terms of the Impax Agreement, Endo paid Impax an upfront payment of $10 million, which was recorded as research and development expense for the year ended December 31, 2010. In addition, under the terms of the Impax agreement, Impax could potentially receive up to approximately $30 million in additional payments linked to the achievement of future clinical, regulatory, and commercial milestones related to the development product.” - Endo’s 2010 Annual Report ↩

24. In some cases, the drug maker’s product-switching or “product-hopping” conduct goes even further. For example, the drug maker, after accomplishing the switch, may go to great lengths to withdraw the older drug from the market, making it more difficult for pharmacists to fill prescriptions for the old drug using the generic product. - Earning Exclusivity ↩

25. FTC press release regarding Endo’s settlement for its anti-competitive case, published January 23, 2017 ↩

26. Council for Impax Laboratories, 2017-02-16, cited on page 109 of FTC’s Motion for Partial Summary Decision ↩

27. ” Laboratory studies have shown that IDU carries the highest abuse potential because it delivers a large bolus of the drug directly into the blood stream, which is then rapidly transported to the brain. In contrast, drugs ingested via other routes (e.g., smoking/inhalation) are filtered through the lungs and/kidneys before being absorbed into the brain (Vann et al., 2009, Porrino 1993)” from page 2 of Comparing Injection and Non-Injection Routes of Administration for Heroin, Methamphetamine, and Cocaine Uses in the United States by Scott P. Novak and Alex H. Kral ↩

28. “The committees will be asked to discuss safety issues for new drug application (NDA) 201655, Opana ER (oxymorphone hydrochloride) Extended-release Tablets, by Endo Pharmaceuticals Inc., with the indication of management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The product is an approved extended-release (ER) formulation intended to have abuse-deterrent properties based on its physicochemical properties, however, this information is not currently reflected in product labeling. The committees will be asked to discuss pre- and post-marketing data about the abuse of Opana ER, and the overall risk-benefit of this product. The committees will also discuss abuse of generic oxymorphone ER and oxymorphone immediate-release (IR) products.” The Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee, occurring from March 13-14, 2017. FDA site on the meeting ↩

29. CDC presentation by Jonathan Broks of CDC’s Division of HIV/AIDS Prevention ↩ ↩² ↩³

30. Pages 22-24 of the CDC presentation ↩

31. The question was: “Do the benefits of reformulated Opana ER continue to outweigh its risks?” with votes as follows: “Yes” - 8, “No”- 18, and one abstaining. ↩

32. Page 334 of the 37th Edition of the Orange Book shows generic non-crush-resistant extended-release oxymorphone from Actavis, Impax Labs, Mallinckrodt, Par Pharmaceuticals, Sun Pharmaceuticals, and West-ward Pharmaceuticals with nothing from Endo. Below, there is a listing for Endo’s new, crush-resistant formulation, approved in late 2011, but this has been discontinued. ↩