The Great American Drug Deal

by Peter Kolchinsky

  339Rob Stein, “Critics Slam Cost of FDA-Approved Drug to Prevent Preterm Births,” The Washington Post, March 28, 2011, https://www.washingtonpost.com/national/fda-approval-of-drug-to-prevent-preemies-prompts-price-jump-from-10-to-1500/2011/03/04/AFmRo6qB_story.html?utm_term=.1d238d582cc9.

  340Ed Silverman, “FDA Statement About Makena Compounding Clouds KV Pharma’s Future, Forbes June 18, 2012, https://www.forbes.com/sites/edsilverman/2012/06/18/fda-statement-about-makena-compounding-clouds-kv-pharmas-future/#68de5b5595d3.

  341Richard Knox, “Preemie Prevention Drug Costs 53 Times More Than Generic, But Researchers Find It’s NO Better,” Common Health, Oct. 3, 2017, https://www.wbur.org/commonhealth/2017/10/03/preterm-birth-prevention-drug-costs.

  342Wikipedia Contributors, “New England Compounding Center Meningitis Outbreak.”

  343David B. Nelson et al., “17-Alpha Hydroxyprogesterone Caproate Did Not Reduce the Rate of Recurrent Preterm Birth in a Prospective Cohort Study,” American Journal of Obstetrics & Gynecology 216, no. 6 (2017): 600, accessed Oct. 15, 2019. doi: 10.1016/j.ajog.2017.02.025, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449222/.

  344Incidentally, KV Pharma’s one-time peer Columbia Labs conducted a study of intravaginal progesterone in women at risk of preterm birth because of premature cervical shortening—this was thought to be another seemingly no-brainer patient population that was already commonly treated with off-label intravaginal progesterone. Columbia’s study seemed to show their drug worked but the FDA refused to approve the drug because its effect was only evident in patients enrolled outside of the US, not those in the US.

  345David B. Nelson, “17-Alpha Hydroxyprogesterone Caproate Did Not Reduce the Rate of Recurrent Preterm Birth in a Prospective Cohort Study,” AJOG 216, no. 6 (2017): 600, https://www.ajog.org/article/S0002-9378(17)30294-6/fulltext.

  346In late 2019, an FDA advisory panel offered the agency conflicting advice about whether the drug should remain on the market until yet another study determines Makena’s efficacy or lack thereof. AMAG argued that because Makena is now widely prescribed in the US, they had to enroll their placebo-controlled study mostly outside of the US, where prenatal standard of care is different (though that hardly makes it clear why Makena wouldn’t work for those patients).

  AMAG, AMAG Pharmaceuticals Announces Topline Results from the Prolong Trial Evaluating Makena, March 8, 2019, accessed Nov. 1, 2019, https://www.amagpharma.com/news/amag-pharmaceuticals-announces-topline-results-from-the-prolong-trial-evaluating-makena-hydroxyprogesterone-caproate-injection/.

  347One could argue that the FDA shouldn’t have granted KV Pharma accelerated approval, but, given that the preponderance of evidence suggested that the drug worked, the FDA’s mandate was to make it available for patients while incentivizing its proper testing. Accelerated approval has been a boon to patients and companies in many cases; it may simply turn out that Makena wasn’t one of them.

  348When drug companies productize a homebrew, they not only confirm that it works but they also standardize the therapy so that it is manufactured consistently and in a clean, sterile environment, which is particularly important in the case of injected drugs. By submitting the GMP-manufactured drug for FDA-approval, they also create a roadmap by which the drug can later go generic, bringing the cost down closer to the cost of the original homebrew or possibly even lower (since there are efficiencies at economies of scale compared to having disparate compounding pharmacies serving individual patients).

  349Transplant Activity Report Covering 2012-2016 (Center for International Blood and marrow Transplant Research, 2018), 1, https://bloodcell.transplant.hrsa.gov/research/transplant_data/transplant_activity_report/bycellsource_.pdf;

  Michael S. Broder et al., “The Cost of Hematopoietic Stem-Cell Transplantation in the United States,” American Health & Drug Benefits 10, no. 7 (2017): 366-74, accessed Oct. 15, 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726064/: (crudely: $250,000/allogeneic * 8,800 allogeneic transplants/year + 140,000/autologous * 12,800 autologous transplants/year = $4.3B)

  350Kyle Blankenship, “The Top 20 Drugs By 2018 US Sales.”

  351Kayana Szymczak, “Drug Companies and Doctors Battle Over the Future of Fecal Transplants,” The New York Times, March 3, 2019, https://www.nytimes.com/2019/03/03/health/fecal-transplants-fda-microbiome.html;

  Jim Doyle, “KV Boosts Prenatal Drug Price 100-Fold,” St. Louis Post-Dispatch, March 20, 2011, https://www.stltoday.com/business/local/article_55dbaf88-4ab0-11e0-ad73-0017a4a78c22.html.

  352Openbiome.org

  353The theme from KV and Marathon seems to be that ostensible retribution for price gouging simply shifts a drug’s profitability elsewhere, to an acquiring company. Society will overpay for productized homebrews if this becomes a validated strategy, with those companies willing to do the dirty work of getting such drugs approved and anchoring pricing “negotiations” at a very high launch price being paid to take the heat by future acquirers who keep their hands clean, swooping in like “white knights” to lower the price a bit and collect future profits. The end result is the same—someone profits from doing the work, except it costs extra to pay for all that financial machination.

  15

  Benefit-Risk Balance: Lessons from the Opioid Crisis

  The opioid crisis is a national disaster that continues to devastate thousands of individuals, families, and communities. Given the scope of the crisis, there is a good chance that you have been affected by it or know someone who has, and there are overwhelming odds that you have seen, heard, or read about it somewhere over the last several years. In seeking to understand the roots of the crisis, much of the coverage has assigned much of the blame to the irresponsible greed of Purdue Pharmaceuticals, the maker of OxyContin, and much of that is indeed warranted.

  You won’t find any defense of Purdue here. Public records reveal that Purdue’s executives either encouraged or tolerated profit-seeking without regard for patient safety, akin to heroin dealers preying on their customers.354 They marketed a drug they knew to be dangerous as being safer than it was, hid data that would have revealed its dangers, and knowingly reaped the revenues associated with the non-medical use and diversion of its product.355 Agencies such as the FDA and the Department of Justice are in charge of regulating potential abuses like this, and even back in 2003, the Drug Enforcement Agency (DEA) reported that “the company’s aggressive methods, calculated fueling of demand, and the grasp for major market share very much exacerbated OxyContin’s widespread abuse and diversion.”356 Still, Purdue got away with it for way too long, and countless lives have been destroyed as a result. Currently pursuing bankruptcy and facing a proposed $10 billion settlement, Purdue is the most conspicuous of several companies facing numerous lawsuits over their roles in fueling and stoking the opioid crisis.357 Also accused are other opioid manufacturers Teva Pharmaceutical, Johnson & Johnson,358 Mallinckrodt, and Endo, as well as pharmaceutical distributors McKesson, AmerisourceBergen, and Cardinal Health,359 and pharmacies like CVS, Walgreens, and Walmart for observing and profiting from, but not stopping, some pharmacies from ordering far more pills than could possibly have been intended for legitimate uses.360

  Hopefully, these lawsuits and future settlements will not only deter drug companies from engaging in improper marketing and distribution but also help people and communities affected directly or indirectly by the current crisis.361 Though for thousands upon thousands of families, it is too late.

  It is imperative that something like this never be allowed to happen again. In order to prevent future crises, we must understand what went wrong, how the system broke down, who is to blame, what we can learn from it, and what we can do about it. Assigning all the blame to a single cause—such as irresponsible marketing—would be oversimplifying a complex problem and not d
eriving full value from the vital lessons we should learn from it.

  Benefit-Risk

  All drugs have benefits and risks, and both can vary from patient to patient, depending on the nature or severity of the disease, other illnesses or drugs a person is taking, and many other factors. We often evaluate drugs based upon their benefits and efficacy—what they purport to do and how well they do it. But when a physician is deciding whether or not to prescribe a drug to a patient or the FDA is deciding whether or not to approve a drug for release, they base their decision on both benefits and risks. That’s also why all advertisements that mention a drug must mention both the benefits and the risks. Drug-associated risks can be annoying (e.g., mild constipation) or they can be dangerous (e.g., addiction), even lethal (e.g., respiratory depression).362

  The FDA approved and physicians prescribe blood pressure-lowering drugs like lisinopril because the benefits are significant (preventing strokes, heart attacks, and kidney damage) and, for most patients, outweigh the risks (which can include cough, dizziness, and headaches). But to someone with normal blood pressure, such drugs do not offer benefit—only risk. So the FDA requires that drug developers demonstrate which types of patients are likely to benefit and to what degree they would benefit before deciding whether to approve it, how it is to be prescribed, and to whom. That information appears on the drug’s label, and from there, it’s up to physicians to determine whether a patient meets the requirements for treatment with that drug. If yes, then the drug is said to be “indicated for” that patient and the physician can prescribe the drug and is said to be using the drug “on-label,” meaning in accordance with how the FDA intended. Sometimes, a physician prescribes a drug for a patient or a purpose not expressly approved by the FDA. This kind of usage is known as “off-label.” Either way, no patient is supposed to be able to obtain a prescription drug unless a doctor has written a prescription for it; this is a critical check in our healthcare system.

  When a company produces a particularly dangerous drug or one that carries the risk of addiction, the FDA can also require the company to take extra precautions to ensure that patients only get the doses they are supposed to, and that drugs are not diverted to people who shouldn’t take them. If a drug is particularly liable to be abused (e.g., opioids, amphetamines, and even anabolic steroids), the DEA also plays a role in deciding how dangerous they are and enforcing proper distribution.

  The bottom line is that all of these factors—whether a drug’s benefits outweigh its risks, whether it is potentially addictive, what’s on the drug’s label, to whom it should be prescribed, and how it is distributed—exist in a balance that must be calibrated for each drug to achieve a favorable benefit-risk profile. In the case of opioids, the balance was (and despite recent efforts to improve, still is) so miscalibrated that hundreds of thousands of lives were destroyed. Sometimes the harm came directly from patients abusing duly prescribed opioid drugs and other times from patients, having become addicted and then cut off from access to prescription opioids, turning to illegal and more potent narcotics, such as heroin and illegally manufactured fentanyl. These illicit opioids don’t come with labels, aren’t standardized from one dose to the next, and can easily result in potentially lethal overdoses in even the most experienced users.

  Societies worldwide have long struggled with the benefit-risk profile of opioid drugs. And while modern medicine is better and safer in countless ways than in centuries past, the opioid crisis we have today was exacerbated not just by companies knowingly engaging in improper marketing but also, perversely, by the hubris of the drug industry, the FDA, and highly trained physicians, all of whom were over-confident in their technology, data, and judgment.

  Let’s unpack that last statement and start with an example of how freely physicians can exercise their judgment when treating their patients.

  Physicians’ Choice: Off-label Drug Use

  When sorting out whether a drug is appropriate for a patient, all a doctor has to do is compare the patient’s medical record and diagnosis with a drug’s label, and then determine if the two match up—right? In practice, it isn’t always so straightforward.

  In some cases, the physician thinks that a drug can help someone for whom it is not strictly indicated, so they prescribe it “off-label,” as discussed above. That can happen without any company promoting its off-label use and without patients even asking for it, though sometimes patients might ask, and pharmaceutical companies have been fined in the past for improper off-label marketing.363 But why would a physician use a drug in a way that the FDA has not approved? Perhaps the physician knows, from her own experience, that the drug has more uses than the ones listed on its label. Some physicians even conduct their own clinical studies to find new uses for existing drugs and publish their results. In this way, off-label uses can eventually gain traction in the medical community as word spreads. These uses can sometimes make their way into medical guidelines, even though these new uses haven’t been granted FDA approval.

  Prazosin—A Case Study In Off-label Use

  Prazosin was first approved in 1976 to treat high blood pressure. These days, it is less commonly prescribed for that purpose because better and safer drugs, like lisinopril, have come along. However, prazosin is used off-label to treat enlarged prostate glands, red scorpion stings,364 and nightmares associated with post-traumatic stress disorder (PTSD).365 Prazosin’s benefits in treating PTSD-related nightmares were discovered serendipitously long after it was generic, when a physician at the Department of Veterans Affairs (VA) observed that a patient taking the drug to treat an enlarged prostate (its main off-label use at the time) also experienced relief from trauma-associated nightmares.366 Since then, a number of studies have demonstrated its benefit-risk in that indication, but you won’t find the words “trauma” or “nightmare” on the label.367

  In this case, the fact that prazosin has long been generic is important for two reasons. One, it means that no one is marketing prazosin for any purpose—either on- or off-label—so physicians looking for ways to treat patients with PTSD nightmares must rely on other physicians, research papers, the internet, or even patients, in order to learn of prazosin’s utility.368 Two, once a patient has been prescribed prazosin off-label, insurance companies will probably pay for it without checking whether the patient actually has high blood pressure, the on-label condition. As an inexpensive generic, prazosin costs the payer so little that it’s not worth it for the payer to worry about it being over-prescribed or over-used. Still, in the case of nightmares associated with PTSD, if an insurance company did push back, a physician could point to the abundance of scientific studies and medical guidelines that justify such usage—and the insurance company would likely relent.

  The bottom line is that medicine has long had a tradition of physicians exercising their own judgment about how a drug can best be used, informed but not necessarily constrained by what the FDA has approved a drug for and what its label says.

  But sometimes it’s important to put guardrails around how a drug is prescribed and make sure only specific patients get it under carefully monitored conditions, helping to shift the benefit-risk balance away from a drug’s risks.

  Risk Evaluation and Mitigation Strategies

  Some drugs are so dangerous, but so essential for patients, that the FDA approves them with special restrictions and careful monitoring of side effects and off-label use. These Risk Evaluation and Mitigation Strategies (REMS) are intended to tip the benefit-risk of a drug away from the risks so that patients can still benefit. Congress created the formal concept of REMS for the FDA to administer in the Food and Drug Administration Amendments Act of 2007, but prior to that moment companies still ran similar risk management programs to protect patients from harm and themselves from liability.369

  In Chapter 9, I discussed Jazz Pharmaceuticals and its use of REMS to prevent generics of its narcolepsy drug Xyrem (brand name for sodium o
xybate) from entering the market. But there’s another story behind Xyrem that is pertinent to the opioid crisis and will help shed some light on how the FDA thinks about protecting the public from a drug’s risks.

  When prescribed and used properly, Xyrem helps patients diagnosed with narcolepsy to experience a profoundly deep, restorative sleep, which can be of great benefit to patients so exhausted from waking up countless times throughout the night that they otherwise can fall asleep at random moments during the day.

  But the risks associated with Xyrem are varied and extreme. For one, sodium oxybate-induced sleep is so deep that patients are rendered oblivious to their surroundings and often have no memory of what transpired while they were unconscious. This can make them vulnerable to sexual predators, which is why sodium oxybate—or “GHB,” as its active component is more commonly known—is considered a date-rape drug. The incidence of sexual assault involving GHB and other sedatives is disturbingly common.370 In addition, at high doses, it can cause a feeling of euphoria, which can lead to addiction, and it can even suppress a person’s ability to breathe. Hundreds of deaths have been reported in association with GHB use.371 In 2000, as its risks became more obvious and its use more widespread,372 the DEA classified GHB as a Schedule 1 drug, in the same category as heroin, LSD, ecstasy, and synthetic marijuana.373

  In 2002, the FDA approved Xyrem for narcolepsy with a strict risk-management program that would later be converted to a REMS program. Today, Jazz tracks every physician who prescribes Xyrem and every patient to whom it’s prescribed, mails the drug directly to patients (it doesn’t go through a local pharmacy), has the patient or a representative sign for the package (it’s never left unattended), and calls patients or their caregivers to explain the dangers of the medication and how to use it properly.374 Jazz also had to get the DEA’s approval to produce Xyrem, which requires Jazz to account for every drop it makes and provide proof to the DEA that none has been diverted from the manufacturing plant.