Latest Drugwonks' Blog

Per this article from the Washington Post, it's important to note that "not doing additional clinical trials," as I was quoted as saying, does not mean ignoring a more regular and robust use of electronically collected and validated real world data to ascertain the performance of off-label use. The FDA is required by the 21st Century Cures act to develop standard protocols for the use of real world data -- and nowhere is this more crucial than in determining the safe and effective use of medicines via off-label prescribing.

Pressure mounts to lift FDA restrictions on off-label drugs
By Michael Ollove

When the Food and Drug Administration gives its okay for a new drug to be sold, it specifies the diseases or conditions for which the medicine has been approved. That does not mean doctors can’t prescribe that drug for other ailments. They do. All the time. And it’s perfectly legal.

But for decades drugmakers have been barred from promoting their drugs for uses that hadn’t gone through clinical trials. Worried about safety issues, the FDA has prosecuted numerous drugmakers for illegal promotion of off-label uses and extracted billions of dollars in fines and settlements.

Those restrictions could be giving way, perhaps in part because of the appointment of Scott Gottlieb as the new FDA commissioner in May. Before his nomination, Gottlieb, a physician and a resident fellow at the conservative American Enterprise Institute, advocated loosening the restrictions on off-label communications.

That’s exactly what Arizona did earlier this year when it became the first state to allow drugmakers to communicate directly with doctors and insurers about alternative uses of approved prescription drugs. Advocates for the loosening of the restrictions say they expect similar measures to be introduced in other state legislatures in the coming year.

These developments come on the heels of two legal cases in which federal district courts ruled that the First Amendment does not allow the FDA to prevent manufacturers from providing truthful information about their products to doctors.

Supporters say it makes sense to get rid of the restrictions on off-label drugs at a time when plenty of information and misinformation about prescription drugs is readily available to anyone with an Internet connection. And, they insist, who better to provide accurate facts about their products than their makers?

“We believe it’s a disservice to patients and physicians to prevent them from getting information from manufacturers who know their medicines best,” said Naomi Lopez Bauman, director of health-care policy at the Goldwater Institute, the libertarian think tank that devised the Arizona legislation and is promoting it in other states.

Bauman said she expects bills to be filed elsewhere in the coming year, but she refused to disclose which states Goldwater is targeting.

Many critics, however, remain firmly opposed to such efforts. “There have literally been dozens and dozens of examples of ­off-label uses of drugs encouraged by pharmaceutical companies in reckless ways that have led to substantial patient morbidity and mortality,” said Aaron Kesselheim, director of the Program on Regulation, Therapeutics and Law at Harvard Medical School.

Wide off-label use

Before a new drug can be sold in the United States, the FDA must affirm that it is safe and effective for specified uses, which are then described in the medicine’s labeling. But once a drug is approved, doctors are free to prescribe it for uses not specified in the labeling. That is because the FDA regulates products but not the practice of medicine.

Prescribing for off-label uses has become common. A 2013 study found that 30 percent of the prescriptions for oncology drugs were used for off-label purposes. Another found that 70 percent of a popular category of pediatric anti­psychotic drugs were prescribed for purposes not cited in the FDA’s approval of those medicines, including, for example, for the treatment of attention-deficit/hyperactivity disorder.

Sometimes the off-label use of prescription drugs comes to be considered the best treatment for certain conditions. “For some cancer drugs, the best therapeutic use is for off-label purposes,” said Peter Pitts, president and co-founder of the Center for Medicine in the Public Interest, a nonprofit research and advocacy organization that is funded by the pharmaceutical industry.

One example is tricyclic antidepressants, a class of drugs that do not have FDA approval as treatment for nerve-related pain yet are considered by doctors to be the first choice of drugs for that purpose.

Nevertheless, a recent study published in the journal JAMA found a higher incidence of adverse drug effects from off-label use than from on-label use.
Pitts does not think the FDA should prohibit drugmakers from dispensing information that might be relevant to those ­off-label uses. “In fact, it’s almost irresponsible not to let them dispense that information as long as it’s truthful, accurate and not misleading,” he said.

Pitts and others say it is unreasonable to expect drug manufacturers to embark on additional clinical trials to demonstrate the safety and efficacy of already approved drugs for new purposes. That effort, like the original process, could cost drugmakers hundreds of millions of dollars in new testing and take years.

“If your drug is approved for X, why would you ever commit millions in additional testing to get approval for Y, when it’s already legal to use it for Y?” Pitts said.

Undermining the process?

The answer, according to opponents of loosening the restrictions, is public safety. If the FDA didn’t approve a drug for off-label uses, they say, that means the drugmaker hasn’t produced evidence to demonstrate the drug is safe and effective for those other uses.

“If you take it as your premise that an objective approval by someone with no financial interest is necessary to protect patients, then marketing a drug for unapproved uses is the same as marketing an unapproved drug,” said Allison Zieve, director of the litigation group at Public Citizen, a consumer watchdog group that opposes loosening the communication restrictions. To allow drugmakers to do so, she said, would undermine the whole system of FDA drug approval.

Zieve and other opponents point out that the limitations do not prevent the manufacturers from sharing peer-reviewed, scientific articles about off-label uses of their drugs with doctors and others. They just can’t promote off-label use in their marketing.

The Goldwater Institute — named for Barry Goldwater, who was a U.S. senator from Arizona — wrote the model law upon which the Arizona legislation was based. “It just seemed to me that this was a way to give physicians more information to help them treat their patients,” said Phil Lovas, a Republican who sponsored the bill while he was a member of the Arizona legislature.

The pharmaceutical industry did not formally lobby on behalf of the bill, although it has called for a revision in the FDA policies on communications about off-label uses.

Some critics say the Arizona law is meaningless because states cannot preempt federal law and because they don’t believe pharmaceutical companies will promote off-label uses unless given more direction from either the FDA, Congress or higher courts.

But the Goldwater Institute insists the federal law prohibiting drugmakers from promoting off-label use is unconstitutional. The group points to two rulings, one in 2012 and the other in 2015, in which federal courts in New York found that the FDA restriction violated the free-speech provisions of the First Amendment.

The Goldwater Institute also was behind another recent issue involving prescription drugs: what is called the “right-to-try” laws that give desperately ill patients the opportunity to receive promising experimental drugs that do not yet have FDA approval. Since 2014, 37 states have adopted right-to-try legislation, although critics too said at the time that those laws didn’t supersede federal law, which sharply restricts the dissemination of experimental drugs.

But the state laws did create momentum, which may have contributed to passage of a right-to-try bill in the U.S. Senate this summer. “I firmly believe state activity with right-to-try pushed it forward at the federal level,” said Lovas, who left the Arizona legislature in the spring to take a position in the Trump administration. “I’d like to see the same thing happen with this.”

It might. U.S. Reps. H. Morgan Griffith of Virginia and Brett Guthrie of Kentucky, both Republicans, filed separate bills this spring to ease the flow of information on off-label drugs. The House held a hearing on the bills in July but has taken no action since.
Per FDA Commissioner Scott Gottlieb:

Complex drugs comprise high cost medicines like metered dose inhalers used to treat asthma, as well as some costly injectable drugs. These medicines generally have at least one feature that makes them harder to “genericize” under our traditional approaches. As a consequence, these drugs can face less competition. In some cases, costly, branded drugs that are complex drugs have lost their exclusivity, but are subject to no generic competition.

When considering the scope of complex drugs, people often first think of drug products where the active ingredient itself is complex. Glatiramer acetate injection, a drug used in the treatment of multiple sclerosis, is a good example. However, the terms “complex drug product” and “complex generic drug” are used to refer to a much larger and diverse group of drug products. In addition to drug products with complex active ingredients, or sites of action, complex drug products also include complex drug-device combination products.

Together, this diverse collection of drug products has one or more elements that are more complex than an average drug product. This complexity, in turn, means that the scientific and regulatory pathways for approval of generic versions of these drug products are not as well traveled by generic drug developers. In some cases, use of another established regulatory pathway may be appropriate to streamline development.

Bioequivalence for complex generic drugs can be challenging with complex drug products that can’t be easily measured in the blood, or when the drug’s therapeutic effect is delivered locally to a particular organ, rather than systemically, through the bloodstream.  In other instances, showing active ingredient sameness can be challenging when the drug product contains an active mixture of components and not a single active molecule.

We recognize these problems and are taking a number of new steps to support the development of high quality ANDAs for complex generic drugs.

First, FDA is issuing a draft guidance to assist ANDA applicants and prospective ANDA applicants in creating and submitting pre-ANDA meeting requests, including meeting package materials, so FDA can give better advice to sponsors looking to develop complex generic drugs.

The guidance provides information on requesting and conducting product development meetings, pre-submission meetings, and mid-review cycle meetings with FDA. These meetings will allow for enhanced communication between generic drug applicants and FDA early in the generic drug development process, allowing for more efficient generic drug development, review, and approval pathways. We’ve found from analyzing our new drug program, that early and better meetings between FDA and sponsors can improve development timelines. We want to bring these same types of opportunities to developers of complex generics.

Second, we’re issuing a draft guidance  to help applicants determine when submission of ANDAs for certain complex products, known as peptides, would be appropriate. Peptides are compounds made up of 40 or fewer amino acids, the building blocks of proteins. There are a number of branded medicines that are peptides, where exclusivity has lapsed, but these drugs face little or no competition. This new guidance applies to ANDAs for certain specific synthetic peptides, namely, glucagon, liraglutide, nesiritide, teriparatide, and teduglutide, that reference brand-name versions of these peptides manufactured using recombinant DNA technology.

We’re doing all of this without sacrificing the scientific rigor of the process one bit. A central aspect of our approach, and our efforts to spur innovation and generic competition, is focused on adopting more rigorous and sophisticated science, including sophisticated quantitative methods and computational modeling, in drug development, evaluation, and review.

We’ll soon release other important policies aimed at spurring competition to complex drugs. But we know that better guidance isn’t the only answer. Some drugs lack generic competition because they cannot be measured through traditional in vivo bioequivalence methods and there’s no efficient and convincing bioequivalence test method available.

In these instances, an applicant needs to conduct more extensive clinical endpoint testing to show bioequivalence of a generic drug to a brand-name drug. This can be burdensome and discourage generic product development. A further barrier to generic competition for certain complex drug products is the lack of established methods for showing the sameness of the active ingredient of a proposed generic drug to a brand-name drug for certain complex drugs.

Over the next year, FDA’s generic drug regulatory science program will work to identify gaps in the science and develop more tools, methods, and efficient alternatives to clinical endpoint testing, where feasible. To help with this task, we’re holding a series of important scientific workshops, beginning today, that will identify opportunities for complex generic drug development, discuss quantitative modeling approaches and principles and aid product-specific guidance development. The workshops will also help in the development of new analytical tools that will help overcome the unique development and regulatory challenges for demonstrating active ingredient sameness in complex products. We intend for these efforts to speed product development, reduce development costs, and improve access to these products.

Scott's full announcement can be found here.
Lay down with dogs, wake up with fleas.

Now replace “dogs” with Prescription Benefit Managers” and “fleas” with lawsuits and you’ve got a pretty good idea of what’s driving the Pfizer/Johnson & Johnson story. But there’s more to it than money.


In brief, Pfizer has filed a complaint against Johnson & Johnson, claiming J&J was taking anticompetitive steps to block the sale of Pfizer’s drug Inflectra. 

(Inflectra is Pfizer's version of J&J's blockbuster drug Remicade — which treats autoimmune diseases like rheumatoid arthritis and Crohn's disease. Approved in 1998, it generated $4.8 billion in sales for J&J. Pfizer and its partner Celltrion got its biosimilar version of Remicade, called Inflectra, approved in April 2016. The two drugs are both versions of infliximab.)

At launch, Pfizer priced Inflectra at a 15% discount to Remicade's list price of $1,113 a vial.  That’s the idea behind biosimilars right, safety, efficacy – and competition to drive down costs. Keep reading.

Per Pfizer’s lawsuit, Remicade still retains 96% of the market. Pfizer’s assertion is that’s because of contracts between J&J and health insurers that require Remicade — as opposed to Inflectra — to be used first before trying other treatments for new patients.

Anti-competitive? That’s for the court to decide. But should insurers be able to block patient access for profit-driven purposes– by contract? Optimizing best practice is one thing. Venality is something else.

Wait, it gets worse. As part of the J&J contract, insurers had to commit to not reimbursing for Inflectra. And since insurers won't cover Inflectra, hospitals (according to Pfizer) don't want to keep it in stock.

Anti-competitive? Per Pfizer, “… due to J&J’s exclusionary conduct, competition has been foreclosed. J&J maintains its monopoly and has continued to capture over 96 percent of infliximab sales even while maintaining prices far above competitive levels."

Inflectra originally came out at 15% discount to Remicade but Pfizer has cut the price as the market has changed. A Pfizer spokesman said last week that the product is now priced at a 35% discount to Remicade’s wholesale acquisition cost. Also the Average Sales Price (ASP --the net price) for Inflectra and Remicade are trending in opposite directions, since launch of Inflectra ASP for Remicade has gone up while ASP for Inflectra is trending down.

As we debate drug pricing, consider this, CMS could save $140 million annually if most of their eligible patients used Inflectra rather than Remicade. It’s important to note that Inflectra has been not been approved as interchangeable with Remicade, but it does not mean (in a regulatory sense) that one product is in any way superior (in a therapeutic sense) to the other. So, why are payers so willing to block the less expensive, clinically equivalent product for new patients? The answer seems to be … because insurers can make more money by effectively maintaining a Remicade monopoly.

Is an insurer-driven monopoly good for patients? Will it lower the co-pay or co-insurance for a single patient? Sadly, these are rhetorical questions.
Is it sounding anti-competitive yet? What about anti-patient? At a time when we are debating both the price and the value of medicines, what’s wrong with this picture?

Here’s what Dominic Caruso, Johnson & Johnson’s Chief Financial Officer said at the Morgan Stanley Healthcare Conference on September 13th:

“ … relatively speaking, the economic incentive is small because the biosimilars … indicated 35% off list. And with Remicade being in the market already for many, many, many years, the way rebates go in the pharmaceutical market, we’re already there.”

But, in terms of “doing the right thing,” is “there” where we really want to be?

J&J’s response to the Pfizer lawsuit, "We are effectively competing on value and price and to date.”

But how do you “compete” if you don’t allow the other team on the field?

At the end of the day, the most important question is, will this lawsuit help or hurt patients? In the long term it will help if it reveals the venality of a rebate-driven reimbursement system. That way we can aggressively (and a lot more honestly) commence the conversation about pricing medicines based on real world value.

Oyez, Oyez.

War Against the Orphans

  • 09.20.2017
  • Robert Goldberg
Great piece in the Weekly Standard by former HHS General Counsel Mike Astrue about the well-organized war against people with rare diseases.  What Mike doesn't note is that the war is being financed largely by the Laura and John Arnold Foundation.   More on this connection after Rosh Hashana.  

Gottlieb Gets Real ... World Evidence

  • 09.20.2017
  • Peter Pitts
Yesterday, at a National Academy of Sciences workshop on Real World Evidence, FDA Commissioner Scott Gottlieb expressed the agency’s commitment to advancing the use of RWE, defended the idea that data from clinical experience should be incorporated into regulatory decisions, and acknowledged that the agency won’t have the last word when it comes to interpreting real world evidence.

BioCentury reports that Gottlieb took on critics who say FDA should only consider data from randomized, controlled trials. “For those who’d challenge the suitability of our effort to incorporate real world evidence into our regulatory model, I’d challenge you with the opposite intention: Should a product be marketed based on a data set that speaks to a limited and rigidly constructed circumstance, when the clinical use, and in turn the evidence we might have to evaluate the product, could have been far richer, far more diverse, and more informative?”

RWE is essential to making FDA’s decisions relevant to entire healthcare system, Gottlieb said. He noted that data gathered from routine clinical experience is already being used to make medical, payment and coverage decisions. “We need to close the evidence gap between the information we use to make FDA’s decisions, and the evidence increasingly used by the medical community, by payers, and by others charged with making healthcare decisions.”

In a move that is unusual for a regulator, Gottlieb acknowledged that FDA’s policies on and interpretation of RWE may not be definitive. “FDA needs to think of itself as a curator of information, not just an arbiter, where a single truth standard is secured to a fixed orthodoxy.” He added: “There’s often no single truth standard when it comes to the evidence used to support medical decisions.”

Gottlieb placed RWE in the context of a regulatory life cycle that extends well beyond product approval. “No product is all risky and uncertain one day, and completely safe and effective the next,” he said. “We can’t allow our need for a point of regulatory accountability to prevent us from looking across the line we have to draw, at practical information that’s collected both before and after our point of demarcation, when a product gains a license for initial market entry."

Getting more reliable RWE will require changes in the way clinical data is collected, Gottlieb said, including a shift from electronic health records designed primarily to support billing to records that routinely capture information about what is happening with patients. He also committed FDA to take steps to provide more clarity about the requirements for using RWE in regulatory submissions.

Vinay Prasad's Fake Pharma Numbers

  • 09.19.2017
  • Robert Goldberg
Attempting to discredit the $2.6 billion drug development cost a developed by Joseph DiMasi is a long-standing tradition among those who think that pharma is too profitable and greedy. [i]

But why contend with the DiMasi numbers and submit your analysis to a leading economic journal when you can just fabricate your own lowball estimates and get published in a second-tier medical journal run by your friends and allies in the war against Big Pharma?

That’s what Vinay Prasad and Sham Mailankody did when they published Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval in JAMA Internal Medicine.  The study looks at 10 small biotech companies that successfully developed a cancer drug over the past 15 years, The authors conclude that on average it costs $648 million (not including capital costs) to develop a drug to generate an average of $7 billion in revenue.   They also claim that “sales of these 10 drugs since approval was $67.0 billion compared with total R&D spending of $7.2 billion.” 

In a shot at DiMasi, Prasad and Sham claim “this analysis provides a transparent estimate of R&D spending on cancer drugs and has implications for the current debate on drug pricing.”

In fact, the article consists of falsehoods, carefully constructed to fit that narrative. And that’s not including many of the study’s methodological flaws such as inflating all prior spending and revenues to 2017 dollars and using a low cost of capital (7 percent) when the cost of capital for biotech is closer to 16-20 percent.

Far worse is the outright distortion of data to reach a preordained conclusion. To get to $67 billion in revenues from $7.2 billion in R&D, the authors had to count the proceeds of acquisitions as product sales. They included Pfizer’s acquisition of Medivation for $14 billion, Takeda’s purchase of Ariad for $4 billion, Abbie Vie’s acquisition of Pharmacyclics for $22 billion.   

Next, the authors understate R&D expenditures. (To find that data and other information the authors “reviewed publicly available SEC 10-K filings, available at the SEC website ...and all expenses listed as R&D were totaled for the cumulative duration of R&D for each drug.”)

In fact, after reviewing the same 10-K filings it is clear the authors deliberately exclude R&D for expanded uses of the approved drug, post-marketing studies and trials needed for approvals in other countries.  They also exclude any R&D spending for new projects even though the revenues of the approved drug were being used to fund those efforts.

The charts below take the data from the 10K reports of the companies the authors surveyed and states it as reported to the SEC. Absent the Enron style accounting of the authors, the data is a more truthful representation of the total R&D and profits (or losses) the companies generated individually and as a ‘portfolio’.  


Whereas the authors want you to believe there is a $60 billion profit from R&D in fact, only 2 of the 10 companies had cumulative profits. As a ‘portfolio’ the group lost money and spent 66 percent of gross profits on R and D. Prasad and Sham claim that it’s only 10 percent of revenues.

Further, the authors are conspicuously uninterested about what companies did with revenues from approved products. In fact, every company increased R&D and spent more on production facilities over the years reviewed. As I noted, much of the added spending went to finding new therapeutic uses for their products, as well as completing post-marketing studies and trials to obtain approval overseas. Ignoring that R&D investment is also hypocritical since the purchase price of the companies that the authors misleadingly count as revenue were based on the pipeline and the platform producing the each firm's approved drug.

Indeed, an objective editor of a journal of economics would have caught this intellectual malfeasance. More broadly, an editor might have if developing new drugs is anywhere from 75 to 90 percent cheaper than reliable and reproducible estimates of about $2 billion, why haven’t more companies jumped in? If these activists have cracked the code of drug development set up a company and sell drugs at their “just price” (slightly above the cost of production) why haven’t venture capitalists funded their startup? Because the model the authors construct is based on lies that promote a fiction that cannot be found in the real world.

But that’s the point. The depiction of profitability especially among the smaller companies that are the largest source of new medicines is deliberately deceptive. It is designed to replace objective truth with a narrative and hard evidence with soft propaganda.

The article should be retracted, but that’s unlikely. Prasad discloses that he receives funding from the Laura and John Arnold Foundation. So does ICER. That connection is important because Rita Redberg, the editor of JAMA Internal Medicine is also working for ICER and her position is largely possible because of Arnold funding as well. Moreover, Redberg wrote an article with Prasad to support ICER’s position on the price of specific medicines and supports Prasad’s assertion that most cancer drugs are not really that effective.

The Prasad and Redberg collaboration, including the use of medical journals as outlets, is part of a bigger effort and group of activists funded by the Arnold Foundation.  In addition to Prasad and ICER (and others), the Arnold Foundation is funding media outlets to spread these mistruths once they are placed in medical journals friendly to the cause. The goal is to replace objective truth with a narrative in which the enlightened Arnold acolytes tell the rest of us what drugs should cost, what medicines we should use and what lives are worth saving. 

Where is the FDA going with off-label speech? Here’s what Commissioner Gottlieb had to say last week:

“It’s very clear right now that the courts recognize commercial free speech as constitutionally protected, and it’s very clear that the agency has lost a series of First Amendment challenges … What I want to make sure is that we have a legally enforceable set of rules that we’re operating from that we’re able to use to promote our public health goals. So we need to have clear regulation that is legally sustainable and we need to enforce against that vigorously.”

“To the extent that we have certain regulatory parameters that either we feel or others feel is in conflict with the court’s interpretation of what constitutes commercially protected speech and the cope of FDA’s ability to regulate that, we need to resolve that. We can’t be operating from a platform where our regulations might be in perpetual conflict with the courts and then we are reluctant to take action for fear that we might run afoul of the courts. We need to have clear regulation that is aligned with the interpretations of the courts around what is and what isn’t permissible and we need to enforce vigorously against that.”

Key phrase, “We need to have clear regulation.” That’s as welcome news as it is unusual since (when it comes to regulating speech), the agency’s default proposition has been vigorous ambiguity.

The Commissioner’s statement also seems to throw onto the dustbin of history, the agency’s memo (issued in the waning days of the Obama administration) Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products, which asserted FDA's stance against off-label communications.

Gottlieb-watchers understand his support of making sure physicians and patients have access to truthful accurate and non-misleading information about FDA-approved medicines –- both on and off-label. Time marches on and regulatory practices must evolve to better serve the public health.

Off-label communications is about getting the right medicine to the right patient in the right dose at the right time.  Off-label communications advances both the practice of medicine and the safe and effective use of medicines.

Stay tuned.
Amid Opioid Crisis, Insurers Restrict Pricey, Less Addictive Painkillers

Drug companies and doctors have been accused of fueling the opioid crisis, but some question whether insurers have played a role, too.
by Katie Thomas, The New York Times and Charles Ornstein, ProPublica

At a time when the United States is in the grip of an opioid epidemic, many insurers are limiting access to pain medications that carry a lower risk of addiction or dependence, even as they provide comparatively easy access to generic opioid medications.

The reason, experts say: Opioid drugs are generally cheap while safer alternatives are often more expensive.

Drugmakers, pharmaceutical distributors, pharmacies and doctors have come under intense scrutiny in recent years, but the role that insurers — and the pharmacy benefit managers that run their drug plans — have played in the opioid crisis has received less attention. That may be changing, however. The New York State attorney general’s office sent letters last week to the three largest pharmacy benefit managers — CVS Caremark, Express Scripts and OptumRx — asking how they were addressing the crisis.

ProPublica and The New York Times analyzed Medicare prescription drug plans covering 35.7 million people in the second quarter of this year. Only one-third of the people covered, for example, had any access to Butrans, a painkilling skin patch that contains a less-risky opioid, buprenorphine. And every drug plan that covered lidocaine patches, which are not addictive but cost more than other generic pain drugs, required that patients get prior approval for them.

In contrast, almost every plan covered common opioids and very few required any prior approval.

The insurers have also erected more hurdles to approving addiction treatments than for the addictive substances themselves, the analysis found.
Alisa Erkes lives with stabbing pain in her abdomen that, for more than two years, was made tolerable by Butrans. But in January, her insurer, UnitedHealthcare, stopped covering the drug, which had cost the company $342 for a four-week supply. After unsuccessfully appealing the denial, Erkes and her doctor scrambled to find a replacement that would quiet her excruciating stomach pains. They eventually settled on long-acting morphine, a cheaper opioid that UnitedHealthcare covered with no questions asked. It costs her and her insurer a total of $29 for a month’s supply.

The Drug Enforcement Administration places morphine in a higher category than Butrans for risk of abuse and dependence. Addiction experts say that buprenorphine also carries a lower risk of overdose.

UnitedHealthcare, the nation’s largest health insurer, places morphine on its lowest-cost drug coverage tier with no prior permission required, while in many cases excluding Butrans. And it places Lyrica, a non-opioid, brand-name drug that treats nerve pain, on its most expensive tier, requiring patients to try other drugs first.

Erkes, who is 28 and lives in Smyrna, Georgia, is afraid of becoming addicted and has asked her husband to keep a close watch on her. “Because my Butrans was denied, I have had to jump into addictive drugs,” she said.

UnitedHealthcare said Erkes had not exhausted her appeals, including the right to ask a third party to review her case. It said in a statement, “We will work with her physician to find the best option for her current health status.”

Matthew N. Wiggin, a spokesman for UnitedHealthcare, said that the company was trying to reduce long-term use of opioids. “All opioids are addictive, which is why we work with care providers and members to promote non-opioid treatment options for people suffering from chronic pain,” he said.

Dr. Thomas R. Frieden, who led the Centers for Disease Control and Prevention under President Obama, said that insurance companies, with few exceptions, had “not done what they need to do to address” the opioid epidemic. Right now, he noted, it is easier for most patients to get opioids than treatment for addiction.

Faced with competition, some pharmaceutical companies are cutting deals with insurance companies to favor their brand-name products over cheaper generics. Insurers pay less, but sometimes consumers pay more. Adderall XR, a drug to treat attention-deficit hyperactivity disorder, is a case in point.
Leo Beletsky, an associate professor of law and health sciences at Northeastern University, went further, calling the insurance system “one of the major causes of the crisis” because doctors are given incentives to use less expensive treatments that provide fast relief.

The Department of Health and Human Services is studying whether insurance companies make opioids more accessible than other pain treatments. An early analysis suggests that they are placing fewer restrictions on opioids than on less addictive, non-opioid medications and non-drug treatments like physical therapy, said Christopher M. Jones, a senior policy official at the department.

Insurers say they have been addressing the issue on many fronts, including monitoring patients’ opioid prescriptions, as well as doctors’ prescribing patterns. “We have a very comprehensive approach toward identifying in advance who might be getting into trouble, and who may be on that trajectory toward becoming dependent on opioids,” said Dr. Mark Friedlander, the chief medical officer of Aetna Behavioral Health who participates on its opioid task force.

Aetna and other insurers say they have seen marked declines in monthly opioid prescriptions in the past year or so. At least two large pharmacy benefit managers announced this year that they would limit coverage of new prescriptions for pain pills to a seven- or 10-day supply. And bowing to public pressure — not to mention government investigations — several insurers have removed barriers that had made it difficult to get coverage for drugs that treat addiction, like Suboxone.

Experts in addiction note that the opioid epidemic has been changing and that the problem now appears to be rooted more in the illicit trade of heroin and fentanyl. But the potential for addiction to prescribed opioids is real: 20 percent of patients who receive an initial 10-day prescription for opioids will still be using the drugs after a year, according to a recent analysis by the CDC.

Several patients said in interviews that they were terrified of becoming dependent on opioid medications and were unwilling to take them, despite their pain.

In 2009, Amanda Jantzi weaned herself off opioids by switching to the more expensive Lyrica to treat the pain associated with interstitial cystitis, a chronic bladder condition.

But earlier this year, Jantzi, who is 33 and lives in Virginia, switched jobs and got a new insurer — Anthem — which said it would not cover Lyrica because there was not sufficient evidence to prove that it worked for interstitial cystitis. Jantzi’s appeal was denied. She cannot afford the roughly $520 monthly retail price of Lyrica, she said, so she takes generic gabapentin, a related, cheaper drug. She said it does not manage the pain as well as Lyrica, which she took for eight years. “It’s infuriating,” she said.

Jantzi said she wanted to avoid returning to opioids. However, “I could see other people, faced with a similar situation, saying, ‘I can’t live like this, I’m going to need to go back to painkillers,’ ” she said.

In a statement, Anthem said that its members have to meet certain requirements before it will pay for Lyrica. Members can apply for an exception, the insurer said. Jantzi said she did just that and was turned down.

With Butrans, the drug that Erkes was denied, several insurers either do not cover it, require a high out-of-pocket payment, or will pay for it only after a patient has tried other opioids and failed to get relief.

In one case, OptumRx, which is owned by UnitedHealth Group, suggested that a member taking Butrans consider switching to a “lower cost alternative,” such as OxyContin or extended-release morphine, according to a letter provided by the member.

Wiggin, the UnitedHealthcare spokesman, said the company’s rules and preferred drug list “are designed to ensure members have access to drugs they need for acute situations, such as post-surgical care or serious injury, or ongoing cancer treatment and end of life care,” as well as for long-term use after alternatives are tried.

Butrans is sold by Purdue Pharma, which has been accused of fueling the opioid epidemic through its aggressive marketing of OxyContin. Butrans is meant for patients for whom other medications, like immediate-release opioids or anti-inflammatory pain drugs, have failed to work, and some scientific analyses say there is not enough evidence to show it works better than other drugs for pain.

Dr. Andrew Kolodny is a critic of widespread opioid prescribing and a co-director of opioid policy research at the Heller School for Social Policy and Management at Brandeis University. Kolodny said he was no fan of Butrans because he did not believe it was effective for chronic pain, but he objected to insurers suggesting that patients instead take a “cheaper, more dangerous opioid.”

“That’s stupid,” he said.

Erkes’s pain specialist, Dr. Jordan Tate, said her patient had been stable on the Butrans patch until January, when UnitedHealthcare stopped covering the product and denied Erkes’s appeal.

Without Butrans, Erkes, who once visited the doctor every two months, was now in Tate’s office much more frequently, and once went to the emergency room because she could not control her pain, thought to be related to an autoimmune disorder, Behcet’s disease.

Tate said she and Erkes reluctantly settled on extended-release morphine, a drug that UnitedHealthcare approved without any prior authorization, even though morphine is considered more addictive than the Butrans patch. She also takes hydrocodone when the pain spikes and Lyrica, which UnitedHealthcare approved after requiring a prior authorization.

Erkes acknowledged that she could have continued with further appeals, but said the process exhausted her and she eventually gave up.
While Tate said Erkes had not shown signs of abusing painkillers, her situation was far from ideal. “She’s in her 20s and she’s on extended-release morphine — it’s just not the pretty story that it was six months ago.”

Many experts who study opioid abuse say they also are concerned about insurers’ limits on addiction treatments. Some state Medicaid programs for the poor, which pay for a large share of addiction treatments, continue to require advance approval before Suboxone can be prescribed or they place time limits on its use, both of which interfere with treatment, said Lindsey Vuolo, associate director of health law and policy at the National Center on Addiction and Substance Abuse. Drugs like Suboxone, or its generic equivalent, are used to wean people off opioids but can also be misused.

The analysis by ProPublica and The Times found that restrictions remain prevalent in Medicare plans, as well. Drug plans covering 33.6 million people include Suboxone, but two-thirds require prior authorization. Even when such requirements do not exist, the out-of-pocket costs of the drugs are often unaffordable, a number of pharmacists and doctors said.

At Dr. Shawn Ryan’s addiction-treatment practice in Cincinnati, called BrightView, staff members often take patients to the pharmacy to fill their prescriptions for addiction medications and then watch them take their first dose. Research has shown that such oversight improves the odds of success. But when it takes hours to gain approval, some patients leave, said Ryan, who is also president of the Ohio Society of Addiction Medicine.

“The guy walks out, and you can’t blame him,” Ryan said. “He’s like, ‘Hey man, I’m here to get help. What’s the deal?’”
When members of the tort bar start to salivate over a piece of legislation, it’s worthwhile to find out where the red meat resides.

In a rush to pass legislation to “lower drug prices,” lawmakers are pushing forward two pieces of parallel legislation, the Senate’s Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act and another House bill the Fair Access for Safe and Timely (FAST) Generics Act of 2017.

Both bills are being viewed by some as possible CHIP “pay for” legislation.  The Senate Finance is holding a hearing next Wednesday and the House wants a vote by end of September. It’s time to take a breath – because neither of these pieces of legislation will speed generic drugs to market or lower the cost of medicines for a single American. What they will most certainly provide is a windfall for the trial lawyers.  

Both bills aim to provide a series of new legal provisions will make it easier for drug companies to introduce generic alternatives, thus spurring competition and bringing down prices. Both are well intentioned. Unfortunately, they’re worded poorly – leading to dangerous unintended consequences. Instead of bringing generics to market sooner, these bills could endanger patients’ lives and encourage costly, needless litigation.

Both bills strip the FDA of its watchdog role. Under their proposals, generic manufacturers aren’t required to outline testing and safety protocols for the FDA to approve. Even if a generic drug maker’s proposed risk evaluation and mitigation strategies are inadequate, the FDA has no authority to reject or halt the transfer of medicines to the generic company for testing.

Both bills contain ambiguously worded liability provisions that subject innovators to unfair legal risk. Generic drug companies often obtain brand-name drug samples and ship them off to third-party research firms to perform clinical trials. If the third party is negligent with the samples, patients could get hurt. Under the bill’s terms, patients would be able to sue the brand-name drug company, even though it had no control over the testing or safety protocols.

Both bills would allow generic drug manufacturers to sue brand-name manufacturers if they fail to hand over their drug samples for testing within 31 days, or if the companies do not reach an agreement on shared risk evaluation and mitigation strategies for risky drugs. Such subjective wording is music to trial lawyers’ ears.

Both houses of Congress deserve praise for trying to bring generic medicines to market faster, relieving consumers from high drug prices. Yet good intentions don’t change the fact that the CREATES and FAST acts, as currently constructed — are deeply flawed.

Congress could help consumers by reworking the legislative language to end bad behavior without gutting safeguards for patients or enabling unscrupulous trial lawyers to file costly, pointless suits. Whether it’s the practice of medicine or the development of public healthcare policy two rules apply – first, do no harm and, second, be wary of trial lawyers bearing gifts.
Yesterday, at the annual RAPS (Regulatory Affairs Professional Society) meeting, I was pleased to speak on the timely topic of real world evidence and to share the podium with Jonathan Jarow (FDA’s point man on RWE) and Enrica Alteri (Head of EMA’s Human Medicines Research and Development Support Division).

The good news is that there was near total agreement that RWE presents important possibilities and opportunities – but the path forward is still nascent, with many crucial questions still to be addressed.

One of the most difficult items on the RWE list is causal inference (the process of drawing a conclusion about a causal connection based on the conditions of the occurrence of an effect). As both FDA and EMA continue to evolve beyond reviewing new medical products exclusively on the traditional substantial evidence standard, it’s a whole new ballgame.

Or is it?

The panel agreed that we're moving forward into a world where there will be many different kinds of reviews for both drugs and devices. Some will be of the “gold standard” large-scale RCT variety, others will be substantially truncated reviews based on dozens (or fewer) patients, and many will be hybrid models (such as using RWE for confirmatory purposes for a surrogate endpoint).

And then there’s the exciting potential in advancing Causal Inference (CI) models through the tools of Artificial Intelligence (AI).

Who said regulatory science was dull?

The panel also stressed that Real World Evidence and “Big Data” are not the same thing, and that developing interoperability (the idea that different systems used by different groups of people can be used for a common purpose because those systems share standards and approaches) must be a priority.

And not just interoperability, but interaction. When it comes to advancing the regulatory science of real world evidence, industry must become comfortable being not just a regulated entity but also a partner in development. In fact, per Dr. Jarow, the FDA is encouraging all comers to submit questions, data sets, and suggestions via a new email link,

Gentlemen and Ladies – start your engines.

The tools for appropriate validation are urgently needed – but cannot be rushed. That being said, the 21st Century Cures Act requires FDA to establish a framework for use of real-world evidence to approve supplemental indications and satisfy post-approval requirements within 2 years.

Tick. Tick. Tick.

Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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