When it comes to Off-Label, let's not forget the role of Real World Evidence

10/08/2017 10:47 PM | Peter Pitts

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.  Read More & Comment...

Complex Generics Simplified ... Sort of

10/02/2017 12:46 PM | Peter Pitts

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.
   Read More & Comment...

Qui cum canibus concumbunt cum pulicibus surgent

09/21/2017 10:26 AM | Peter Pitts

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.

Really.

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.  Read More & Comment...

War Against the Orphans

09/20/2017 01:29 PM |

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.    Read More & Comment...

Gottlieb Gets Real ... World Evidence

09/20/2017 10:49 AM | 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.  Read More & Comment...

Vinay Prasad's Fake Pharma Numbers

09/19/2017 01:54 PM |

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. 







[i] http://csdd.tufts.edu/news/complete_story/tufts_csdd_rd_cost_study_now_published  Read More & Comment...

Off-Label Comms and Vigorous Predictability

09/18/2017 07:57 AM | Peter Pitts

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.  Read More & Comment...

How PBMs are exacerbating the opioid epidemic

09/17/2017 08:30 PM | Peter Pitts

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?’”
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Why the Tort Bar Loves the CREATES Act

09/14/2017 06:32 AM | Peter Pitts

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.  Read More & Comment...

Causal Inference and RWE at FDA and EMA

09/13/2017 10:44 AM | Peter Pitts

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, cderomp@fda.hhs.gov.

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.
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Gottlieb: Speed Saves

09/11/2017 06:00 PM | Peter Pitts

But how will Pharma calculate the speed-to-price equation? And what of PBMs?

From the pages of Politico:

Gottlieb promotes FDA move away from traditional three-phase clinical trials

FDA Commissioner Scott Gottlieb on Monday laid out new clinical trial approaches and digital techniques that he said could get medicines to patients sooner and at a lower price by moving away from the time-honored, traditional three phases of clinical trials.

"We're on an unsustainable path, where the cost of drug development is growing enormously, as well as the costs of the new medicines. We need to do something now, to make the entire process less costly and more efficient. Otherwise, we won't continue to realize the practical benefits of advances in science, in the form of new and better medicines," Gottlieb said in a speech delivered at the RAPs Convergence Conference.

Although development costs aren't necessarily mirrored in treatment prices, they are an important factor, he said. The steep price of development may also be causing fewer drugs to get developed, particularly because so much of the cost burden of drug development is front-loaded at the earliest stages, he said.

He called for savings in development costs to be passed along to consumers, but gave no details on how the government might ensure savings are shared.

"We need to reduce the risk and uncertainty that makes drug development increasingly costly, he said, "and make sure that we have markets that are competitive, and let us capture those savings in the form of lower prices."

FDA is taking a number of steps to modernize how clinical data can be collected, Gottlieb said.

One approach is "seamless" trials, which already have been used to test drugs on various cancers at a single time. In such studies, instead of conducting the usual three phases of clinical trials, a company conducts one large adaptive trial where data can be observed at certain intervals. This reduces the number of patients needed in the trial and saves time and money.

"This approach is well suited" to drugs being developed now to target specific changes that can be found in different disease states, Gottlieb said.

FDA is also encouraging companies to pursue common control studies, where multiple drugs are tested against the same control arm, and large simple trials, which have large sample sizes and statistical power, thereby providing less ambiguous results and minimizing the effects of random errors.

Another new approach is the master protocol concept, in which a single trial evaluates multiple treatments in more than one subtype of a disease or type of patient. Master protocols have been used in cancer drugs and in antibiotic development, to evaluate medicines targeting pathogens in different parts of the body.

The FDA plans to issue new policy and guidance documents to help companies make better use of these approaches, Gottlieb said.

To protect patients, the agency is adapting its safety screening to these new trial types, he said. For example, informed consent documents for seamless trials need to be updated throughout the trial to reflect new safety and efficacy evidence gathered in the process.

Since these trial designs may allow an entire drug development program to take place in just one study, FDA may also need to build in new regulatory milestone meetings to check on progress and provide oversight and advice.

"This is not 'business as usual' approach. It may require a much more iterative process, with greater communication between all of the stakeholders involved in the clinical trial processes," Gottlieb said.

FDA is also modernizing its evaluation of company data, with more advanced software and sophisticated statistical and computational models. Gottlieb said he wants to increase FDA investment in high-performance computing because access to this technology at the agency is limited.

Computer modeling can help select the optimal dose of a drug or better estimate effect size to figure out the ideal number of patients needed in a clinical trial. It can also help FDA determine whether the trial endpoint a company wants to study is appropriate for the disease at hand.

The agency will convene a series of workshops, publish guidance documents and develop policies and procedures for translating modeling approaches into regulatory review, Gottlieb said. It will also conduct a pilot project to test use of these new computer tools with willing drug companies.

The agency has ongoing projects underway to use software to develop natural history models of diseases like Parkinson's, Huntington's and Alzheimer's disease. This information can make trial recruitment more efficient and help evaluate the effect of a treatment again the normal course of disease.

The agency is developing algorithms that could help speed trials. For example, its working on a lung cancer algorithm it hopes can help classify how well a tumor responds to a drug treatment.  Read More & Comment...

Embedding CDER's Centaurs

09/07/2017 09:34 AM | Peter Pitts

The FDA needs centaurs – and that’s no myth.

Huh?

In the parlance of Artificial Intelligence (AI), a “centaur” is a combination of a human brain and computer intelligence. The centaur model sparked the growth of freestyle chess, a context in which Garry Kasparov concluded that “weak human + machine + better process was superior to a strong computer alone and, more remarkable, superior to a strong human + machine + inferior process.”

Now replace “weak human” with “FDA reviewer.” Get it? According to Brad Bush (COO of Dialexia), “Being a centaur in the workplace means taking advantage of the vast analytical capabilities of AI-enabled technology and adding human thinking.”

As AI innovation continues to advance, we should carefully review the centaur model in terms of the FDA review process and consider how combined human and computing power can augment the evolving methodologies for adaptive clinical trial design and statistical analytics being used to achieve approval via the agency’s various expedited review pathways.

Centaurs, far from being mythological, represent a very real opportunity for drug reviews that are both faster and more accurate – a crucial public health double play.

But isn’t AI risky? Consider this -- machines are terrible risk takers and have no capacity to make leaps of faith. It’s easy for a conversation about AI to devolve into a philosophical discussion about consciousness, because that’s what humans bring to the table — a sense of consciousness and intuition that machines don’t possess. AI isn’t about replacing reviewers, it’s about freeing them to do what they do best – think outside the box! It's precisely that kind of hiuman risk taking the FDA's senior leadership want to see from it's staff.

If you’re an FDA reviewer, ask yourself this question, which end of the centaur do you want to be? Perhaps the FDA needs a new position on its organizational chart – Centaur Director.

As Philip K. Dick wrote, “Reality is that which, when you stop believing in it, doesn’t go away.”  Read More & Comment...

Fahrenheit 483

09/01/2017 10:54 AM | Peter Pitts

FDA Commissioner Scott Gottlieb has gotten the message – closing the loop on agency inspections is taking too long.

Per the Commissioner:

Manufacturing of drugs has become increasingly complex and global, requiring us to remodel our oversight of these tasks, to improve FDA’s efficiency and reach. As a step toward achieving these goals, FDA previously announced that we’re restructuring our field activities, to direct our focus and organization around the programs we regulate, instead of our previous structure, that organized our activities and resources based on geographic regions. This allows us to better align the expertise of our staff and make more efficient use of our resources.

As another key step towards achieving these goals, the FDA’s Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs (ORA) are implementing a new, historic concept of operations agreement to more fully integrate the drug review programs with the facility evaluations and inspections for human drugs. This new collaboration is a model for how we’ll modernize other parts of our organization to better achieve our mission.

This new agreement leverages two efforts to ensure alignment between FDA’s field professionals and the agency’s review staff. First is the use of “Integrated Quality Assessment” teams. This new, team-based approach aligns field and review staff so that we can make closer consideration of all elements that create risk including the drug substance, the drug product, manufacturing processes, and the state of the facilities we regulate.
Second, on May 15, 2017, we previously announced the structural realignment of ORA. It moved ORA’s previous geographically organized staff and management into program-aligned commodity areas, more closely mirroring the organizational model of FDA’s centers and the industries we regulate. This step enhanced the Integrated Quality Assessment, and the new concept of operations that operationalizes these approaches, by enabling better alignment between our field professionals and the review staff who evaluate the products that are being manufactured in the facilities that we inspect. The unifying hallmark of the integrated quality assessment team and the concept of operations agreement is the closer integration of the professional staff charged with inspecting facilities and the review staff involved in evaluating applications. Experts in our drug program, and our field force, will be aligning their efforts. We believe that this sort of collaboration can better inform the work done across each of these domains. Our inspectional force will benefit from insights that might be offered by the review teams who have carefully evaluated products being manufactured. Meanwhile, our review staff will benefit from the deeper understanding they will glean through more direct and regular contact with the professionals who are inspecting facilities and seeing the kinds of things that can go wrong during the manufacturing process.

Bravo.

His full announcement (and explanation) can be found here. Another victory for enhanced regulatory predictability.
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A Real World Continuum

08/25/2017 06:46 AM | Peter Pitts

In a JAMA Viewpoint piece, CDER director Janet Woodcock and colleagues reinforced FDA’s stance on the incorporation of real-world evidence into clinical trials, as well as the use of pragmatic studies pre or post-market to collect data on optimal dosing and treatment effects in subpopulations.

In the piece, FDA defines real-world evidence as any data collected as part of routine clinical care, including electronic medical records and administrative claims data as well as data generated from personal electronic or “smart” devices, social media and socioeconomic tools.

The agency also notes that there is no clear dichotomy between real-world and “non-real-world” evidence and that the two exist in a continuum.

Woodcock and her colleagues reiterated what she told BioCentury in its 2016 Back to School essay about the value of studies that are randomized within the healthcare system, which can allow for the collection of data and results that are more generalizable to how the drug candidate will be used in the real world. They also noted that these studies can be cheaper to conduct and can help to address other regulatory questions post-approval, including optimal dosing, long-term outcomes and benefits in various subpopulations.

Per Woodcock, et al., “It is not feasible to answer all of these questions with traditional RCTs. Using RWE to begin to address these questions is preferable to having no evidence whatsoever.”  Read More & Comment...

CRISPR Questions

08/24/2017 05:55 AM | Peter Pitts

Cancer survivors can carry germline mutations that will be transmitted to their progeny. Today, many of these mutations have been identified and can be tracked. With the recent development of genome-editing technologies and CRISPR (clustered regularly interspaced short palindromic repeats), the possibility of genetically modifying the human germline—gametes and embryos—has never been closer.

This perspective has sparked a controversy within the scientific community with reactions ranging from calls for a ban on germline modification to cautious approval of further research.

A new article in the DIA journal, Therapeutic Innovation and Regulatory Science, analyzes the possible adoption of CRISPR-based germline engineering to prevent the spread of cancer predispositions in the human population. Implications of CRISPR-Based Germline Engineering for Cancer Survivors discusses whether the genomic edition of human sperm and eggs would contribute to rectifying or altering the heritable genome.

The paper anticipates the emergence of a new form of liberal eugenics fueled by a logic of offer and demand from stakeholders such as cancer survivors and their relatives and offspring, but also from fertility clinics, biotech firms, insurers, and clinicians. From a regulatory perspective, validating the clinical safety and utility of CRISPR-based germline engineering is an essential step. However, with time, gradually perfecting the technology and assessing the economic benefits for stakeholders could soften society’s resistance and align opinions in support of genomic decontamination of human germlines. This progressive shift would be justified in the name of cancer prevention as well as a moral obligation to facilitate the conception of cancer-free children at a cost that is acceptable to individuals and health systems.

It’s a worthwhile read.  Read More & Comment...

Missouri, the Show Me (the money) State

08/23/2017 10:42 AM | Peter Pitts

Up until recently, Missouri was the only state without a Prescription Drug Monitoring Program for opioids. The good news is that’s changing — sort of. Last month, Gov. Eric Greitens issued an executive order creating one.

The governor’s order directs the state Department of Health and Senior Services to build a database, which will be designed to help identify suspicious patterns of prescriptions of controlled substances — including opioids.

Good news? Seems to be, until you look into the details — where the devil resides. In every other state, doctors and pharmacists can access the database as they write and fill prescriptions, to see where else their patients are getting medications. That won’t be the case under Greitens’ order. What’s wrong with this picture?

Under the new system, dispensers will be required to submit information, but the governor’s order doesn’t give them access to the information. According to Alexandra Dansicker, a policy analyst for the Missouri Foundation for Health, “The intent is to help identify the issues from the supply side of the equation, rather than looking at patient demand and doctor shopping.”

That’s a huge problem that’s being called out by many, including U.S. Sen. Claire McCaskill (D-Mo.), “While I certainly welcome the governor’s attention to this crisis, I have serious questions about how meaningful this action will be if doctors writing prescriptions — and pharmacists filling those prescriptions — don’t have access to this database,” she said in a statement. “The welcome mat is still out for drug dealers to shop for prescriptions in our state.” Instead of an executive order, McCaskill said, state lawmakers should “get off the sidelines and pass a robust statewide program into law that gives law enforcement, pharmacies, and doctors the tools they need.”

Seems obvious, right. What’s going on? Where’s the missing piece? The Kansas City Star offers some valuable reportage: The governor’s executive order was announced “at the St. Louis headquarters of Express Scripts, a pharmacy benefits management company (PBM).”

A seemingly innocuous detail? Hardly. What you smell is the whiff of a smoking gun. It seems that Express Scripts wasn’t recipient of just a gubernatorial visit, but also of a no-bid state contract to administer the PDMP. And here’s another important detail: Express Scripts donated $10,000 to the governor’s inauguration — the PBM’s largest contribution this year and the only one it has made in Missouri.

In addition to the no-bid contract for Express Scripts, Greitens appointed Julia Brncic, the company’s vice president and deputy general counsel, to the governing board of the University of Missouri System.

The Kansas City Star pulls no punches: “The secrecy surrounding Greitens’ fundraising has translated into near constant questions about his motives. And to ethics reform advocates, who argue voters have a right know if special interests are trying to curry favor with politicians, the situation has a corrosive effect on the public’s faith in government.”

Cui bono? Why such largesse from Express Scripts? Is it just a nice gesture for their home state governor? Before you sign onto that chimera, consider this — a $10,000 donation results in a $250,000 no-bid contract. That’s a pretty good return on investment and a nice resume-padder for Ms. Brncic.
Ryan Burns, spokeswoman for the state agency that handles contracting, said data held by Express Scripts and the tools that perform analysis of that data are unique to the company. Under these circumstances, Burns said, state law permits a contract to be awarded without a full competitive bidding process.

But, according to Dr. Robert Twillman, executive director of the Academy of Integrative Pain Management, “No one has designed even simple analytics that make any sense in this arena. If they [Express Scripts] succeed, it will be a modern statistical miracle worthy of some kind of prize. But, of course, we won’t really know what goes into their analytic algorithms, because they’ll keep all that secret. They will just show up to arrest docs and pharmacists on the basis of their black box analytics.”

Now consider with whom the governor is doing business. In 2014, pharmacies sued Express Scripts over its “scheme to deny all claims” for certain customized medications. “The scheme is forcing patients to go without treatment,” the suit stated, “jeopardizing their health and causing bodily harm, or forcing them to pay out-of-pocket sums that they may or may not be able to afford for basic health care needs that have been prescribed by their doctors.”

At a 2014 meeting at the Federal Trade Commission, Dr. Steven Miller (senior vice president and chief medical officer, Express Scripts), said he had research showing that physicians don’t want information from pharmacists telling them which patients have filled a prescription. (Miller was unable to cite the source of this data point.) Well, there are a lot of things “physicians don’t want” — like having to adjust to a world where opioids prescribing must better monitored – but that doesn’t mean they need to be iced out of PDMP access. What does Missouri know that the rest of the nation doesn’t?

Why are Express Scripts and Gov. Greitens being complicit in this illogical PDMP design that is so contrary to the public health? Why the disregard and disrespect for physicians? Part of the answer must lie in the PBM’s historic distrust of doctors’ ability to prescribe what’s best for their patients — as opposed to what’s cheapest. Cui bono indeed — and at whose expense? The opioid epidemic cannot be controlled by disrespecting physicians and pharmacists.  Read More & Comment...

Faux Patient Group Peddles Falsehoods About CAR-T Funding Source

08/22/2017 08:04 PM |

Patients for Affordable Drugs (P4AD) is the faux patient group fronting for the Laura and John Arnold Foundation funded syndicate pushing for European style price controls on drugs.  Along with other Arnold funded academics and organizations, including ICER-  P4AD is demanding that Novartis price it’s breakthrough gene therapy for acute lymphocyte leukemia  ‘fairly’ because “of the fact that U.S. taxpayers invested hundreds of millions of dollars to develop CAR-T before your company became seriously involved.” 

The demand was part of a letter sent by P4AD founder David Mitchell (formerly an executive in a PR firm that received $12 million in drug company funding for Obamacare ads) to Novartis CEO Joe Jimenez. According to a fawning article by Arlene Weintraub in Fierce Pharma, “Mitchell requested a meeting with Jimenez, even offering to bring along two experts in drug pricing: Steven Pearson, president of the Institute for Clinical and Economic Review (ICER), and Aaron Kesselheim, professor at Harvard Medical School and head of its program on regulation, therapeutics and law.” 
Mitchell never reveals that Pearson and Kesselheim also receive funding from the Arnold Foundation.  Weintraub never mentions it either. 

This factual oversight is important since Mitchell proposes that Novartis hold its “price in the United States to the average of prices you receive in six other wealthy nations.”  Or “accepting a value price as established by an independent organization such as the Institute for Clinical and Economic Review (ICER), discounted to reflect American taxpayers’ contributions and assumption of risk.”   

Mitchell’s assertion that NIH invested $200 million in CAR-T that directly contributed to the Novartis drug is a well-crafted lie.  But before dealing with that deception we should explore why discounting the prices of newly developed products that have benefitted in some way from federal support of basic research is a bad idea:

1. It penalizes companies that are successful.

What if the Novartis drug had failed.  Most new medicines never make it to market. Should companies get an NIH rebate when companies invest in products that don’t work? 

2. Why shouldn’t this principle be applied to all successful products developed by people or organizations that at some point in time received federal funding for basic research?

The government had provided billions in support for computing research. About 40 percent goes to universities and 60 percent going to industry and government labs. 
Applying Mitchell’s logic, we should demand that Google, Facebook, Apple, Oracle, etc. should be setting prices “discounted to reflect American taxpayers’ contributions and assumption of risk”.

3. Why stop there?  The government hands out $33 billion a year in Pell Grants to college students.  Shouldn’t these kids starting salaries be “discounted to reflect American taxpayers’ contributions and assumption of risk.”  A third of students getting Pell Grants do not graduate.  Should that money be given back?

When we sell or buy houses, should the prices be “discounted to reflect American taxpayers’ contributions and assumption of risk” in the form of mortgage interest tax deductions?

4. So-called fair pricing requirements reduce private sector investment in NIH sponsored research. 

In 1989 the NIH imposed a reasonable pricing clause on drugs developed using federal basic research support.   The number of direct partnerships between NIH and biotech companies declined steadily declined from 42 in 1989 to 32 in 1995. 

In 1995, the clause was removed.  The NIH director -- Harold Varmus -- noted at the time that the pricing clause had driven industry away from many collaborations with N.I.H. scientists that could have benefited the public. "Eliminating the clause will promote research that can enhance the health of the American people," he said.

By 1997 the number of partnerships surged to 153.  (The NIH averages about 80 such agreements each year. )

Mark Rohrbaugh who ran the technology transfer office at the institutes from 2001 to 2013 and is now an adviser to the agency states that “Companies will not take technologies from us if we say the government will decide in the future what the price will be,” said Mark.  He goes on to say (as noted above) that “after the “reasonable price” clause was struck, he said, there was a threefold increase in partnership deals.”

Now let’s turn to the canard that the NIH invested $200 million in CAR-T research before Novartis dropped a dime. P4AD claims it found 356 NIH projects from1993-2017 containing the phrase “chimeric antigen receptor” (CAR) totaling $204 million. 

There are several problems with this analysis:

1. It includes NIH funding after 2012, the year Novartis began investing.  Replicating PD4D’s search and limiting to 1993-2011 generates 43 grants totaling $18.9 million.
2. Its search is overly broad. It should have at least searched for CAR therapy since CARs are engineered for a variety of research purposes apart from T cell therapy.

A search using the phrase CAR “ therapy” from 1993-2017 yields 33 projects receiving $22.9 million.  But all that funding came AFTER 2011.  Which means that the NIH spent zero dollars on zero CAR therapy projects until Novartis stepped into the picture and after the first results of the CAR-T therapy were published (in 2011). 

Indeed, the Association of Cancer Gene Therapy provided Dr. Carl June who developed the genetically engineered CAR-T approach all the initial funding. NIH provided no funding. 

Dr. June received two grants from ACGT in 2004 and 2008 for his studies in CAR-T therapy for lymphoma and leukemia, and ovarian cancers. On August 10, 2011, Dr. June’s study results were reported in the New England Journal of Medicine and Science Translational Medicine. The results exceeded everyone’s wildest expectations.”

When the FDA advisory committee approved the therapy, June noted: “The funds from ACGT sustained us. When other organizations, including the NIH, considered gene therapy too risky, ACGT believed in the science and funded us when no one else would. ACGT really kept us going and kept the research alive. Without them, we wouldn’t have had a clinical trial and I don’t think we’d be where we are today.”

In 2012, the University of Pennsylvania and Novartis announced a major partnership, in which Penn granted Novartis exclusive rights to its CAR-T therapies. In return, Novartis gave Penn $20 million to fund CAR-T research. Additionally, Novartis is spending hundred of millions of dollars to support clinical trials, manufacturing of genetically engineered T cells and the actual production of the CAR-T therapy which must be tailored to a person's specific genetic and tumor profile. An innovation is something that can be widely used.

P4AD was hoping that the public and media would accept it’s phony $200 million NIH funding estimate at face value to support its equally bogus assertion because it fits the narrative that drug companies are simply free riding off taxpayer funded research or that NIH supported the riskier part of the development process. 

Neither is true.  P4AD is running a  deceptive campaign on behalf of the Arnold Foundation to promote policies that have reduced private investment in NIH research.   If Novartis had been required to negotiate the launch price of CTL019 it would not have provided the $20 million.  It would not have spent hundreds of millions of dollars developing a pilot facility for producing genetically modified T-cells.  In short, many people who were are death’s door and who are alive today – as well as thousands of people in the future facing the same fate – would be dead.




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Narrow Provider Networks: Not Who You Know But What They Do

08/20/2017 11:56 AM |

Last week I started a twitter argument about narrow networks with Yevgeniy Feyman a (very nice) fellow at the Manhattan Institute.
 
He wrote that we don’t know whether narrow networks negatively impact patients.
 
I responded: BS.  Plenty of evidence.
 
Feynman asked me to show him the data.
 
So, after lobbing a couple of snarky comments (that YG swatted away) I realized I had engaged in a Twitter tantrum instead of responding to his request.  
 
I needed to become more mature and substantive to improve on my original response.  Thank you Yevgeniy for a second chance to act like an adult!
 
So here goes.
 
By narrow networks, I meant and mean excluding or restricting access to hospitals, doctors and other services based on price or cost considerations. That includes the VA, Medicaid and now many exchange plans under the ACA.  (Doug Badger doesn’t call these exchange plans “Medicaid lite” for no good reason.)
 
To be sure, consumer surveys suggest that most people are willing to forgo more choice of providers, hospitals, and medicines in exchange for lower premiums.  People have picked narrow network plans over broader options with increasing frequency and surveys show they tend to be satisfied with their choices.
 
Moreover, while research examining the quality of care provided by plans with limited networks is relatively sparse, there is some evidence to suggest that these plans have performed just as well as those that offer access to a broader range of providers. 
 
At the same time, “according to a Consumer Reports survey, 44 percent of those who bought an Affordable Care Act (ACA) plan for the first time in 2015 reported that they did not know the network configuration associated with their plan. 
 
For the clear majority of consumers, a narrow network can be a good choice and provide good care.
 
For the 5-10 percent of Americans with chronic, fatal or rate conditions narrow networks, evidence suggests, not only fail to deliver the care people are paying premiums (and deductibles) for.  They can also increase the cost and seriousness of the condition.
 
It should also be noted that restrictions go beyond access to doctors and hospitals.  Health plans restrict access to medicines in many ways such as formulary exclusions, prior authorization, high cost sharing and step therapy.  In addition, if someone receives care from a doctor outside of a network than the drug prescribed is also not covered.
 
For example, a recent examination by Harvard researchers of the network composition of health plans offered on the federal Marketplace during 2015 found that nearly 15 percent of the sampled plans lacked in- network physicians for at least one specialty
 
Narrower provider networks are more likely to exclude oncologists affiliated with NCI-Designated or NCCN Cancer Centers. Health insurers, state regulators, and federal lawmakers should offer ways for consumers to learn whether providers of cancer care with affiliations are in or out of narrow provider networks. http://ascopubs.org/doi/abs/10.1200/JCO.2017.73.2040?journalCode=jco
 
There are dozens of studies demonstrating that narrow prescription drug formularies and narrow pharmacy networks hurts patients.  (I link to those articles that review a number of these studies as well as the most impactful citations.)
 
While the ACA bars discrimination in proving coverage, health plans, and PBMs narrow choices because by doing so they can discriminate against the chronically ill.  Offering high priced drugs, hospitals and specialists will attract sicker enrollees into the plan

If plans and PBMs narrow networks to avoid adverse selection once someone is enrolled, it is hard to make a convincing case that they do not shift the burden of disease to patients in one way or another.  And the results of studies examining the impact of narrowing on patient well-being (as well as out of pocket costs) strongly suggest that for chronically ill people, such skinny choices can be sickly as well.  
 
But what if networks were limited to hospitals and medicines that provided the best overall quality and access customized to the specific needs of patients?
 
This quality and patient-focused approach to network development has guided Horizon Blue Cross Blue Shield of New Jersey’s the development of its network of providers, called the OMNIA plan.  Unlike many top-down efforts that require doctors to follow a cookbook or force people into narrow networks, Horizon Omnia has been collaborating with doctors, hospitals and health professionals to encourage wellness and patient-centered care.  About 750,000 of its members are now receiving this type of care from more than 6,500 physicians.
 
Horizon has provided the tools but it’s the doctors that are leading the change.  Primary care doctors now see their patients 3-4 times a year because keeping in touch and engaging in some coaching keeps people healthy.   Orthopedists have partnered to reduce lengthy hospital stays and replaced them with teams of physical therapists and home health aides to get people back home and on their feet more quickly.  And important, Horizon, while making these design changes have made this new arrangement one of many choices available to patients. And so far, that has translated into lower premiums and out of pocket costs.
 
In addition, HBCBS is partnering with GNS Healthcare, a precision medicine company that applies causal machine learning technology to match health interventions to individual patients, to further refine and personalize the Omnia offerings.   As Colin Hill, the CEO of GNS, notes: HBCBS and his company will analyze claims and medical records to predict the disease risks of patients and customize the best treatments.   The goal is to “know the value and efficacy of an intervention for a specific individual, as well as an entire population.”
 
So, the moral of the story is: The quality of a network is not about who you know, but what you know about who you are treating.   That's the difference between most narrow networks and the Omnia approach. 
 
 
 
 
 
   Read More & Comment...

Expanded Access Sturm und Drang

08/11/2017 04:20 PM | Peter Pitts

From the pages of MedPage …

Will 'Right To Try' Bill Actually Help Anyone?
Little effect from state laws, and industry largely uninterested
By Shannon Firth, Washington Correspondent, MedPage

WASHINGTON -- If a new federal bill is made law, terminally ill patients anywhere in the country would be allowed to request access to experimental treatments that haven't yet received FDA approval -- and deal directly with the companies developing them.

"Patients with terminal diseases ought to have a right to access treatments that have demonstrated a level of safety and could potentially save their lives," said Sen. Ron Johnson (R-Wis.) in a press statement following the Senate's unanimous approval of his bill, "The Trickett Wendler Right To Try Act," a week ago.

The latest draft of Johnson's bill now heads to the House, where similar bills have already been filed.

Critics of the right-to-try movement say it's unsafe, exploitative, and a "smokescreen" for an anarchist agenda.

Others argue that right-to-try laws are redundant, since the FDA already has an "expanded access" pathway (sometimes called "compassionate use") that allows patients to receive investigational treatments.

The American Society of Clinical Oncology (ASCO) made this argument in stating its opposition to right-to-try legislation.

"ASCO supports access to investigational drugs outside of clinical trials, when adequate patient protections are in place," ASCO chief medical officer Richard Schilsky, MD, said in a statement in April. "We don't support right-to-try legislation, however, because these laws ignore key patient protections without actually improving patient access to investigational drugs outside of clinical trials."

Instead, ASCO backs the FDA's expanded-access program.

But right-to-try proponents view the new federal bill as a critical tool for seriously ill patients, allowing them to bypass the FDA's red tape and decide the course of their own care.

"If a patient truly is dying, and there truly is no other remedy, and they want to try for a 'Hail Mary,' and truly understand the risks and benefits, then it is hard not to offer them an opportunity -- assuming the integrity of clinical trials can be maintained. Because, if not, there can be risks to future patients," said Robert Field, JD, PhD, MPH, a professor of law and health policy at the Dornsife School of Public Health at Drexel University in Philadelphia.

The Senate Bill

As passed by the Senate, Johnson's bill requires that, to be eligible for early access, treatments must be under an active Investigational New Drug application and have completed a phase I trial. And it obliges drug companies to submit annual reports to the agency that include adverse events.
A physician must certify that patients have "exhausted approved treatment options and [are] unable to participate in a clinical trial involving the eligible investigational drug," and patients must have "written informed consent" to the referring physician. Also, current FDA regulations limiting what companies can do to promote or market investigational drugs would still apply.

But the bill also includes several protections for drugmakers who participate. They can't be sued except for "reckless or willful misconduct, gross negligence, or an intentional tort," and the FDA can't use clinical outcomes from use of investigational treatments in its regular review process, unless senior FDA staff make a documented determination that "use of such clinical outcome is critical" for judging the product's safety.

The bill does limit what patients can be charged for investigational drugs to companies' actual direct costs of providing them. (But enforcement could be difficult: companies are not required to inform regulators of what they provide to individual patients, nor the costs to patients.)

The legislation already appears to have support from the White House. Vice President Mike Pence, former governor of Indiana, signed his state's right-to-try bill in 2015.

In 2014, Colorado was the first state to pass a right-to-try law. But the movement began long before that amid the HIV epidemic of the 1980s, as portrayed in the film "Dallas Buyers Club."

In more recent years, the Goldwater Institute, a Phoenix-based libertarian think tank, has led the right-to-try movement. "There's no more fundamental freedom than the right to save your own life ... Right to Try will open new paths to treatments for many patients who are currently out of options," said Victor Riches, the institute's president and CEO, in a press statement.

If someone is desperate, "I don't think a person or agency has a right to tell that terminally ill person, 'I'm sorry I don't think I'm going to let you try this' ... It should be up to them," added Jeffrey Singer, MD, a senior fellow at the Cato Institute, another libertarian think tank.

Singer, a general surgeon in private practice in Phoenix, said passing a federal bill would prevent the FDA from simply overriding state laws.

Industry a No-Show

For the legislation to have any real effect, it will naturally require participation by industry. But that is far from assured. The bill doesn't oblige drug companies to make treatments available. And no pharmaceutical companies have come forward to embrace the bill or promise to make drugs available; some have opposed it.

"While well-intentioned, current 'Right-to-Try' legislation is not in the best interest of patients and is unlikely to help us bring forward innovative, safe, and effective medicines to all patients as quickly as possible," pharma giant Merck & Co. said in a statement issued earlier this year.

Richard Garr, formerly CEO of Neuralstem Inc., which is developing cell therapies and small-molecule drugs for a variety of neurological conditions including spinal cord injury and amyotrophic lateral sclerosis, testified in support of Johnson's bill at a September 2016 hearing.

But Neuralstem's current management disagrees. In a statement sent to MedPage Today, the company said, "We feel that providing access to our investigational therapies outside of our ongoing and critical clinical trials may delay or jeopardize the approval of therapies, by reducing the supply of study agents or adversely affecting the data collection process. By focusing on clinical development and seeking regulatory approval, it is our goal to offer our therapies to the largest number of patients as quickly as possible."

The Pharmaceutical Research Manufacturers Association (PhRMA) has issued a series of noncommittal statements about the legislation as it worked its way through the Senate, all of which stopped short of endorsing the bill.

"We appreciated the opportunity to work with Sen. Johnson on the bill and look forward to continuing to work with his office," wrote Andrew Powaleny, director of public affairs for PhRMA, in a recent email to MedPage Today. "The revised Right to Try legislation that passed the Senate includes important protections for patient safety and the clinical trial process."

Medical ethicist Arthur Caplan, PhD, of New York University, noted that early access to investigational drugs puts drug companies instead of the FDA into the role of gatekeepers, and negative publicity is among their major concerns.

If one patient has a serious adverse event following an experimental therapy, that could scare off investors, Caplan said.

"As long as you have private sector investment driving drug development, the priority is to get the drug approved and sold and not to start giving it away," he noted.

The record with state-level right-to-try laws also suggests lackluster interest from industry. "It's telling that although 37 states have adopted these laws, when asked to provide examples of success stories, one of the primary groups pushing for their adoption can only provide the testimonies of six patients who received access to experimental medicines through a single physician in a single state," Rachel Sachs, an assistant professor of law at Washington University in St. Louis, told RAPS recently.

"The net impact of state right-to-try laws has been absolutely nothing. I don't expect a federal right-to-try law will change that," said Caplan, dismissing Johnson's bill as "a feel-good" exercise.

Redundant, Fraught with Risk

"It's entirely [for] show ... This bill is not going to expedite, accelerate or ease the burden of a single patient getting access to experimental medicine," said Peter Pitts, president and co-founder of the Center for Medicine in the Public Interest, a nonprofit medical issues research group. Pitts is also a former FDA associate commissioner for external relations.

The FDA already approves 99% of the requests for expanded access that it receives, Pitts noted. In fact, in 2016 the agency introduced a streamlined pathway to further accelerate the process, and one report indicated that the agency's average response time is 4 days. An FDA official told MedPage Today that emergency requests are usually granted immediately.

"It's not as if the agency is turning people away," Pitts said.

Carolyn Engelhard, MPA, director of the Health Policy Program at the University of Virginia School of Medicine's Department of Public Health Sciences, in Charlottesville, Va., told MedPage Today that the FDA's expanded access program already offers the same options as right-to-try but with more "checks and balances."

Engelhard predicts that a federal right-to-try program won't produce a "groundswell of drugs" that couldn't have already been accessed through the expanded use program.

Critics also said the bill's stipulation that drugs must have completed phase I testing does not offer very much assurance of safety.

Most drugs entering phase II trials never make it to market, usually because they turn out to be ineffective or because of safety issues not spotted in phase I. "So it is possible that patients will be taking something of no help, or that creates new health problems," Field said.

Mat Staver, JD, founder and chairman of Liberty Counsel, a self-described "international litigation, education, and policy ministry," said he supported the right-to-try concept. But he stressed that whatever new path develops should be monitored from a cost and availability standpoint, and studied to determine whether people are being exploited and whether the pathway is effective.

Engelhard, meanwhile, called the entire effort a "political smokescreen" for anti-regulation ideologues hoping to get patients believing they can sidestep the FDA and go straight to drug companies for treatments.

"It sounds like it's pro-patient, but by removing the FDA it opens the door for greater risk for fraud and abuse," she said.

Senior Associate Editor Charles Bankhead and Managing Editor John Gever contributed to this story.  Read More & Comment...

Embracing Generic Complexity

08/09/2017 07:24 AM | Peter Pitts

“Generic” does not mean “identical” – nor does it mean “easy.” FDA Commissioner Scott Gottlieb understands these basic tenets of drug development and has created a working group of senior FDA staff that will look for ways to increase generic competition by embracing complexity.

The working group will propose options for using FDA's existing authorities and may develop legislative proposals to respond to changes in technology and in the marketplace that have occurred since the Hatch-Waxman Act was enacted in 1984. For example, it will consider whether and how ANDAs for complex products, such as those combining a drug and a device, may include clinical data. This isn’t a simple change. It’s a revolution in generic drug labeling – recognizing what pharmacologists and physicians have known for decades – that “bioequivalent” doesn’t mean “identical” – and that for some products, that’s more important than for others.

Just as the agency recognizes that biosimilar labeling can recognize both similarity and differences, that recognition will now be used to help determine the appropriate use of generic medicines. Gottlieb has expressed concern for years that FDA policies don’t adequately support the development of generic versions of complex products. To paraphrase Dr. Harry Lever of the Cleveland Clinic, we mustn’t lose control of what patients are swallowing.

Per the FDA, “Consistent labeling will assure physicians, health professionals, and consumers that a generic drug is as safe and effective as its brand-name counterpart.” But “consistent” doesn't mean “identical” – especially when the data says otherwise. We live in the Information Age. Knowledge is power.

Working group members will include Elizabeth Dickinson, an attorney in FDA's Office of the Chief Counsel who served as the agency's Chief Counsel during the Obama administration; Grail Sipes, director of the Office of Regulatory Policy at FDA's Center for Drug Evaluation and Research (CDER); and Maryll Toufanian, deputy director of CDER's Office of Generic Drug Policy.  Read More & Comment...