Latest Drugwonks' Blog

HRSA's 340B Fix

  • 08.28.2015

HHS's Health Resources and Services Administration (HRSA) has issued draft guidance on the 340B program that addresses some of industry's concerns with the program. Per BioCentury, the guidance includes a clearer definition of 340B-eligible patients.


The 340B program is intended to provide discounted outpatient drugs to hospitals that serve a disproportionate share of poor and uninsured patients. The 340B hospitals can then dispense the discounted drugs to their non-Medicaid outpatients and use the savings to pay for the care of indigent patients.
However, the number of 340B-eligible entities and discounted drugs sold to those entities has grown over the last several years, and industry has said some hospitals are not using the money to pay for charity care and are dispensing the discounted drugs to individuals who are not patients of the hospital.

 In the draft, HRSA clarifies which patients would be eligible for 340B: those who receive care at the hospital and who have received a prescription from a provider directly affiliated with the hospital. The rule notes that a patient would be ineligible if the drug is dispensed while they are still an inpatient; if the only service provided by the hospital or provider is to dispense or infuse the drug to the patient; if the patient's physician has credentials or privileges at the hospital but who is not an employee of the hospital; or if the patient is an employee of the hospital but may get care elsewhere. 


Additionally, if patients of the covered entity choose to have their prescription filled at a pharmacy not affiliated with the hospital, the drug would be ineligible for the discount. 
The guidance also would allow manufacturers to audit covered entities if the manufacturer "has reasonable cause" to believe that the entity is providing duplicate discounts to Medicaid patients or diverting drugs to ineligible patients.


The draft guidance will be published in the Federal Register on Friday. Comments are due October 27th.

On Tuesday OMB completed its review of a proposed rule entitled "Designation of Official Names and Proper Names for Certain Biological Products."

It's as predicted ... and good news.

According to the Wizards of White Oak, “ Our current thinking is that shared nonproprietary names are not appropriate for all biological products. There is a need to clearly identify biological products to improve pharmacovigilance, and, for the purposes of safe use, to clearly differentiate among biological products that have not been determined to be interchangeable. Accordingly, for biological products, we intend to designate a nonproprietary name that includes a suffix composed of four lowercase letters. Each suffix will be incorporated in the nonproprietary name of the product.

This naming convention is applicable to biological products previously licensed and newly licensed under the PHS Act. The nonproprietary name designated for originator biological products, related biological products, and biosimilars will include a unique suffix. However, FDA is considering whether the nonproprietary name for an interchangeable product 2 should include a unique suffix, or should share the same suffix as its reference product. FDA invites comment on the draft guidance and solicits comments on ways to improve active pharmacovigilance systems for the purposes of monitoring the safety of biological products.

 The Proposed Rule says:

"The official names and proper names of these products would include distinguishing suffixes composed of four lowercase letters and would be designated as filgrastim-bflm (BLA 125553), filgrastim-jcwp (BLA 103353), filgrastim-vkzt (BLA 125294), pegfilgrastim-ljfd (BLA 125031), epoetin alfa-cgkn (BLA 103234), and infliximab-hjmt (BLA 103772). Although FDA is continuing to consider the appropriate naming convention for biological products, including how such a convention would be applied retrospectively to currently licensed products, FDA is proposing to take action with respect to these six products because of the need to encourage routine usage of designated suffixes in ordering, prescribing, dispensing, recordkeeping, and pharmacovigilance practices for the biological products subject to this rulemaking, and to avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathway."

A win for sanity and patient safety.

Also, if you'd like more on the related biosimilar J-Code issue, see here.
 

Over at Forbes, the always thoughtful Matt Herper asks, “Remember when the FDA rejected drugs?”

Per Matt, “As recently as 2008, companies filing applications to sell never-before-marketed drugs, which are referred to by the FDA as “new molecular entities,” faced rejection 66% of the time. Yet so far this year the FDA has rejected only three uses for new chemical entities, and approved 25, an approval rate of 89%.”

(These numbers come from a new analysis commissioned by Forbes from BioMedTracker. The way BioMedTracker follows new molecular entities is slightly different from the way the FDA does. BioMedTracker users want to know about every use of a new medicine. That means that the 2015 rejection count includes rejections of Avycaz, a new antibiotic from Allergan, for hospital-acquired pneumonia, and selling Jardiance, a diabetes drug from Eli Lilly and Boehringer Ingelheim , in combination of metformin. But Avycaz was approved for two other uses and Jardiance is on the market by itself.)

Herper, “… it’s worth sticking to BioMedTracker’s definitions, because it allows us to compare this incredibly high approval rate with the past. And that tells a story of an agency that has been giving the green light more and more often.”

Interesting stuff – but what’s missing is a discussion of how the evolution of regulatory science has impacted the dynamic relationship between the FDA and the innovative pharmaceutical industry and has changed over the course of time (by design, and largely through the mechanism of PDUFA negotiations) the quality of NDAs reaching agency review.

More agency/sponsor meetings earlier in the process not only result in better submissions (more likely to be approved because of higher quality science and more sophisticated protocols), but fewer applications of questionable value . As one senior FDA official told me yesterday, “We’re seeing fewer dogs.”  

Another factor that’s important to consider is that failed NDAs are expensive. The following figures are illuminating.

  • A 10% improvement in predicting failure before clinical trials could save $100 million in development costs.
  • Shifting 5% of clinical failures from Phase III to Phase I reduces out-of-pocket costs by $15 to $20 million.
  • Shifting failures from Phase II to Phase I would reduce out-of-pocket costs by $12 to $21 million.
When he was asked why he was so successful, Thomas Edison replied, “Because I fail faster than everyone else.” One of the reasons the FDA is seeing fewer dogs is because they are helping innovators to recognize failure earlier in the process. And that also means more money that can be reinvested in new clinical programs. Furthermore, a high turndown rate is not a badge of honor--it is indicative of a dysfunctional system.

The good news is that more R&D time, talent, and treasure is being focused on personalized medicine using more sophisticated tools (i.e, biomarkers). Failure is being found sooner, targeted clinical success is easier to predict earlier – and can be expedited through the regulatory process through many new and exciting review pathways (i.e., Breakthrough Designation).

(PS/ Those who don’t think the FDA has “adaptive licensing” opportunities don’t understand what’s going on. And those who choose to blame the FDA for biotech investor anxiety had better find some new excuses.)

Those who wave their arms about the FDA “approving everything” don’t see (or choose not to see) the important success story behind the headline. That dog don’t hunt.

Lots of news about a survey by the Kaiser Family Foundation (KFF) showing that a majority of Americans (76 percent) strongly or somewhat support government price controls on prescription drugs.  

Let's set aside the survey's skewed approach to polling:  It singled out prescription drugs for such polling (i.e. there was no question asking people if they knew what they paid for drugs was already controlled -- by health plans -- and that prices were increasing though drugs remained a small share of insurer costs) and it undersampled Republicans and healthy, middle income people.   Indeed, the oversampling of Democrats and Independents and the focus on drug prices appears to be part of a broader effort to get drug price control referendum on the ballot in key primary and battleground states like Ohio and California.  

Let's instead ask what is the implication of the findings.

According to KFF CEO Drew Altman.. 

“Rightly or wrongly, drug companies are now the number one villain in the public’s eye when it comes to rising health-care costs,” said Foundation President Drew E. Altman, Ph.D. “People want to rein in the cost of prescription drugs, and just about anything we poll on with that aim gets public support.”

Altman did say that. But not about the recent poll.  He said it about a survey taken a decade ago. 

The same could be said about other surveys conducted by Kaiser or by their partner in polling, Harvard's Robert Blendon..

In 1984 seventy seven percent of Americans favored prices controls on all medical services.  In 1994 that figure was 72 percent.  

I bet if I surveyed people to see if they favored price controls on data plans or college tuition or food, I'd get the same number. 

All of which proves what polling pioneer Daniel Yankelovich concluded after looking through mounds of Gallup polling data:

The factual ignorance and fickleness reflected in surveys like the KFF tracking polls are often counterbalanced by a remarkable sureness of judgement in applying basic values... 

These polls generate headlines and help groups supporting such referendum to raise money.  They don't shape policy.  In fact, with one or two exceptions that were disastrous (Truman and Nixon's wage and price controls) the American electorate has shied away from outright price controls or laws that would limit the choice of medicines to what is cheapest such as mandatory generic substitution.  

As a result, American has since the 1960s, outpaced the world in the development of important treatments for HIV, cancer, Hepatitis C and heart disease that -- since 1990 -- have reduced death and disability as well as made treating people with these illnesses much less expensive (and more effective) compared to older therapies. 

So perhaps in addition to polls and ballot initiatives promoting price controls, stakeholders and patient groups should commission surveys and propose referendum about how health plans limit access to new medicines by hiking drug prices and saying no to new medicines.  


In the immortal words of Don Draper, “If you don't like what is being said, then change the conversation. And nowhere is that more true than in our national dialogue over opioid pain medications.

Senior leadership at the FDA has returned again and again to the role the agency must play in facilitating physician and patient education -- and not only through labeling language. Former FDA Commissioner Hamburg specifically mentioned CME and working to develop (with a broad constituency) validated tools for physicians to use in determining which patients may be more prone to slide into abuse so they can choose their therapeutic recommendations more precisely.

“It all comes back to provider education,” she said. Amen.

Education – the Hamburg Manifesto.

That’s not regulatory mission creep; it’s the appropriate application of the agency’s Safe Use of Drugs initiative. The way you make a drug “safer” is to ensure that it is used by the right patient in the proper manner.

In keeping with that philosophy, an important announcement from Purdue Pharma:

Purdue Pharma L.P. Launches TeamAgainstOpioidAbuse.com

New Resource Aimed at Educating About Opioid Analgesics with Abuse-Deterrent Properties and Team Efforts to Deter Abuse of Prescription Medicines

 STAMFORD, Conn., August 17, 2015 – Purdue Pharma L.P. proudly introduces Team Against Opioid Abuse, a new website designed to help healthcare professionals and laypeople alike learn about different abuse-deterrent technologies and how they can help in the reduction of misuse and abuse of opioids. Combating misuse and intentional abuse of prescription pain relievers involves more than just the person holding the prescription pad. It is a team effort, including pharmacists, nurses, counselors, caregivers, patients, and payers, both public- and private-sector. Public health experts have stated that Opioids with Abuse-Deterrent Properties (OADP) are an essential component of a comprehensive, evidence-based strategy to reduce opioid abuse that requires coordinated and sustained efforts from the healthcare team along with multiple other players, such as manufacturers, policymakers, regulators, educators, and law enforcement.


“Education about the proper use of opioid analgesics is a top priority at Purdue Pharma. Everyone on the team should understand their role and responsibilities, so they can do their part in combating abuse of opioids, while ensuring their availability for appropriate purposes,” said J. David Haddox, DDS, MD, Vice President, Health Policy, Purdue Pharma L.P. “Opioids with Abuse-Deterrent Properties are one tool to help the team in their efforts in fighting drug abuse. We developed this website to inform everyone who influences how drugs are prescribed, taken, stored, and destroyed, when no longer needed.”


Opioid abuse is a critical problem in America and one that healthcare professionals, payers, law enforcement, policymakers and drug makers are all working to combat. The 2013 National Survey on Drug Use and Health reported that, among persons age 12 or older in 2012 to 2013, approximately 68 percent of people who used prescription pain relievers for nonmedical purposes said they got the medicines from a friend or relative, for free, by purchase, or by theft.[1] In 2011, the White House identified prescription drug abuse and misuse as a major public health and public safety crisis.[2]


Using clear graphics and easy to understand language, the website features sections about why it’s critical to deter abuse and how all the members on the healthcare team can make a difference. It also outlines the 2015 Food & Drug Administration’s Guidance on Abuse-Deterrent Opioids — Evaluation and Labeling, which informs drug developers about FDA’s current thinking on what kinds of testing potentially abuse-deterrent opioids should undergo. Because FDA states that having information about an opioid’s abuse deterrence available for healthcare professionals and patients, the website also reviews how Section 9.2 of a drug product’s Full Prescribing Information is the key to identifying opioid formulations with FDA-approved abuse-deterrent properties.[3]


The Team Against Opioid Abuse website can be can be accessed at http://www.teamagainstopioidabuse.com.

 [1] Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-48, HHS Publication No. (SMA) 14-4863. http://www.samhsa.gov/data/sites/default/files/NSDUHresultsPDFWHTML2013/Web/NSDUHresults2013.pdf. Accessed August 8, 2015.

2 White House Office of National Drug Control Policy. Epidemic: Responding to America’s Prescription Drug Abuse Crisis. 2011. https://www.whitehouse.gov/sites/default/files/ondcp/issues-content/prescription-drugs/rx_abuse_plan.pdf. Accessed August 8, 2015.

3 Food and Drug Administration, Center for Drug Evaluation and Research (CDER), US Department of Health and Human Services. Abuse-Deterrent Opioids — Evaluation and Labeling: Guidance for Industry. Accessed August 8, 2015. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdf.

 Well done Team Purdue.





Dear President Carter:

I was sorry to learn that you are fighting an advanced form of cancer that has spread to your liver and other parts of the body.   There is good news, sort of.

As a recent article in the Boston Herald noted:

Former President Jimmy Carter revealed yesterday that he will undergo treatment for cancer that has spread to various parts of his body — and doctors say that despite his advanced age, the 90-year-old may fare well thanks to recent advances in personalized medicine.

“With cancer cells, there are many different mechanisms that make them grow, and a lot of the science has been dissecting genes and proteins that cause it,” said Dr. Andrew M. Evens, director of Tufts Cancer Center. “There’s work around identifying treatment for the patient’s individual cancer and doing it at a genetic level.”

Not so fast Mr. President.

Even as a former President, you will be faced with what is called “step therapy” or “quality pathways” that determine what treatments you get.   You have to fail first on the first step of therapy before getting to up to five other ‘approved’ treatments before getting to the ‘advances in personalized medicine.’ 

You were a plain spoken president, so I probably don’t have to tell you that for people with advanced form of cancer,  ‘fail first’ is code for getting sicker and closer to death.

Health insurers claim these pathways don’t affect outcomes.  But they refuse to cover the advances that have a very good chance of keeping you alive and well.
Neither the tests for the genetic makeup of your cancer cells to identify where it started, and guide treatment are not at the end of any of these pathways.  Under the Affordable Care Act, anything not on a pathway has to be paid for in full by you.

You might think that your doctor will fight to get you the treatments that could save your life.

Sorry to disappoint you.

The leading cancer doctor group -- The American Society For Clinical Oncology (ASCO) – has developed a calculator of value that treats all patients as the same; ignoring the genetic variation in patient response that allows doctors to personalize care.

Indeed, ASCO wants insurers to use their calculator to “evaluate the relative value of new treatments” as they develop “benefit structures, adjustment of insurance premiums, and implementation of clinical pathways and administrative controls.” 

That’s not good news either.   I’ll give you a couple of examples.   I read that you have a family history of pancreatic cancer.   So I used the ASCO calculator to come up with a value score (the highest score is 130).  The most common treatment for advanced pancreatic cancer that has spread everywhere adds, on average, about 2.5 months of life.  That’s worth a whole 32 points.  But then 20 points are deducted because of side effects, leaving you with 12 points of “net health benefit” out of 130 which the app helpfully notes will cost $5000 a month.  Other treatments that provide less survival and are cheaper are given a higher score.  Guess which treatments you have to use before getting to the most effective treatment covered?

The news is even worse if you have advanced colorectal cancer.  The newest drugs add more survival for this deadly disease.  But ASCO doesn’t think it’s worth more than 16 points.  Deduct 20 points because ASCO doesn’t like the side effects (rashes, nausea, fatigue) and you’re in negative territory. According to ASCO, that treatment has no clinical value at all.  And the advances Dr. Evens mentioned aren’t even measured.  And they won’t until randomized trials that take years to organize and complete are published.

It’s sad and ironic.   You lead a 30-year effort to eradicate guinea worm disease around the world.  The disease is not fatal but extremely painful and debilitating.  In 1986, there were an estimated 3.5 million cases in 21 countries in Africa and Asia. Your effort was criticized as not cost-effective from the start.  You ignored the bean counting because it only focused on 2-3 measures of value.   (Sound familiar?)

Today, that number has been reduced by more than 99.99 percent, with the vast majority of cases remaining in South Sudan.

It’s a good thing it was you – not the alliance of insurers and ASCO – tackling that challenge.   Unfortunately they are putting a price tag on whether you live or die.  Maybe you can change that.  A grateful nation is pulling for you to win one more campaign.

Wither Off-Label?

  • 08.14.2015

The debate over off-label communications doesn’t begin or end with the Caronia or Amarin decisions. It’s a continuing dialogue between manufacturers and the FDA, between doctors and patients, between doctors and academics, between lawyers and judges, and between advocates on all sides.

And the red thread that ties these conversations together is responsible off-label communications. Not sales strategies. Not DTC tactics. Not managed market negotiations – the responsible sharing of truthful and accurate information.

It’s important to say early in the conversation that almost no one is against sharing valuable information about FDA-approved medicines. The discussion – the heated discussion – is over how (or if) that conversation should be regulated by the FDA.

Steve Jobs said, “Innovation distinguishes between a leader and a follower. And make no mistake, off-label communications is about innovation. Innovation in the safe and effective use of medicines. Off-label communications is about getting the right medicine to the right patient in the right dose at the right time – even though the right medicine or the right dose may not correspond precisely to the FDA label.

But who is the leader and who is the follower? Or perhaps a better question to ask is, why can’t we all be leaders?

Off-label communications, properly done, advances precision medicine, delivering speedier positive patient outcomes, and reducing costs to our healthcare system. Off-label communications provides patients with more options for effective medicines.

Those who think that the argument over off-label is just about marketing and sales are looking at this issue through very narrow blinders.

What is the role of the FDA is off-label communications. Well, first let’s stipulate that the FDA doesn’t regulate the practice of medicine. Then let’s discuss the fact that the agency can (and indeed must) help to facilitate the free and fair dissemination of timely, truthful, and trustworthy scientific knowledge.

Also, initial licensing approval is not based on data for every possible indication. Initial approval is based on a “best foot forward” approach. But that doesn’t mean there isn’t robust scientific evidence to support broader therapeutic uses. In fact, initial approvals, based on a narrow, randomized population, only provide a window into future clinical possibilities.

According to the House Energy & Commerce Committee’s 21st Century Cures Initiative initial white paper:

Communication about how certain treatments are working in certain patients is happening through a multitude of media around the globe. These conversations between and among doctors, patients, researchers, and scientists in academia and industry should be facilitated. This includes the free flow of data, research, and results related to what a therapy or combination of therapies does or does not do well and in what types of patients.

 Off-label communications is about recognizing that the speed of scientific discourse impacts clinical practice years before it drives official label changes.

You don’t have to look much further than oncology and many orphan diseases to see that off-label use is regularly considered first line therapy. And payers in the US and elsewhere reimburse off-label prescribing. Why? Because it enhances outcomes.

How do physicians learn about off-label usage? Medical meeting presentations, professional journal articles, discussions with their peers, and through materials from manufacturers. Please note that I haven’t listed DTC. There is a difference between off-label communications and off-label marketing – and it is a distinction with a difference.

So, what do academics and physicians, payers and patients know about off-label communications that the FDA does not? Asked in a more progressive way, how can the FDA be an accelerator rather than a sea anchor when it comes to facilitating off-label communications?

In a word, the answer is clarity. Alas, regulators love ambiguity because it gives them unlimited options. And nowhere is this more evident than when it comes to issues concerning communication. It would be generous to call the FDA’s views on the dissemination of off-label information ad hoc. With the important exception of the agency’s guidance on Good Reprint Practices. According to the March 2014 revised guidance, reprints that discuss off-label use mustn’t:

  • Be false or otherwise misleading;
  • Recommend or suggest use of the product in such a way that the product is dangerous to health when used in the manner suggested; nor
  • Be marked, highlighted, summarized, or characterized by the manufacturer, in writing or orally, to emphasize or promote an unapproved use.

Those are pretty broad guideposts. More interesting and germane to current events are those related to Clinical Practice Guidelines (CPG):

Any CPG that includes information on unapproved or uncleared uses must meet Institute of Medicine (IOM) standards for whether it is a “trustworthy” guideline.  According to IOM, a guideline is “trustworthy” if it:

  • Is based on a systematic review of the existing evidence;
  • Is developed by experts in the subject area;
  • Considers important patient subgroups and patient preferences;
  • Is transparently developed and funded such that biases are minimized;
  • Provides logical relationships between treatment recommendations, health outcomes, and includes the quality and strength of the underlying evidence; and
  • Is reconsidered and revised as new information becomes available.

Beyond this, what will the FDA do next? More importantly, will it lead or follow, or follow and then lead? And this brings us to the recent court decisions in the Caronia and Amarin cases.

The Caronia decision, a 2012 decision from the Second Circuit Court of Appeals, overturned the conviction of Alfred Caronia, a sales representative for Orphan Medical, which was later acquired by Jazz Pharmaceuticals. After Caronia was caught talking to physicians about various off-label uses of the narcolepsy drug Xyrem, the court said the First Amendment protected truthful and non-misleading off-label speech. Key words, “truthful and non-misleading.”

That’s a good off-label equation: Truthful + Non-Misleading = Trustworthy.

Although the agency said that the decision wouldn’t impact it’s views and practices concerning the regulatory oversight of off-label communications, the decision, combined with increased pressure from industry, forced the FDA to put the issue of off-label communications on the front burner.

Unfortunately, it was put on the front burner on a low flame.

Between Caronia and Amarin, the FDA issued some very valuable draft language on the issue. Under the proposal, FDA would not “object to the distribution of new risk information that rebuts, mitigates, or refines risk information in the approved labeling.” The studies must be “well-designed” and “at least as informative as the data sources” that the FDA used in generating the official warning.”

The new FDA draft guidance opens the door for companies to share truthful, scientifically accurate, and data-driven information with healthcare professionals to inform treatment decisions. For example:

—  Observational data and “real world evidence”

¡ Information on the safety and effectiveness of medicines taken from medical records based on actual use of approved medicines.

—  Sub-population data

¡ Information on the safety and effectiveness of medicines in sub-populations including gender and race. Such information can help healthcare professionals tailor their treatment to meet the needs of individual patients.

—  Observational and comparative data

¡ Information from the use of a medicine outside of randomized clinical trials, especially comparisons between two or more therapies.

—  Pharmaco-economic information

¡ Healthcare economic data and information on the economic value of medicines can improve the efficiency of patient care.

—  Information on medically accepted alternative uses of medicines

¡ Information on new uses of approved medicines that are listed in major compendia and/or routinely reimbursed by the federal government and major payers.

Things seemed to be moving ahead and the FDA seemed to be driving the conversation – and then came Amarin and it’s drug Vascepta – approved by the FDA for treatment of patients with “Very High” triglycerides.

In April, the FDA rejected Amarin’s claim for “Persistently High” triglycerides and also decided Amarin couldn't include clinical trial data in Vascepa labeling about the extent to which the pill may effectively treat people with slightly lower levels of triglycerides.

In May Amarin filed a lawsuit in Federal Court claiming it “finds itself in a bind,” since it “may not freely communicate truthful and non-misleading information about Vascepa to health-care professionals…without fear of criminal prosecution and civil liability.” In its lawsuit, Amarin included a list of medical journal articles it would like to distribute to physicians.

In June, the FDA sent a letter to Amarin saying the types of materials the drug maker would like to distribute to doctors actually would not be a problem and “would not consider the dissemination of most of that information to be false or misleading.” Then the FDA suggested that Amarin might have known this if the drug maker had discussed the issue before filing its lawsuit, “as other pharmaceutical companies sometimes do.”

 Earlier this month the court agreed Amarin materials are truthful and took the government to task for essentially arguing that speech alone can be the basis for liability and that the agency’s action is at odds with the Caronia holding and the First Amendment.

Post-Caronia and pre-Amarin, hoping to maintain its ability to apply “regulatory discretion, “the FDA signaled it was going to loosen the reins on off-label communications. And, in fact, this was part of the government’s argument in the Vascepta case. The Judge asked when the FDA would be issuing further guidance on off-label communication, asking if it would be in 2015 or afterwards, or before Labor Day. The government’s attorney said she had “no idea” when the agency would act or if more speech will be permitted when it does. Bad answer.

 So what happens now?

I predict that the FDA will continue to develop its new thinking on off-label (informed and influenced by both the Caronia and Amarin decisions). It will then issue a more complete draft guidance and collect feedback via a Federal Register docket. That’s the way the system works and rules must be follows.

I further predict, barring overly ambiguous and wimpy language from the agency, that most pharmaceutical companies will declare victory and follow the FDA’s lead. That being said, the agency will need to carefully monitor i’s off-label oversight – and his means a lot more than the usual and customary OPDP review. It means senior management attention to how the agency views “trustworthy” and a very careful eye on any actions it considers taking.

All this to say that off-label communications is now on the agency’s front burner and the flame is on high. As Everett Dirksen used to say, “When I feel the heat, I see the light.”

Can the FDA recapture a leadership role in the off-label conversation? I believe it can – and will. But it will require the agency to trade ambiguity for predictability because, when it comes to trustworthy off-label communications, predictability is power in pursuit of the public health.

Stay tuned.


Dr. Jack Kevorkian


Lowell Schnipper, the chairman of the ASCO Value Framework Task Force was also part of a group that supported Dr. Jack Kevorkian and pushed to legalize physician-assisted suicide.

It raises the question: Does the Value Framework recycle the arguments and assertions Dr. Schnipper made in pushing euthanasia as an option for cancer patients in determining how to value drugs and why?

To my mind, it does. 

Schnipper, who is also Chief of Hematology/Oncology at Beth Israel Deaconess Medical Center in Boston, has been a driving force in making ASCO focus on the costs and value of cancer care.  His support of Kevorkian and assisted suicide legislation are relevant. Specifically, just as Schnipper believed that hastening death when further treatment could only add a few months of life was legitimate, the Task Force he leads asserts that a few months or weeks of life have no clinical value and that further treatment is a waste of money at that point. 


Background

In 1998 Schnipper was part of “a high-powered collection of area doctors, academics and lawyers has been meeting privately, working to draft a model bill allowing physician-assisted suicide. "We'd like to get this bill introduced in Massachusetts and elsewhere," says Boston College law professor Charles H. Baron.
The group includes James Vorenberg, former dean of Harvard Law School; Judy Johnson, associate general counsel at the New England Medical Center; Dr. Lowell Schnipper, chief of oncology at Beth Israel Hospital; and Dr. Sydney Wanzer of the Harvard Law School health services. Most of the 10 members, says Baron, support legalization "in the hopes that this will make relief from suffering more readily available and in a less discriminatory fashion and with greater patient autonomy."

Schnipper’s Working Group Supported Dr. Jack Kevorkian

Dr. Wanzer noted: "If Dr. Kevorkian does it a little outside the niceties of proper practice, I can't condemn him for that. If I do this privately and quietly and discreetly, it doesn't force the issue. But he does. I think it's a good combination of the quiet people who go ahead and do what they think is right and the Dr. Kevorkians who do it more flamboyantly."

"Kevorkian is a result of failures of our medical system in caring for someone with intractable or chronic problems," says Dr. Lowell Schnipper, chief of cancer treatment at Boston's Beth Israel Deaconess Medical Center. "But Kevorkian is becoming more and more marginalized as legitimate groups begin to weigh in with the resources and sensitivities the problem demands, which to me is good news."

Schnipper also described hastening death as "consistent with the highest goals of the physician as healer and must be an option in a pluralistic society."

Today Schnipper Believes Cancer Treatment That Adds ‘Only’ Three Months of Life is Not Worth It.

In 2010 Schnipper was the lead author of an article that argued:

“Patients' high expectations of cancer therapy may be another cost driver
In a culture that favors treatment and has an overly optimistic view of what medicine can offer, it is an uphill battle for cost-conscious oncologists to communicate the true value of various forms of therapies, particularly when curative treatment options are lacking.”

He also notes:

“This problem may be particularly American one; other cultures do not seem to view the postponement of death by a few months as holding an equivalent importance. Culturally, are we entirely honest in our assessment of what a few months, particularly spent in illness, can accomplish?”


Value Framework Also Embraces Notion That A Few Months More Of Life Is Not Worth It

Schnipper, writing for the Task Force concludes:

“Cancer drug spending is being driven by “sometimes unrealistic patient and family expectations that lead clinicians to offer or recommend some of these services, despite the lack of supporting evidence of utility or benefit.”

Patients “ also overestimate the benefits of treatments that sometimes extend life by only weeks or months or not at all. 


Schnipper Established A Cut Off Point For Value Measured By a 20 percent increase (3 months) in yearly survival

Over the past two decades Schnipper has advanced an economic argument for cutting off cancer treatments.  Initially, he maintained that survival time should be increased beyond a specified amount of time:

“On average they (cancer treatments) may delay death for only a very short time, for example 3 months. Although some patients may live for more than 3 months, others will not necessarily live even that long. The drug only slows the progression of the patient's cancer by a few months; it does not “cure” the cancer. The psychological force of the rule of rescue should be much weaker in the context of this cancer care than in mine collapses. It should not make it impossible to resist providing the treatment, and certainly does not justify doing so. “  (In this regard, applying Schnipper's logic to everyone means stopping treatment for  every patient that does not gain more than 3 months on average, including babies, HIV patients and children with rare diseases. ) 

The Task Force Cutoff for Value Is The Same As Schnipper’s

Under his leadership of the Value Task Force, the 3 month cut off was turned in to a specific increase in survival as a percentage of a year of life: “It was generally agreed that relative improvements in median overall survival of at least 20% are necessary to define a clinically meaningful improvement in outcome. “    On average, 20 percent ranges from weeks to a few months.   This is a value judgment that applies to all patients with all forms of cancers with all different tumor types.


Schnipper believes that below a certain increase in survival money spent on dying cancer patients should be spent elsewhere to ensure resources are distribution ‘fairly.’

He claims: “The result of abandoning reasonable value standards in the face of urgency would be the use of much very high-cost, marginal-benefit care for dying patients. This situation is arguably our current practice in much care, including cancer care, of dying patients. But it is neither a rational nor ethical use of limited resources. The money spent on this very expensive, but marginal benefit, end-of-life care, could produce greater benefits if spent elsewhere either within or outside the health care system.

Schnipper goes on to state a cut off level:

“A cancer treatment that postpones death on average for 3 months at a cost of $100,000 does not produce…a large benefit.   The opportunity costs of securing that treatment are much too great.”

Schnipper has argued that spending on overage increase of three months comes at the expense of other uses of money. 

“A life-saving treatment like an appendectomy generally produces a very large benefit; it prevents the patient's death and returns him or her to a healthy life. But a cancer treatment that postpones death on average for 3 months at a cost of $100,000 does not produce such a large benefit. The life extension is short, and the quality of life during it is often poor. It is not a large enough benefit to trump the greater benefits to many that would have to be foregone to provide it.”


Similarly, the Value Framework declares:

“Oncologists should be aware of the value of an intervention in terms of societal cost. Clearly, increasing health care costs are eventually transferred to the consumers of health care, if not in the form of out-of-pocket costs, then in the form of higher insurance premiums, higher taxes, or limited wage increases as employers confront the escalating costs of providing health care to their employees."


What Schnipper and The Task Force Ignore

The task force asserts that spending on new cancer drugs bankrupts individuals and our healthcare system.  But the benefits to patients are palpable.  Drugs that emancipate our immune system to attack tumors or target specific genetic cancer causing mutations have transformed cancer care.  These cancer drugs are expensive no doubt.  Yet they account for only account for 0.7 percent of the $2.9 trillion we spend on health care.   Cancer spending has increased in 1995 from $42 billion to about $130 billion today.  But its share of total health spending declined from 4.7 percent to 4.4 percent during the same time period. 

New medicines reduce the cost incurred by a cancer diagnosis, for instance in part by reducing hospitalization.  In 1996 drugs were 3.7 percent of cancer spending and 62.4 percent went to hospitalization. By 2012, drug spending was 9.3 percent of cancer costs while the share going to hospital stays dropped to 41.3 percent.    If we were allocating the same proportion of money to hospitals today, as we were in 1996, we’d be spending about $18 billion more a year on cancer.  And we have yet to see the full benefit of the cancer drugs not yet included in these estimates. 

As the price and number of new treatments increases, their value increases too. A recent Bureau of Economic Analysis study found between 2000-2010 that “medical technology (for treating cancer and other costly illnesses) is improving over time, leading to better health outcomes at a lower cost per patient.”   A lot of that has to do with medicines displacing less effective and more costly oncology services.  Why does the ASCO Value Task Force ignore that. 


Conclusion

Between the time Schnipper was pushing for assisted suicide until the time that he has begun pushing to limit the use of cancer drugs for people with “only” three months to live cancer survivorship has surged from 10 million to 14 million people and life span expressed by 36 million life years worth about $3 trillion.

If Schnipper’s vision had become common practice how many of those survivors would not be alive today?  How many will not live because of his current plans? 





The announcement that Aprecia Pharmaceuticals has produced the first 3-D printed drug approved by the Food and Drug Administration  prompted a slew of articles about the technology that produced it.   There as no coverage about what it took to move 3-D printing from being a science fair project to a tool for mass production of customized medicines. Nor has their been any discussion about the implications of such commercialization on medicine. In particular,  the marketing of 3-D printed drugs underscores Sir Harold Evans observation that “innovation is not simply invention; it is inventiveness put to use. Invention without innovation is a pastime.”

















The emphasis  on ‘pragmatic’ is what distinguishes invention from innovation.  Michael Shrage,  a research fellow at MIT Sloan School's Center for Digital Business says that innovation is not what innovators do but what customers adopt.    Semi-conductors were an amazing invention but no one really saw any use for them beyond industrial applications:  then someone came up with idea of using one programmable chip to make personal electronic calculators.   It wasn’t long after that the PC revolution was launched.  

While Human Genome Project was a worthwhile investment, it was only made so by the efforts and investment undertaken to make it’s tools accessible and to product medicines and devices that millions could use.  Otherwise it would have been a very expensive science fair experiment as well.

The sale of 3-D printed medicines demonstrates that it is possible to make targeted medicines or treatment combinations widely and quickly available.   Often overlooked in the discussion about Aprecia is the fact that it applied it's manufacturing process to medicines that are in short supply because generic companies have found them too expensive to make using existing technologies or because they are products -- such as those for neurological conditions -- require absorption and availability within very narrow therapeutic indexes.   Finally,  the Aprecia approval is notable because it takes an injectable drug and turned it into a pill (Spritam).   Levetiracetam is used to control pediatric (and adult) epileptic seizures.   A stable, oral medication that works more quickly and can be produced in real time meets an important clinical need and solves a growing problem of drug shortages.  Can we say disruptive? 

Finally,  it should be noted that Tom Arrington, who invested in Aprecia many years ago, placed a huge bet on 3-D printing of drugs.  He didn't need the money.  In fact, Mr. Arrington has a successful authorized generic company Prasco Laboratories. .  Like many other entrepreneurs, Arrington's goal was not making more money. There a less risky ways to make a return.  Rather, profit is a means to an end that other incentives cannot easily achieve.  As Sir Harold noted: "Iinnovators are committed to making their developments as widely available to the populace as possible. This mass market democratization has been a hallmark of American success in the world."

Commercialization is part of the virtuous cycle that has made progress against disease and in enriching and extending life possible.  Aprecia has opened the door to the commercialization of medicines that can serve unique populations and it creates unprecendented opportunity to repurpose injectable medicines so that they are easier to administer, ship and store.  But the effect of commercialization cannot be divorced from the character of the person making it possible.

The Talmud observes:  Which is the best path for someone to choose for themselves?  Whatever is harmonious for the one who does it, and harmonious for mankind.

That sums up the path Tom Arrington took when he invested a small fortune in Aprecia. 
Frances Kelsey,  a medical officer with the Food and Drug Administration in the 1960s died last week at the age of 101.  She has been celebrated as the FDA official who kept thalidomide from being marketed in the United States.  

Thalidomide was never approved in the US.  In fact, as noted in Regulating New Drugs: The application was delayed for reasons having nothing to do with potential risks and was moving towards approval when the company itself reported the horrible side effects.  It took four months for the FDA to realize that people were at risk and in fact Helen Taussig, a cardiologist at Johns Hopkins University had been sounding the alarm about thalidomide for years.  The FDA finally acted after John F. Kennedy insisted on it.  

The current FDA approach -- a product of the 1962 amendments to the Food and Drug Cosmetic Act -- and dependency on the randomized controlled trial is a legacy of the political reaction to a problem.  Efforts to increase regulatory flexibility at the FDA are opposed, the critics always invoke "another thalidomide." 

Most people stop the story there. It’s an open and shut case, they say, thalidomide was a horribly dangerous and deforming drug allowed to get onto and stay on the market due to grossly inadequate safety testing and monitoring and the callous actions of companies interested in profits over patients. This, they believe, is why we cannot be too careful about any drug that might be risky. But the tale of thalidomide doesn’t end with its withdrawal – and millions have lived better, longer lives because of it.

In the mid-1960s, thalidomide came back to life. As many discoveries in medicine are, it was due to chance. Dr. Jacob Sheskin was the head of the Jerusalem Hospital for Hansen’s Disease (or what most people call leprosy) when one day he was sent a patient with extremely advanced erythema nodosum leprosum or ENL, a very painful and debilitating side effect of leprosy that causes boils, joint pain, inflammation, and intense pain. Patients waste away, unable to eat or sleep and dependent on morphine and sedatives to control their agony. About 60 percent of people with advanced leprosy get ENL.
The patient who arrived at the Jerusalem Hospital in 1964 was close to death and had received almost no benefit from any sedative available. While trying to figure out whether there was anything that could be done for him, Dr. Sheskin stumbled upon a small stash of thalidomide, now no longer sold. But remembering the use of the drug in mental patients who similarly responded to no other sedative, the doctor decided it was worth a try. It worked. Spectacularly. Not only was the patient finally able to sleep but his ENL began to improve radically. The same thing happened with other patients with ENL. Sheskin then embarked on a series of controlled clinical trials in Venezuela, where thalidomide could still be purchased, and confirmed his findings. Soon the drug was promoted by the World Health Organizations for use in ENL patients and because of it the vast majority of facilities to treat leprosy have been able to be closed. Even the US allowed highly controlled use of thalidomide for ENL beginning in 1975.

In the 1980s, thalidomide found another use: AIDS patients. Like those with ENL (and tuberculosis patients, who had also been helped by thalidomide), people with AIDS suffered from severe wasting. They also got sores in the mouth and esophagus called aphthous ulcers, caused like the wasting by caused by a chemical called TNF-ɑ (tumor necrosis factor alpha), and a rare cancer called Karposi’s sarcoma. The drug worked well, but it was hard to get a hold of. Many AIDS patients obtained it from abroad, mostly via Mexico, through buyers’ clubs but these channels were dubious and the quality and purity unsure. Researchers into the uses of thalidomide had likewise found that it was difficult to obtain and so one, Dr. Gilla Kaplan, finally managed to convince a small pharmaceutical firm called Celgene to apply to the FDA for approval to produce thalidomide.

While the process to get the drug through the FDA was ongoing, research into its potential use as an anti-cancer drug was in process by leading cancer researchers Dr. Robert D’Amato and Dr. Judah Folkman. They were working on angiogenesis, the growth of blood vessels, and hoped that finding a way to inhibit it would allow the development of drugs to fight cancer, as well as several other diseases. It was thalidomide’s anti-angiogenic effects that caused the birth defects but also made it a perfect candidate from D’Amato and Folkman’s research. Subsequent study found that the drug is also very effective against multiple myeloma, a difficult to treat cancer that attacks the plasma cells in the blood.  In July 1998, after a long and spirited debate and heartfelt stories from both victims of thalidomide and those helped by it, the Celgene drug --Thalimid was approved by the FDA under the condition that patients are carefully monitored and extensive safeguards enacted to prevent pregnant women from taking thalidomide.  Once in use, the benefits of thalidomide analogues in resetting the immune system to reduce tumor growth, became apparent.  It launched a whole new field of treatments and the introduction of several new medicines.  New uses, especially for rare autoimmune conditions, are still being discovered, even as old ones are sometimes superceded. In its current usages, the drug has benefited millions of patients around the world.

The thalidomide story is a many told tale:  Each year millions of people suffer because fearmongers invoke the handful of side effects or deaths from the use of a medicine.  Indeed, the number of adverse events from drugs as a percentage of all prescriptions did not change after the 1962 amendments.  The number of withdrawals as a percentage of all medicines has remained the same.   FDA regulation is a very expensive tranquilizer to calm the nerves of the public.  We have more expensive medicines, fewer new medicines for specific groups of patients and less competition.   

Enshrining Francis Kelsey as a hero is a ritual detached from the truth.  It is an exercise designed to reinforce the precautionary approach that has slowed down the development and use of medical innovations for over 50 years.  
CMPI

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

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