Are free samples only skin deep?

04/17/2014 09:37 AM |

According to a new study published in JAMA Dermatology, dermatologists who receive free drug samples are more likely to give their patients prescriptions for expensive medicines.

Not surprisingly, that results in headlines such as “Free samples of prescription drugs are costly to patients, study says” (Los Angeles Times) and “Doctor’s free samples have a hidden cost” (NBC News). Sexy, but is that the real story?

The study reports that, for a single visit, the average retail cost of prescriptions for patients whose doctors received free samples from drug makers was about $465, compared with about $200 for patients whose doctors did not receive free samples.

What the study does not report (because they did not collect the data) was whether the free samples were the more therapeutically appropriate choice.

The reporting on the article (various news media) makes it sound as though generic and brand name drugs that treat the same condition are identical (and equally appropriate and efficacious) to each other. Not so. But why let important facts get in the way of a good story.

Most nauseating is the following study factoid:

In contrast, such drugs (sampled brand name drugs) only accounted for 17 percent of prescriptions written by doctors at an academic medical center that doesn't allow its doctors to accept free drug samples.

Well, duh. No samples in, no samples out. (Not to mention the fact that academic medical centers often dictate narrow formulary choices. Not surprisingly, that fact wasn’t mentioned in the study) It would also be interesting to match up patient outcomes of those derms who dispense samples vs. their ivory tower colleagues. Will any of these additional data sets be included in a follow-up study? Inquiring minds want to know.

The full study can be found here.

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Ad Comity

04/16/2014 11:25 AM |

As the saying goes, everything you read about in the news is true –except for those things you know personally. Case in point: coverage of the FDA’s approval of the pain medicine, Zohydro.

Yesterday, U.S. District Court Judge Rya Zobel granted a request by a drug manufacturer Zogenix for an injunction temporarily halting Gov. Deval Patrick’s attempt to ban the prescribing of the painkiller Zohydro.

Massachusetts Governor Deal Patrick and others who want to ban Zohydro argue that the FDA Advisory Committee voted against approval.

True, but not necessarily accurate.

At an FDA advisory committee, the agency is asked to defend its scientific thinking in public, before a panel of experts who can dissect results, challenge conclusions, and ensure no clinical stone goes unturned.  Seldom reported, however, is that advisory committee votes are recommendations. They aren’t binding on the FDA.

An analysis of advisory committee recommendations compared to agency actions shows FDA followed committee advice 74% of the time. Interestingly, the agency overruled “no” votes only three times: (Tarceva for maintenance therapy in lung cancer, Avastin for breast cancer, and Micardis to lower blood pressure.) Since their approval, these medicines have saved, extended, and improved hundreds of thousands of lives.

So, what about the Zohydro decision? The soundbite you’ve likely heard is that the vote was against approval of the drug. That’s true. What you probably don’t know is that, by a vote of 11-2, the experts affirmed that there was no evidence to suggest Zohydro had greater abuse or addiction potential than any other opioid.

When the committee voted, Dr. Bob Rappaport, Director of the FDA’s Division of Anesthesia, Analgesia, and Addiction, asked members to explain their votes. All but two said that while Zohydro had met their requirements for approval, their votes were meant to call greater attention to the agency’s regulation of opioids in general – not Zohydro specifically.

The FDA decided to approve Zohydro based on the agency’s judgment (and the advisory committee’s concordance) that the medicine is safe and effective. But the FDA also heeded the expert panel’s advice for better post-approval regulation of opioids.  Shortly before Zohydro’s approval, the agency strengthened opioid labeling and post marketing requirements to address the concerns raised by the advisory committee.

A report by the Institute of Medicine found that 100 million Americans now live with chronic pain. That’s a third of the U.S. population. Ten million of those have pain so severe they are disabled by the pain.

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D-structive

04/15/2014 07:01 AM |

As many as 36 million Americans narrowly dodged a recent proposal from the Centers for Medicare and Medicaid Services (CMS) that would have advanced unprecedented government intrusion within the Medicare Part D prescription drug program.

CMS never offered a satisfactory reason for its proposed tinkering with something that's working. Part D is a real rarity -- a genuinely popular and cost-effective federal health program. The proposed reforms were not only unnecessary; they would have compromised affordability, limited treatment options for patients, and stifled innovation in the insurance industry.

Though the misguided proposal has been shelved, Part D is still at risk. The Obama administration has pledged to push through a similar plan in the near future.

By all accounts, Medicare Part D is overwhelmingly successful. The program offers drug coverage to seniors for a monthly average of $31 and enjoys a 90 percent approval rating among beneficiaries.

Unlike other healthcare benefits, Part D is also cost-effective for taxpayers. The nonpartisan Congressional Budget Office (CBO) reports expenditures are now 45 percent below original cost projections.

And because Part D provides access to vital medicines, the program helps seniors avoid expensive stays in hospitals and nursing homes. Over half of beneficiaries report they would be "more likely to cut back or stop taking medicine altogether" without Part D coverage. In this way, Part D saves our healthcare system $12 billion annually, according to a study in the Journal of the American Medical Association.

In light of the program's remarkable track record, it's inexplicable why CMS would attempt to tamper with important aspects of Part D.

As part of the proposed changes to Part D, CMS wanted to eliminate rules that provide "protected class" status to mental health drugs and drugs used for autoimmune diseases and organ transplant patients.

If the reform had taken effect, private plan providers may no longer have covered many of the medicines included in these designated categories. Countless Part D beneficiaries would have lost access to the drugs they were currently receiving and need to stay healthy.

CMS claimed that the proposal would lower prices by giving private plan providers better negotiating leverage with pharmaceutical companies. But that rationale ignores the fact that costs for these drugs have already been falling for years. From 2006 to 2010, in fact, prices for protected-class drugs dropped by two percent, despite an explosion in overall healthcare costs.

The idea that federal regulators can intervene to help negotiate better prices is dubious at best. And CMS didn't offer any quantitative evidence that restricting vital medications would benefit either seniors or the federal government.

Indeed, Part D works specifically because it encourages open competition between private insurers who are eager to serve Medicare's huge prescription drug market.

Nevertheless, federal regulators sought to reinterpret certain parts of Part D's "non-interference clause" -- the part of the law that forbids regulators from distorting the market by intervening in drug price negotiations. The proposed changes would have allowed the government access to all agreements struck by drug manufacturers, pharmacies, and insurers.

The new rules would have also limited the number of bids an insurance plan may offer in a region to two. By reducing the number of plans available, CMS would have weakened competition between insurers while also preventing plan providers from experimenting with new policies. Uncle Sam wants to reduce competition? What would the Federal Trade Commission have to say about that?

On top of all that, the agency suggested changes that would encourage nearly every employer who offers health insurance for retirees to drop prescription drug coverage.

There was one common thread running through these proposed changes to Part D: they all restricted choice and discouraged competition. The Obama administration, it seems, isn't content with a healthcare entitlement that relies on market forces -- no matter how cost-effective or popular the program may be.

When the Obama team shelved its plan, CMS Administrator Marilyn Tavenner only promised to pull it only "at this time." In fact, she committed to "advancing some or all of the changes in these areas in future years." So Part D isn't yet safe. In the future, if regulators want to sabotage the most successful federal health program in the country, the least they could do is explain why.

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Pharmitzvah 2014

04/14/2014 07:00 AM |

Last week’s 14^th annual meeting of Pharmaceutical Research and Manufacturers of America (PhRMA) was a memorable pharmitzvah. Smart folks, old friends, challenging panels, and a bevy of good speeches on challenging topics.

And while there was the appropriate serving of rah-rah, there was significant substance alongside the Beltway style.

This was best summed up by Ian Read (Chairman and CEO of Pfizer) in his inaugural remarks as the incoming Chairman of PhRMA. It wasn’t a Morning in America oration. Read shared his concern about the industry’s failure in getting the message out about “the value we generate.” His key message, “We need to fix the misperception gap.”

Specifically he talked about the industry’s need to broaden the conversation from the economic performance of biopharmaceutical companies to the value that accrues to society and called for a “dialogue with society.” Bravo.

He asked, “Where are the headlines?” They’re not about societal value – and they need to be. There’s a strong story to tell. It’s not happening. And it needs to, because minus that narrative, nothing the industry wants to make happen (with government being a focus since the meeting was in Washington, DC) will be possible.

Read called for “industry speaking for itself.” After all, if you can’t be your own best advocate, you’re suspect in the minds of many – and rightfully so. He spoke to “better ideas and clarity” versus “more tactics.” That’s a foundational shift and a timely one. Innovators win when the discussion is about the future.

Read called for transparency in data sharing and physician relationships. Doing it is one thing – and most members of the pharmaceutical brethren are doing the right thing. But it’s equally important to tell the industy’s various constituencies what programs are in place, what they are designed to do, and how they work. Transparency mustn’t be allowed to be a cudgel used to beat innovators but a tool in it’s own communications arsenal.

Value to society. It was Read’s mantra. It needs to be the industry’s manifesto.

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Kathleen Sebelius

04/11/2014 06:52 AM |

Mission Accomplished?  Read More & Comment...

Don't politicize FDA decisions on pain medications

04/10/2014 08:46 AM |

Our elected officials should act to protect medical progress in chronic pain relief. One hundred million people in the United States deal with debilitating chronic pain and need access to approved medications every day to stay productive and attain some measure of quality of life.

We must protect medical access for those afflicted with the most severe pain
The FDA did its job correctly by approving a unique treatment option based on its safety and efficacy data.

Do not let politicians overturn the FDA’s legitimate and expert approval of a pain medicine option that can bring relief.  Do not infringe on patient access to approved pain medication options in any State. Help us send a message to Washington and state capitals across the nation to do the right thing.

Stand up and show your support for people with chronic pain.  Please sign (and share) our petition today.

The on-line petition can be found here.

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Expedited Reviews? Context Matters

04/09/2014 06:55 AM |

I was recently interviewed by Context Matters on Expedited Reviews and the Current State of Drug Development. Here’s Part One of the conversation

Regardless of what you want to call it, whether it’s expedited review or special protocols, limited use medicines, the theory is, “How can the FDA help bring important therapies to the market faster?” And, there are a lot of pieces to that puzzle.

At the end of the day, the agency still has to meet with the sponsor, who still has to have data. They have to meet and decide how to move forward.

There are two issues that also have to come into this conversation:

1. The patient voice
2. Benefit / risk profile

Those are two things that really are not usually discussed. Generally speaking, in this type of conversation what comes about in the discussion is time. How quickly can something happen? Obviously faster is better than slower, but you don’t want to ever sacrifice proper review.

Blood From a Stone: Expedited or Standard, It’s All the Same FDA Resources

A key issue not being widely talked about is that the FDA isn’t hiring a whole new team to deal with expedited reviews. It’s the same people. So does an expedited review take precedence over a non-expedited review? How does the agency determine who gets the resources at what point in time?

Obviously, if you’re going to file a regular old-style NDA, you get a PDUFA (Prescription Drug User Fee Act) date and the agency is responsible for that. How do you weigh that against “critical medical need”?

The answer is it’s on a case-by-case basis. You can’t say, “Hey, we’re not going to make the PDUFA date because we’re reviewing someone else’s drug,” that’s a non-starter. You have to view expedited review situations in the broader context of everything else the agency has to do.

And then the agency is then going to define (on a case-by-case basis) what it feels is most important to the public health. Here’s an example: MS (multiple sclerosis) or IPF (Idiopathic pulmonary fibrosis) – Are either of those more or less important from an expedited review / resources perspective than a new anti-infective? It depends who you talk to. If MRSA issues are on the top of your agenda, then it’s one thing. If it’s orphan diseases, it’s another or if it’s pain-mitigation it’s something else again. Where you stand on these issues depends on where you sit.

I don’t really think having people specifically tasked to working on expedited reviews is the way to go, unless you have more people. And then the question is, where do they come from and do you take the best and brightest away from standard review, to put them there? How do you weigh the general importance of staff time and agency resources? Do you want it to be for a disease that is not an orphan disease that’s an important therapy, or do you want it to be on an orphan disease that can have a profound difference on people’s lives? Those are really philosophical questions, but it comes down to resources. I don’t think you can have dedicated teams when you don’t have people that can dedicate their time exclusively, otherwise it is just rhetoric. It’s just another committee on which the same people sit.

Comparing the Agencies

What might be interesting (and is generally not part of this conversation) is a move towards greater FDA / EMA harmonization on certain disease categories. There’s been a lot of chatter on this issue, but at the end of the day nothing really happens. I think the EMA would be interested in that, probably more than the FDA, because one of the main differences is the type of data accepted by the EMA. The EMA casts a wider net in terms of the types of data they accept for any given application.

One of the reasons the EMA has gone beyond the FDA is that their national economies are so much more financially strapped than we are here. It is important to remember that EMA decisions are only the first part of gaining market access. After the EMA, drugs go on to be evaluated by different country Health Technology Assessment (HTA) agencies to determine reimbursement and pricing in various markets. And from a reimbursement perspective, the HTA agencies are moving away from the QALY (quality-adjusted life year) towards a more value-based insurance design.

From a review proposition, from the FDA’s perspective, obviously they don’t get involved in cost issues, only clinical issues. I think what innovator companies are going to find out (especially with the expedited review pathways) is that the risk of getting a drug yanked quicker (meeting a quick death) rises. So they are going to have to understand, from a business perspective, the risk of asking the FDA for these special medical use reviews – it could backfire unless you understand what you are asking the FDA to do. The FDA is trying to signal that there are multiple ways to get an important new therapy to market quicker, but that has to be based on a public health need and not on a marketing strategy.

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Keeping the Bay State at Bay

04/08/2014 04:13 PM |

Governor Deval Patrick wants to ban Zohydro in Massachusetts.

That's what he wants, but what he needs is an intro level course in federal jurisdiction -- and he's about to get one.

US District Court Judge Rya W. Zobel would not grant an immediate restraining order as requested by drugmaker Zogenix, but scheduled a followup hearing for Monday, saying it appeared that Zogenix would have a likelihood of winning the case.

 “I think, frankly, the governor is out of line on this,” Zobel said..”

 She urged both sides to discuss the issue before Monday.

 “I do not expect this to be a very long hearing,” he said.

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Channeling Patty Delaney

04/08/2014 07:05 AM |

Returning to the subject of expanded access to developmental medicines (When Compassion Isn’t Enough), I want to be clear that it wasn’t me who coined the term “expanded access.” As one of my former FDA colleagues commented, “In March 1990 the IOM Roundtable for the Development of Drugs and Vaccines Against AIDS held a workshop “Expanding Access to Investigational Therapies for HIV Infection and AIDS.”  FDA staff, including me, participated in the Keystone national policy dialogue (Expanded access to promising therapeutic drugs for HIV infection and AIDS with implications for other life-threatening diseases) in the early 1990s.  Also in the early 90s, FDA used the term expanded access at advisory committee meetings and at meetings of the National Task Force on AIDS Drug Development.”

Naming issues aside, this remains a highly contentious issue – and for all the wrong reasons. A new paper from the Goldwater Institute, “Everyone Deserves the Right to Try: Empowering the Terminally Ill to Take Control of their Treatment,” points the finger at the FDA as a roadblock to access, “Sadly, over half a million cancer patients and thousands of patients with other terminal illnesses die each year as the bureaucratic wheels at the FDA slowly turn.”

Nothing could be further from the truth.

What the paper presents a libertarian platform, “The burdens imposed on a terminal patient who fights to save his or her own life are a violation of personal liberty.” Maybe so, but the Supreme Court has ruled otherwise. In January 2008, the U.S. Supreme Court, without comment, opted not to accept an appeal of Abigail Alliance v. von Eschenbach. In other words, the federal appeals court ruling that patients do not have a constitutional right to experimental drugs stands

The paper continues, “Such people should have the option of accessing investigational drugs which have passed basic safety tests, provided there is a doctor’s recommendation, informed consent, and the willingness of the manufacturer of the medication to make such drugs available.”

I don’t think that anyone of those constituencies has any argument on that point. But should the FDA be cut out of the process? According to the paper, “… bureaucratic impediments violate an individual’s fundamental right to try to save his own life.”

But that’s consistent with the author’s libertarian philosophy. She believes that the “vast new granting of power (of the Kefauver-Harris Amendments) “was unwarranted.” So, consider the source of the argument.

Alacrity is important, certainly. But process is important too, as is collecting data on expanded access use.

The paper does raise important questions, such as at what point in the drug development process should an investigational product be available to patients? The author argues for Phase I. That’s an aggressive position, but one worth debating.

One item that paper ignores is that for the FDA to address single patient INDs with both more careful attention and speed is funding. That’s more than the 800-pound gorilla sitting in the room – it’s the 800-pound gorilla sitting on the chests of desperately ill patients who want access to investigational medicines.

The author quotes Patty Delaney. Patty (who passed away in 2008) was the FDA’s main liaison to the cancer community and a tireless soldier for “doing the right thing.” She was a pit bull on behalf of patients.

According to the paper, “As Patty Delaney, the former director of the FDA’s cancer liaison program explained in 2007, “the patient has a right to be heard, but in the end, it’s the data that matters. FDA opinions about safety and efficacy are always based on data.”

I’ll side with Patty.

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One of these things is not like the other

04/07/2014 07:25 AM |

Much chatter about Janet Woodcock’s Energy & Commerce Subcommittee on Health testimony last week.  Much of it ill-informed.

Dr. Woodcock stood firm that separate labeling for generic drugs will advance the public heath by advancing 21^st century drug safety. Subcommittee Chairman Joe Pitts (no relation) didn’t agree. His comment, “The only outcome I see is confusion,” demonstrates his own confusion.

“I’d like to dispel the notion that labels are the same now with respect to safety information,” said Janet. Representative Pitts was not mollified, moving on to suggest the agency’s motives were other than for advancing the public health – specifically that “trial lawyers” were to blame for the agency’s actions.

Trial lawyers? Clearly he’s met with representatives of the GPhA.

Janet made it clear that the decision to move forward on the labeling change rule was CDER and no one other than CDER. “The personnel in the Center for Drugs did not meet with the trial layers.”

Mr. Pitts’ suspicions were not assuaged. Whatever.

(PS/Representative Waxman commented that he found the GPhA’s report that distinct labeling would increase consumer spending on generic drugs by $4 billion annually “highly invalid.”)

Dr. Woodcock also clarified that the discussion about generics labeling did not extend to biosimilars.

Per Janet, “This rule does not apply to that because those would be under the Pubic Health Service Act – and they’re not considered generics, so that’s a separate issue.”

Much consternation over this last remark. Some see it as a nod and a wink that the agency is going to allow biosimilars to have the same name and labeling language as innovators. I disagree for two reasons:

(1) Janet was precisely correct in stating that generic drugs and biosimilars are two distinct things. Biosimilars are not generic drugs.

(2) The fact that the FDA has made distinct generic drug labeling such an important policy initiative certainly does not send a signal that they will view biosimilars in a more laissez faire manner. Au contraire.

So, for people trying to read too much into Janet’s statement that generic drug labeling is different from biosimilar naming and labeling, relax. If anything, the news is good.

Prediction is very difficult, especially about the future. – Niels Bohr

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The Hamburg Manifesto

04/04/2014 07:05 AM |

As a wise man once said, “He who tooteth not his own horn, that horn shall go untooted.

This is a valuable lesson that the FDA has learned to be true. And it couldn’t have happened at a better time. Specifically, I refer to opioids.

The FDA has taken the bit out of its mouth and taken hold of the reins of pain.

While scene-stealing members of Congress, some governors, and a gaggle of state attorneys general are trying to run roughshod over science-based regulation to great attention from the media, the FDA has been quietly doing the right thing without anybody noticing.

But when you do the right thing and don’t tell anyone about it, the assumption is that you’re not doing anything. That began to change with FDA Commissioner Hamburg’s aggressive testimony in front of the Senate HELP Committee defending the agency’s October approval of Zohydro ER.

And it continued yesterday with the agency’s approval of EVZIO™ (naloxone hydrochloride injection) for the emergency treatment of known or suspected opioid overdose. Smartly, the FDA used the approval to speak, more broadly, to the topic. There was a lot to say – and it’s about time the FDA said it.

Peggy’s complete remarks can be found here.

During the stakeholder teleconference the Commissioner laid it all on the table. It turns out that the FDA is doing a lot to mitigate opioid risk after all! Most importantly, they are doing so while understanding the need to ensure appropriate access for the tens of millions of Americans suffering from chronic pain.

She got specific:

Combatting the serious public health problem of misuse, abuse, addiction and overdose from opioid analgesics is a high priority. Since 2001 the FDA has taken a number of actions designed to help address prescription opioid abuse and to encourage the development of new drug treatments for pain. These actions include:

Revising the labeling for opioid medications to foster their safe and appropriate use, including recent changes to the indications and safety warnings of extended-release and long-acting opioids.

Requiring that manufacturers conduct studies of the safety of long-term use of prescription opioids.

Improving appropriate prescribing by physicians and use by patients through educational materials required as a part of a risk mitigation strategy for extended-release and long-acting opioids.

Using the agency’s expedited review programs to advance development of new non-opioid medications to treat pain with the goal of bringing new non- or less-abusable products to market.

Working with other federal agencies and scientists to advance our understanding of the mechanisms for pain and how to treat it, including the search for new non-opioid medications for pain.

Recommending that hydrocodone-containing combination products have additional restrictions on their use by rescheduling them from Schedule III to Schedule II.

Strengthening surveillance efforts to actively monitor the changing nature of prescription opioid abuse and to identify emerging issues.

And, importantly, encouraging the development of medications to treat opioid abuse, such as buprenorphine for use in medication-assisted treatment, and to reverse opioid overdoses, such as naloxone.

I can’t say I agree with all of these things. (Upscheduling impacts appropriate access), but it’s a pretty powerful list.

And, it seems, recalling drugs that are currently on the market isn’t on the agenda.

In the immortal words of Don Draper, “If you don't like what is being said, then change the conversation.

Peggy returned again and again to the role the FDA must play in facilitating physician education, not only through labeling language but physician education. She 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.

Provider 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.

Importantly, the Commissioner regularly referred not to “abuse” but to “misuse and abuse.” That’s more than a rhetorical flourish since it recognizes that misuse is a gateway to abuse.

Joining Dr. Hamburg on the call were Michael Botticelli, Acting Director, Office of National Drug Control Policy, Douglas Throckmorton, M.D., Deputy Director for Regulatory Programs, Center for Drug Evaluation and Research, FDA, Melinda Campopiano, M.D., Senior Medical Officer, Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration, and Wilson Compton, M.D., Deputy Director, National Institute on Drug Abuse, National Institutes of Health.

Oh, and HHS Secretary Kathleen Sebelius, who never mentioned the word “recall” either. It looks like the specter of Secretarial interference is off the table. Kudos to Secretary Sebelius for making it clear this is a cross-departmental priority.

The take away message was loud and clear –misuse and abuse of opioids is a serious issue that must be addressed in an appropriate manner.

And, per today’s teleconference, “appropriate” means science-based and patient-centric.

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Peggy on Opioids

04/03/2014 12:09 PM |

For Immediate Release: April 3, 2014
Media Inquiries: Sandy Walsh, 301-796-4669, sandy.walsh@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA Commissioner Margaret A. Hamburg Statement on Prescription Opioid Abuse

For more than a decade, the U.S. Food and Drug Administration has been working to address the important public health problems associated with the misuse, abuse, addiction and overdose of opioid analgesics, while at the same time working to ensure continued access to effective and appropriate medications for millions of Americans currently suffering from pain. I firmly believe that these goals are compatible, and that actions to address one should not be at the expense of the other.

Tragically, the most recent data shows that more than 16,000 lives are lost each year due to opioid-related overdoses. In fact, drug overdose deaths, driven largely by prescription drug overdose deaths, are now the leading cause of injury death in the United States – surpassing motor vehicle crashes. We know that the illegal diversion, misuse, and abuse of prescription opioids are often fueled by inappropriate prescribing, improper disposal of unused medications, and the illegal activity of a small number of health care providers. This highlights the important role that education of prescribers and patients can play in addressing this epidemic. The FDA has taken steps to address this but more work remains to be done.

Combatting the serious public health problem of misuse, abuse, addiction and overdose from opioid analgesics is a high priority. Since 2001 the FDA has taken a number of actions designed to help address prescription opioid abuse and to encourage the development of new drug treatments for pain. These actions include:

Revising the labeling for opioid medications to foster their safe and appropriate use, including recent changes to the indications and safety warnings of extended-release and long-acting opioids.

Requiring that manufacturers conduct studies of the safety of long-term use of prescription opioids.

Improving appropriate prescribing by physicians and use by patients through educational materials required as a part of a risk mitigation strategy for extended-release and long-acting opioids.

Using the agency’s expedited review programs to advance development of new non-opioid medications to treat pain with the goal of bringing new non- or less-abusable products to market.

Working with other federal agencies and scientists to advance our understanding of the mechanisms for pain and how to treat it, including the search for new non-opioid medications for pain.

Recommending that hydrocodone-containing combination products have additional restrictions on their use by rescheduling them from Schedule III to Schedule II.

Strengthening surveillance efforts to actively monitor the changing nature of prescription opioid abuse and to identify emerging issues.

And, importantly, encouraging the development of medications to treat opioid abuse, such as buprenorphine for use in medication-assisted treatment, and to reverse opioid overdoses, such as naloxone.

Today’s FDA approval of Evzio (naloxone autoinjector) provides an important new tool in our arsenal to more effectively combat the devastating effects of opioid overdose, which is one part of our comprehensive work to support opioid safety. Reflecting the FDA’s commitment to encouraging important new therapies, the FDA’s review of Evzio was granted priority status, and the application was reviewed by the FDA in just 15 weeks.

This product is the first auto-injector designed to rapidly reverse the overdose of either prescription or illicit opioids. While the larger goal is to reduce the need for products like these by preventing opioid addiction and abuse, they are extremely important innovations that will help to save lives.

The FDA will continue to work to reduce the risks of abuse and misuse of prescription opioids, but we cannot solve this complex problem alone. A comprehensive and coordinated approach is needed; one that includes the White House Office of National Drug Control Policy, the Drug Enforcement Administration and many of our sister agencies within the Department of Health and Human Services, as well as state and local governments, public health experts, health care professionals, addiction experts, researchers, industry, and patient organizations.

I am confident that this can be accomplished, but we will all need to work together to invest in strategies and responsible approaches that deter or mitigate the effects of abuse while preserving access to pain medicines for the patients that need them the most.
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You can call me Al ... Jazeera

04/03/2014 07:36 AM |

On Tuesday I appeared on Al Jazeera America program, “The Stream.” The episode was titled “Inside the medicine cabinet,” and here’s how it was described:

Nearly 70% of Americans are on at least one medication. But for millions, combining too many of them could lead to dangerous consequences – even with safeguards in place to protect patients. We’ll explore what you need to know about your medicine cabinet.

Hosted by Lisa Fletcher, my fellow panelists were

Michael Carome 
Director, Health Research Group at Public Citizen 

Dr. Natalie Boulware 
Naturopathic Physician, Tulsi Holistic Living 

Dr. Caleb Alexander  
Co-Director, Johns Hopkins Center for Drug Safety and Effectiveness

David S.H. Lee 
Assistant Professor, Oregon State University College of Pharmacy

Good topic. Good panelists.

Click here for the full video.

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Adherence 'Appens

04/03/2014 06:53 AM |

According to a new study from Adherent Health, a mobile health engagement advisory focused on medication safe-use, adherence, and health outcomes attainment, nearly three-quarters of prescription-takers use mobile apps, including most older adults and seniors.

Mobile app adoption rates are high across all medication-taking adult age groups: 93% (age 18-24), 90% (age 25-34), 88% (age 35-44), 80% (age 45-54), 66% (age 55-64), and 50% (age 65+).

Among other study findings, prescription-taking patients using mobile apps were similar to their non-app using counterparts in terms of annual income, education level, and geographic region.

Conducted in the first quarter of 2014, the 2014 Patient Preference Study surveyed the mobile app behaviors and medication support preferences of 2,216 prescription-taking patients aged 18-65+.  

"This is a high rate of mobile app use among prescription-taking patients of all ages, including those 65+" remarked Michael A. Weber, MD, Professor of Medicine at the SUNY Downstate College of Medicine in Brooklyn, and Editor-In Chief of the Journal of Clinical Hypertension. "Apps represent an attractive communications medium to better support patient understanding, medication adherence, and medication safe-use."

Approximately half of America's 187 million prescription-takers are non-adherent, meaning they do not take their medications as prescribed.

App-using patients prefer a privacy-protected single app (such as Adherent’s Mobile Health Library system) by a factor of 11 to 1 over email programs often offered by medication manufacturers.  This high preference for a privacy-protected single app, customized to a user's needs for medication education and support services, was observed across all adult age groups.

"I'm not surprised that most patients would prefer a single privacy-protected app that supports medication dosing reminders, ongoing education, and co-pay and affordability needs" said Amy C. Sidorski, MS, CRNP, BSN, RN of Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, and member of the ONS:Edge Oncology Nurse Experts Panel.  "Especially one they receive from their physician or nurse."

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When Compassion Isn't Enough

04/01/2014 09:38 AM |

A very important series of stories in this week’s issue of BioCentury (authored by Steve Usdin) addressing the thorny, urgent (and too frequently ignored) topic of expanded access to experimental medicines. The articles generally refer to “compassionate use” and “compassionate access.” That’s the wrong terminology – and a good place to begin the conversation.

In January 2008, the U.S. Supreme Court, without comment, opted not to accept an appeal of Abigail Alliance v. von Eschenbach. In other words, the federal appeals court ruling that patients do not have a constitutional right to experimental drugs stands.

This is a tough, emotional issue and, with such heated rhetoric on both sides, it's easy to lose sight of the fact that everyone wants the same thing -- expanded access to drugs under clinical investigation.

For me this issue began (when I was Associate Commissioner for External Affairs at the FDA) during a meeting with Theresa Toigo (then the Director of the agency’s Office of Special Health Issues) and Frank Burroughs (founder of the Abigail Alliance for Better Access to Developmental Drugs). The meeting centered on Frank’s assertion that the FDA could do more to expand its parameters for patient access. We all agreed more could be done. Frank left. Terry stayed – and I asked her why we (the FDA) used the term “compassionate use.” Her answer was simple – “It’s what we’ve always called it.”

I said, “Let’s change what we call it." Allowing desperately ill patients into clinical trial programs shouldn't be an act of noblesse oblige it should be an act of civil society. We decided to work towards changing the term to “expanded access.” And we did. It’s one of the things I am most proud of accomplishing during my time at the FDA.

But it has to be more than rhetoric. The words have to mean something – and what they have to mean is that more patients get more access to more experimental medicines more expeditiously. In many cases it is, literally, a life-or-death situation.

When it comes to pharmaceutical safety, pure libertarianism isn't in the best interests of the public health. Expanded access to experimental drugs simply can't and shouldn't morph into total, unfettered access.

That doesn't mean the status quo is working. What it means is that the FDA needs to figure out a way to dramatically broaden and facilitate expanded access to experimental drugs under its review. And the Abigail Alliance and its supporters need to keep up the pressure to improve the current system.

This is best done in a spirit of collegiality rather than a confrontational courtroom or in Congress. Should expanded access design and development planning discussions be binary conversations between a sponsor and the FDA? What about the patient community? Perhaps, as part of the FDA’s current initiatives to enhance both the timeliness and weight of the patient voice, expanded access plan development and execution should involve patient organizations.  

In the BioCentury articles, Usdin speaks to the phenomenon of social media and the pressures it can (and does) bring to bear on sponsors. Maybe it’s time to harness that power to make the process both more inclusive and better.

It’s time.

The BioCentury articles can be found here, here, and here.

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Unfulfilled Expectations

03/31/2014 09:17 AM |

A new analysis by the Alliance for Integrity and Reform of 340B indicates that a substantial portion of hospitals enrolled in the 340B program provide only a minimal amount of charity care; as such, they may not be fulfilling Congress’ expectations. 

The study, compiled from newly available public data analyzed by Avalere Health, noted that the 340B drug discount program was designed by Congress to help safety net providers improve access to prescription medicines for uninsured, vulnerable patients in the outpatient hospital setting. Yet, the analysis shows, most hospitals that benefit from the program provide less charity care than the national average for all hospitals, and charity care in about a quarter of all 340B hospitals represents 1% or less of total patient costs.  A small number of 340B hospitals provide the lion’s share of all charity care delivered by 340B hospitals.

The analysis raises questions about whether the current 340B eligibility criteria specifically used for DSH hospitals are serving the spirit and intent of the law in that they may be overly broad and not just target those entities that serve high numbers of vulnerable, uninsured patients.  Specifically, the new research shows:

•       More than two-thirds of hospitals that receive 340B drug discounts provide less charity care as a percent of patient costs than the national average for all hospitals, including for-profit hospitals which do not qualify for 340B under current eligibility criteria.

•       For approximately a quarter (24%) of 340B hospitals, charity care represents 1% or less of the hospitals’ total patient costs.

•       Approximately one-fifth (22%) of 340B hospitals provide 80% of all charity care delivered by 340B DSH hospitals.

Currently, hospitals that qualify for the program claim 340B discounts for most outpatient prescription drugs, for both insured and uninsured patients.  And while the 340B program lowers outpatient drug costs for qualifying hospitals on the presumption that it will help significant numbers of vulnerable, uninsured patients, participating hospitals currently see no restrictions on the way they spend the revenue generated if they charge both insured and uninsured patients higher prices than the 340B-discounted price. 

This stands in contrast to many other covered entities that participate in the 340B program as a result of a specific grant (often referred to as “grantees”) from the U.S. Department of Health and Human Services.  The grant-approval process typically requires these providers to demonstrate that they provide services to certain specified vulnerable populations, at times based upon the patients’ “ability to pay”, and that the entities reinvest resources into services for those populations.

340B's broad eligibility criteria for hospitals have led to an explosion in the number of hospitals that have come into the 340B program. Today, one-third of all hospitals in the country participate in the 340B program and get 340B discounts; that number is expected to grow, particularly absent an effort to tighten eligibility requirements. Drug purchases through the 340B program will almost double, from $6 billion in 2010 to $13.4 billion by 2016, though little of the billions of dollars in discounts has been directly tracked to or linked with charity care for vulnerable indigent patients.

The complete report, “Unfulfilled Expectations,” can be found here.

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Delta Force

03/27/2014 10:15 AM |

BioCentury reports that NICE is seeking input on proposed changes to its health technology assessment methodology that the agency said would more explicitly take into account the burden of a person's illness and the wider impact of a disease on people's ability to be part of society. NICE is proposing to measure burden of illness as the proportional shortfall in quality-adjusted life years (QALYs) for those with a disease compared with the expected QALYs for those of the same age and gender without the disease. NICE said evaluating burden of illness as a proportional difference "recognizes the position of those patients who stand to lose the greatest proportion of their remaining health expectancy." The agency noted that the measure "is not particularly sensitive to the age at which people are diagnosed."

What NICE calls "societal impact" would be measured as the absolute difference between the expected QALY in a patient with a disease and the expected QALY in people of the same age and gender without the disease. The agency noted that for an absolute shortfall, "the larger the shortfall, the larger the effect" on society. Comments on the proposed methodology changes are due June 20, with NICE planning to introduce the changes this fall.

In 2010, the U.K. government proposed to establish a system under which NICE would have assessed the value of a new drug and assigned a value-based price. But the 2014 Pharmaceutical Price Regulation Scheme (PPRS) agreement essentially marked the end of value-based pricing as it was originally proposed, with NICE instead shifting toward a "value-based" assessment process.

It’s important to consider VBID in the broader conversation of clinical effectiveness and more specifically HTA modeling a la QALY – because that brings you into the direct path of VSLY – the value of a statistical life year.  According to Dr. Frank Lichtenberg of Columbia University, for a healthcare technology assessment scheme (such as the NICE model) to yield valid decisions in practice, it is necessary to have reliable estimates of:

ΔCOST
ΔQALY
and VSLY (Value of a Statistical Life Year)

and his main point is that the devil is in the details.

Lichtenberg believes that incorrect estimates of some or all of these key inputs are often used:

ΔCOST is frequently overestimated
ΔQALY and VSLY are frequently underestimated

And due to these estimation biases, health technologies that are truly cost-effective may often be rejected as cost-ineffective.

Per the recent debate over the utility of new cancer treatments, he makes a very interesting point -- that even though, over the past 30 years, the U.S. Mortality Age-Adjusted Rates for cancer have remained relatively constant -- (leading to such mainstream media headlines as Fortune Magazine's "Why have we made so little progress in the War on Cancer?” and NEJM articles like "The effect of new treatments for cancer on mortality has been largely disappointing” -- the often ignored reality is that 5-year relative survival rates, for all cancer sites, have increased from 50.1% in 1975 to 65.9% in 2000.

Lichtenberg cites two crucial studies, pointing out how health care economists must seriously reconsider the outdated estimates of a QALY:

Viscusi and Aldy: The value of a statistical life for prime-aged workers has a median value of about $7 million in the United States

Viscusi, W. Kip and Joseph E. Aldy, “The Value of a Statistical Life: A Critical Review of Market Estimates Throughout the World,” The Journal of Risk and Uncertainty, 27:1; 5–76, 2003.

and

Murphy and Topel: The value of a life year is $373,000.

Murphy, Kevin M., and Robert H. Topel, “The value of health and longevity,” Journal of Political Economy, 2006.

If the devil is in the details (and it is) -- it's time for a deep dive beyond simplistic and self-serving "comparative effectiveness."

Attention must be paid. Are you listening PCORI?   Read More & Comment...

Is Off Label on the Table?

03/26/2014 08:59 AM |

From the pages of the Wall Street Journal ...

Pharma and the First Amendment: A Proposal From the FDA

By Ed Silverman

On one hand, the agency is being praised for trying to move the ball forward, given ongoing uncertainty over disseminating material that contains off-label uses. Although physicians may prescribe a drug as they see fit, many drug makers have been fined for promoting their medicines for uses not approved by the FDA.

Yet at the same time, the FDA is being criticized for being overly restrictive concerning some materials and for also failing to specifically address First Amendment issues that have figured prominently in some recent court rulings about drug marketing.

“The fact that they’re starting to pay attention and open up off-label communications indicates they know they have to do a better job of defending the limits they have, and specifying what can and can’t be used and how that’s done,” says John Kamp, executive director for the Coalition for Healthcare Communication, a trade group for medical publishers and advertising agencies. “There are steps forward here. But in some cases, baby steps.”

One portion that was welcomed by industry representatives pertains to clinical practice guidelines, the official recommendations for patient treatment that are issued by professional medical societies. Until now, the FDA had not addressed these guidelines, which are closely tracked by doctors and may include off-label uses. The guidance says that CPGs must be distributed separately from promotional information and should display a statement that some of the products described might not approved or cleared by the FDA, among other things.

By devoting a portion specifically to clinical practice guidelines, the agency has now carved out a separate road map for distributing these missives to physicians.

“They’ve brought some clarity to this issue, which is very important,” says Alan Bennett, an attorney who represents more than a dozen drug makers that last fall filed a citizen’s petition (PDF) with the FDA in hopes of gaining clarity on distributing materials that contain references to off-label uses. The drug makers include Eli Lilly, Novartis, Sanofi, Genentech, Purdue Pharma, Pfizer and Johnson & Johnson.

But the FDA raised some hackles with its other dictums. For one, the agency did not add much understanding to an earlier guidance from 2009 that was devoted to medical and scientific journal reprints containing off-label information. This time around, though, the FDA noted that it does want companies to limit reprints to “adequate and well-controlled clinical” studies.

The earlier guidance also mentioned pharmacokinetic, pharmacodynamics and meta-analysis studies.

This would appear to preclude almost anything other than a double-blind, placebo-controlled study, according to Richard Samp, chief counsel at the Washington Legal Foundation, a nonprofit that frequently agitates for commercial free speech rights. “Against the great weight of medical opinion, FDA continues to insist that other types of studies have no scientific validity,” he says.

There was also disappointment that the FDA did not address the simmering debate over distribution of off-label materials that may be protected by the First Amendment. One closely watched case involved the 2008 conviction of a former pharmaceutical sales rep, who was prosecuted for encouraging doctors to prescribe a drug on an off-label basis.

A federal appeals court, however, overturned the conviction in late 2012 after agreeing that his First Amendment rights were violated because the federal government failed to prove his remarks were false or misleading. But the FDA did not discuss free-speech issues in its guidance at all. “They were silent on this and at some point they’re going to have to address it,” says a disappointed Bennett.

For now, the guidance may be sufficiently restrictive to discourage drug makers from taking many chances. “The hurdles for any meaningful dissemination of peer-reviewed information on off-label uses are very high,” says Arnie Friede, a former FDA associate chief counsel and former senior corporate counsel at Pfizer, who is now at Sandler, Tavis & Rosenberg, a law firm based in Miami.

And he notes that many drug makers may already be gun shy due to Corporate Integrity Agreements. These stem from settlements relating to off-label promotion, and many already regulate the dissemination of this material. “In theory,” he says, “a company subject to a CIA will have to run a dual gauntlet – compliance with the CIA and compliance with the draft guidance. So it becomes a fair question to ask: why bother?”

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Clinical Trial Data: Will the EU go Open Kimono?

03/24/2014 12:51 PM |

The Wall Street Journal reports that, “Drug companies and researchers will no longer be able to withhold the results of unfavorable clinical trials, if changes to European law are passed as expected next month.”

The new law would require the results of all trials plus a full clinical-study report to be published within a year of the trial ending. The European Parliament is expected to vote on the new legislation April 3, and it would come into force in 2016.

What the Journal did not report was that in May 2013 the General Court of the European Union prohibited the Euro­pean Medicines Agency from releas­ing data from two AbbVie and Inter­mune trials in an interim ruling, part of a challenge by the two drugmakers to the agency’s decision to grant access to information the companies provid­ed as part of their market approval ap­plications. The challenge is the first to be made to the EMA’s three-year old access-to-documents policy.

The Journal, “Around half of all trial results go unpublished, according to current estimates, including a 2009 paper that looked at 677 studies conducted in different countries. A 2012 paper found just 45% of 635 U.S. National Institutes of Health-sponsored trials were published within 30 months of completion.”

Unreported is that in 2000, the National Institutes of Health (NIH) launched ClinicalTrials.gov to provide public access to information on clinical studies.  Although it initially contained information primarily on NIH-funded research, it has been expanded to include both publicly and privately supported clinical research. 

Since the launch of the site, it has been enhanced to significantly increase data sharing. The ClinicalTrials.gov database includes information on nearly 140,000 clinical trials in all 50 states and 182 countries. 

Is anyone accessing this wealth of information? Yes!  The NIH reported last year that ClinicalTrials.gov “receives more than 95 million page views per month and 60,000 unique visitors daily.

At the July 2013 Clinical Trials Disclosure and Transparency Summit, Sir Alasdair Breckenridge, former Chairman of the MHRA and currently the Chair of United Kingdom’s Department of Health Emerging Science and Bioethics Advisory Committee, noted that transparency is “a process without a beginning or an end. It is a continuum.” And, “Transparency is like feeding a hungry dog – you more you give it, the more it wants.”

Sir A. suggested four key questions:

(1) Should the public have access to data on which regulatory decisions are taken?

(2) What are the advantages and disadvantages of increased transparency?

(3) What are the key distinctions between transparency and communication (specifically the issue of public health literacy and numeracy – and the “road testing” of released information)?

(4) Will increased transparency lead to increased trust in regulators and industry?

On that last point, Dr. Breckenridge points out that increased transparency does not lead to increased trust. Trust depends on perceptions of honesty and competence, and transparency may expose inherent inefficiencies in a system. And that’s a good thing – if we really mean to make the most of transparency.

Transparency cannot be “for thee but not for me.”

And he offers five keystones for moving forward:

(1) Agreement on timing of release of information

(2) Agreement on nature of information to be released

(3) Standards of protection of personalized data

(4) Standards for meta-analyses

(5) Rules of engagement for observational studies

Per the European Parliament vote, some policy issues to consider:

* Should transparency be a government dictate or a working collaboration between interested parties both private and public – and what role should patients play.

* Should there be formalized transparency consortia? Should it be global?

* What are the implications for intellectual property and the connected question of incentivizing (or dis-incentivizing) investment in innovation? Is transparency a Trojan horse to attack patents and intellectual property rights?

* Can transparency become a competitive advantage as well as a public health imperative?

After all, good things happen when everybody wins.

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The Not-So-White Coat Effect

03/18/2014 09:49 AM |

According to Reuters, “Some U.S. doctors are becoming concerned about the quality of generic drugs supplied by Indian manufacturers following a flurry of recalls and import bans by the Food and Drug Administration.”

"I'm just beginning to realize the gravity of the problem," said Dr. Steven Nissen, head of cardiology at the Cleveland Clinic. "It's terrible and it is starting to get a lot of traction among physicians."

(Maybe he can do a meta-analysis.)

India's drugmakers, a $14 billion industry, reject any criticism that their products are inferior to drugs made in other countries.

"We have heard doctors making generalized statements, without being specific on any product or company," said D.G. Shah, Secretary General of the Indian Pharmaceutical Alliance, a trade group representing large Indian drugmakers. "This is a deliberate and serious campaign to malign the Indian generic industry."

Denial, it seems, is more than just a river in Egypt.

"We are losing control over what people are swallowing," said Dr. Harry Lever, a cardiologist at the Cleveland Clinic who is trying raise awareness of the matter among U.S. lawmakers. "Now, when a patient comes in who is not doing well, the first thing I do is look at their drugs and find out who makes it."

FDA is addressing these concerns by establishing an Office of Pharmaceutical Quality to improve the agency’s scrutiny of brand-name, generic and over-the-counter drugs. The agency is talking with the industry to develop data that may signal which manufacturing plants are straying from standards and need inspection, she said.

FDA now collects such information only during inspections. The thrust of the effort would be to head off potential concerns before the agency wields penalties such as banning products from troubled factories. According to CDER Director, Dr. Janet Woodcock, “We want to use leading indicators. These people aren’t in trouble yet but they could be.”

And, per Commissioner Peggy Hamburg, “All companies must understand that quality is the basis for the public’s trust and confidence in their products and maintaining high quality standards is part of the cost of doing business.” Hamburg said the new office will “improve our oversight of quality throughout the lifecycle of a pharmaceutical product.”

Some Indian physicians do not share these concerns.

"Our drugs are being sold in many countries and being accepted, so we have no issues," said Narendra Saini, Secretary General of the Indian Medical Association, a voluntary body of 215,000 doctors. "How do I know that Western drugs are better than our drugs?"

Not so. The truth is that nation’s across the globe are uncovering serious issues with products manufactured in India. This is particularly true for generic oncology medicines -- where there isn’t room for error.

It’s too simplistic to call these “quality” problems. There’s a range from sub-standard API and manufacturing issues, to excipient changes and, most importantly, bioequivalence and bioavailability standards.

Dr. Joel Zonszein, director of the Clinical Diabetes Center at Montefiore Medical Center in New York, said he is concerned about the quality of generic drugs in general, not just those from India. He cited, as an example, his experience with the diabetes drug metformin.

"When patients open the bottle of medication it smells like dead fish," he said. Zonszein did not know which company made the foul-smelling drug.

Dr. Richard Kovacs, who heads a number of American College of Cardiology committees and sits on its board of trustees, said doctors may need to play a greater role monitoring the medications prescribed by their practices.

"The average U.S. cardiologist has been able to assume that the drugs were safe and effective. It now appears we need to be more vigilant as a profession, and assist the FDA by reporting cases where we are concerned about irregularities in the drugs supplied to our patients," he said.

FDA’s recent draft guidances on bioequivalence for both generic and innovator products, as well as the move towards independent labeling for generic products are additional steps the agency has recently taken to address the issue of drug quality beyond safety and efficacy. And the implications for biosimilars is obvious

(Something else to consider is for the FDA to report BE and BA and PK data in generic labels.)

Small is the new Big means we must think differently about pharmacovigilance. While we must continue to capture adverse event data, we must also strive to capture Substandard Pharmaceutical Events (SPEs). SPEs occur when a product does not perform as expected—perhaps because of API or excipient issues. SPEs can arise because of an issue related to therapeutic interchangeability. When it comes to 21st-century pharmacovigilance, we have to both broaden and narrow our views about bioequivalence to the patient level.

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