Latest Drugwonks' Blog

New technologies that support postmarketing patient communication and safety surveillance can produce a mountain of data.  But are these new tools creating value or just more noise?

YourEncore recently convened a panel of experts to discuss this topic after the 2015 Regulatory Affairs Professional Society (RAPS) Convergence conference in Baltimore, Maryland. To watch the panel discussion, click here.

YourEncore Executive Partners, Peter J. Pitts, former FDA Associate Commissioner, and Dr. Don Therasse, former VP of Global Patient Safety and Global Medical Affairs at Eli Lilly & Co., shed some light on the topic.

Peter Pitts: There is no such thing as a risk-free product. From a regulatory perspective, when you’re looking at outcomes, we’re learning the difference between efficacy in a clinical trial and effectiveness in the real world and how to capture and compare the data sets.

The general consensus is that MedWatch captures around 10 percent of adverse events. That’s probably high. But even if it’s spot on, it’s remarkably and dangerously low.  How are we capturing and reporting substandard pharmaceutical events when a drug doesn’t necessarily have an adverse event but just isn’t working?  API problems, excipient problems, manufacturing problems—from a lexicon perspective, unless you can put a name to it and put systems in place, it’s anecdotal.  If we want to bring drugs to market faster with truncated clinical trials, we’re going to need a much more robust post-marketing proposition.

There are a lot of ways to collect data.  Social media is one that has caused problems.  The signal to noise ratio issues are profound, but we can’t ignore it because within all that noise there are gems that we must capture.  The challenge is how to put robust modern pharmacovigilance or pharmacoepidemiology programs in place for established drugs and decide who leads the effort.  We need to do a better job of capturing and sharing data in real time. This requires better staffing and an openness to finding new things.

A couple of years ago I was talking to a pharmaceutical company in New Jersey, and someone said to me, “We don’t use social media because we don’t want to find adverse events.”  We must embrace negative information, because it’s happening in the real world.

Don Therasse: Everybody talks about how we can do these things and manage the entire post-approval safety environment more effectively and efficiently.  The fear is not that we will find new information; it’s that we would overwhelm our current systems and capacity with poor quality information – and just generate more noise as opposed to real signals.  That’s the primary concern about the social media space.

The goal of the pharmacovigilance enterprise is not to simply generate more signals; it’s to generate better signals and to apply our finite resources to identifying safety issues and implementing programs to help mitigate them.  In terms of regulatory convergence, or divergence in this area, we need work not only in this and other areas that define sources of information for signal detection, but also for how we manage the data, how it’s reported, how you’re inspected and how you implement your risk mitigation programs.  Everybody has the same goals, but everyone seems to want to put their own spin on it which causes redundant effort and diverts way too many resources from the important work at hand creating a very inefficient system.

There are many good ways to advance the science.  At the same time we have to be disciplined and willing to give up older, less effective activities.  There are finite resources on both industry and regulatory sides, and we’re diverting too much of our attention to nonproductive activities at the expense of fully implementing powerful new tools.

Pitts:  We have a tool at our disposal that is poorly used, which is physicians.  How many hours do medical students spend learning about drug safety management and adverse event reporting?  None.  How much time do physicians spend in their daily practices thinking about adverse event reporting?  How friendly is the MedWatch system?  Obviously, the first mission of doctors is to address their patients’ immediate needs.  Once that’s done there is an obligation to share information that can advance the science and ultimately help to prevent similar issues for future patients. We need greater awareness and more effective, user-friendly processes to encourage and enable them to do so.

To paraphrase Homer Hickam (of "October Sky" fame), “A docket won't fly unless somebody lights the fuse.”

Here are my comments to the CDC’s docket Proposed 2016 Guideline for Prescribing Opioids for Chronic Pain:


In determining appropriate guidelines, CDC should engage as part of an intramural HHS team. FDA has issued labeling changes for this category along with thoughtful and strategic roadmaps for how and why they can be successfully implemented. The FDA’s statements and actions on the approval, labeling, and future development of abuse-deterrent products and technologies are designed to both protect and advance the public health relative to the balance of benefit/risk and access. Further, FDA has identified prescriber, dispenser, and user education as a major focus for pursuing a safe-use agenda for opioids. CDC must broaden its vision when it comes to the development of opioid guidelines to include the thoughtful, dynamic, patient-focused programs already instituted by the U.S. Food & Drug Administration.


  • 12.17.2015
The arrest of Martin Shkreli will come as a disappointment to those who learned to hate a brilliant social misfit for spiking drug prices rather than for the reason he jacked up the price of a lifesaving medicines to cause a drop in the price of drug stocks that, for anyone who made millions short9ng drug stocks as did Shkreli. Shires was arrested for driving down the price per share of the company he owned to enrich himself. Shkreli was a metaphor for the Pharma haters and so his real crime was ignored. His hubris was ultra annoying because he lacks a filter. But being a jerk is not a crime. Defrauding people to enrich oneself is. As Shkreli's favorite rap group, Wu-rTang once noted 'cash rules everything around each me. Cream gers the money'. Dolla dolla bills y'all.'

From the fine folks at RAPS:

CDER’s Woodcock Outlines Priorities for 2016

By Zachary Brennan

With a banner year for new drug approvals under its belt in 2015 (42 approvals and counting), the US Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) is now looking at how it can not only negotiate three new user fee agreements but fill an enormous number of staff vacancies.

CDER Director Janet Woodcock, speaking Monday at the FDA/CMS Summit in Washington, DC, outlined 2015’s achievements and a number of the agency’s top priorities for 2016, particularly as CDER, with its $1.2 billion budget, continues to work with Congress on legislation like the House-passed 21st Century Cures Act.

2015 Recap

As far as meeting CDER’s priorities for 2015, Woodcock said the agency did “pretty well,” noting that there were some serious concerns in the year prior on addressing the backlog of abbreviated new drug applications (ANDAs), though she said there’s been “a huge turnaround.”

FDA has been particularly interested in reducing the number of multiple cycle reviews for generic drugs, she said, noting that in the not-too-distant past the average was four review cycles, though the reduction in such cases has occurred over the past year as more companies understand what it takes to submit a complete ANDA.

John Jenkins, Director of the Office of New Drugs at CDER, also outlined a number of the drug approval statistics, particularly as CDER has seen a steep rise in orphan drug approvals, though he noted that such approvals aren’t always to the benefit of public health (some of his slides can be viewed here).

On the international front, Woodcock highlighted FDA’s work with the International Conference on Harmonisation (ICH), noting that it “was headed off a cliff,” though after “strenuous efforts,” FDA was able to help sign new agreements and make the group more inclusive, which should be a boon for negotiating more global standards for drugs.

And while many in Congress and industry are still waiting on new biosimilar draft guidance documents on labeling and interchangeability, among others, Woodcock said that CDER has been working extremely hard behind the scenes to ensure the US market for biosimilars can be robust in the near future as education efforts continue.

She also highlighted the success of the new “drug trials snapshots” program under CDER, which offers a look at the demographics of clinical trial data for newly approved drugs, which she said has been “very popular” for consumers.

A Look Ahead

As far as what to expect for 2016, Woodock offered a wide-ranging laundry list of topics that the agency will look to address, though the 680 vacancies at CDER seem to be one of the focal points.

The re-negotiations of the prescription drug, generic drug and biosimilar user fee programs will also be at the forefront of CDER’s work next year as these agreements with industry need to be ironed out before the programs expire in 2017.

In addition, CDER is looking to:

  • Reevaluate the regulations on drug advertising and promotion in light of current jurisprudence around the First Amendment
  • Issue draft guidance on generic versions of abuse-deterrent opioid formulations
  • Integrate the Sentinel Network into routine drug safety activities
  • Further implement statutory provisions on track and trace legislation
  • Continue drug label improvement initiative as “a lot of labels are out of date,” Woodcock said
  • Develop a more robust process and policy documents on how to evaluate a biomarker as a surrogate endpoint for accelerated approvals
  • Streamline clinical trial monitoring and data cleaning practices
  • Conduct more outcomes assessments of breakthrough therapies, modernize clinical evidence assessments and further utilize electronic health data (which Woodcock said is a priority for FDA commissioner nominee Robert Califf)
  • Make significant progress on FDA’s mutual reliance initiative with the European Medicines Agency
  • Improve combination product inter-center review process
  • Develop an implementation plan and training for a new pregnancy/lactation labeling rule
  • Continue to push standards development and standardized electronic submissions to CDER
Jeanne Whelan’s article “Why the US Pays More for Than Other Countries for Drugs” is misleading and inaccurate. Whelan overstates the price gap in several ways. She ignores that vast majority of medicines that are launched at the same or lower price in the United States. She cherry picked countries with lowest prices and excluded those with higher prices such as Ireland, Belgium and Germany. Finally, she focuses on older (mostly) cancer drugs that been price controlled for a decade in order to overstate the difference even more. Whelan assumes that drug prices increase cost and reduce access. It turns out most countries – including Norway, UK and Canada – spend more on cancer care as a share of total health care spending as America. Adjusting cancer drug prices to EU levels would cut total health spending in the US by .33 percent. Applying price controls would mean more Americans would die from cancer and other serious illnesses such as heart disease. A study of European cancer spending and mortality concluded countries that with faster access and increased spending on new drugs had a 17 percent decrease in cancer deaths, mortality, compared to 8 percent in such as Canada and UK that Whelan selected. 1 Price controls are also associated with more heart attack deaths. Other countries that spend less on new drugs, spend more on health care and have more premature death.

From the pages of Politico:

CDC opens opioid prescription guidelines to public comment

 The CDC plans to publicly post draft guidelines on opioid prescribing after being criticized by pain advocates, professional associations and some within HHS for developing them behind closed doors and with limited public input.

A notice posted this morning provides 30 days for public comment, which means that the guidelines - a key part of the Obama administration's response to the opioid abuse and overdose epidemic - won't be released in January as the agency had planned.

"Opening a docket will tack months on to the process [and also] increases the likelihood that the guideline may never be released," said Andrew Kolodny, a founder of Physicians for Responsible Opioid Prescribing and the chief medical officer at Phoenix House. "This is an enormous win for the opioid lobby."

CDC hadn't planned to publish the document ahead of its release in January but came under fire earlier this month from members of the administration's Interagency Pain Research Coordinating Committee, which announced that it would file a formal objection to CDC's prescribing guideline after agency officials briefed them at a meeting.

The level of evidence cited to support the guidelines, which are non-binding on physicians and apply to chronic pain patients outside of the cancer or palliative care treatment, "is low to very low and that's a problem," Sharon Hertz, FDA's director of the Division of Anesthesia, Analgesia and Addiction Products, said at the meeting.

AHRQ health scientist Richard Ricciardi, another member of the interagency committee, called the recommendations "ridiculous" and "an embarrassment to the government."

The document had already been circulated among HHS agencies for final review ahead of its planned release in January, but it had drawn criticism from the American Cancer Society Cancer Action Network and the American Medical Association after it was previewed for some health care groups at a webinar in September.

CDC didn't immediately respond to a request for comment.

Dear Santa:

I’ve been a good policy wonk this year, so here’s my FDA wish list for 2016 …

·      Thoughtful guidance on differential nomenclature for biosimilars that recognizes that “similar” doesn’t mean “identical” and prioritizes the need for savvy pharmacovigilance

·      Further agency thinking on biosimilar label extrapolation

·      Physician notification x 50 states, Puerto Rico, and the District of Columbia (not under FDA authority -- but since we're on the subject)

·      21st century bioequivalence written guidance for generic drugs (including tighter ranges for narrow therapeutic index medicines and critical dose drugs)

·      A super effort from the FDA’s new Super Office of Pharmaceutical Quality

·      Aggressive intramural efforts on biomarker development and validation

·      A first quarter meeting on off-label communications

·      Smart efforts on abuse-deterrent opioid PROs

·      Next-step traction for Patient-Centered Drug Development

·      More attention to combination products

·      And IVDs

·      Continued sophisticated thinking (from management) – and action (on the Division level) on adaptive clinical trials

·      Completion of the Generic Labeling Rule

·      Better oversight of compounding pharmacies

·      And drug shortages

·      For-real updating of the PMA and 510k processes

·      Continued sanity on drug importation

·      And medical mobile apps and social media

·      Sharper teeth on dietary supplements

·      21st Century Cures legislation with both mandates and budget

·      A standardized benefit/risk analysis grid

·      Wider lanes on expedited pathways

·      A potent PDUFA that recognizes that FDA resides at the center of the precision medicine ecosystem.

·      A potent PDUFA that doesn’t use “fast and clean” as it’s sole metric for success.

·      A swift, positive vote for Rob Califf

And Santa, this is only a partial list.

Various congressional committees have 'investigated' what are deemed 'rising' drug prices.  These exericses have basically concluded that drug companies charge too much.   But sometimes you stub your toe on the truth en route to drawing a pre-ordained conclusion.  In two cases in particular, the WSJ 'investigation' of Pfizer's pricing and the Senate Finance Committee review of Gilead's Sovaldi pricing noted that the sticker price of a medicine is deeply discounted to about 86 percent of the marketplace, in the form of drug rebates and deals with PBMS, health plans, Medicaid, public hospitals, the Veterans Administration and the Defense Department.    

Nothing was said about how, after pocketing those discounts (a Credit Suisse report estimates that $90 billion is handed over to these entities each year) many of the drugs, let alone the discounts, are available to consumers.    And nothing was said about how drug companies are in fact negotiating and involving health plans with data about the long term value of products years before a drug is approved.  Or that, PBMs and AHIP launched a cynical campaign to blame drug companies for the high costs that they were in imposing on consumers that was paired by an concerted effort to hike the cost of more and more medicines to patients even as they were pocketing rebates

Scott Gottllieb wrote an excellent article in Forbes descrbing how this affects patients with MS: 

"I examined the plans marketed in the state’s most populace county, selecting the median-priced Silver plan offered by each carrier in that market. I examined how the plans covered the 12 leading oral and injectable drugs for treating multiple sclerosis. What I found was discouraging.

All of the plans were closed formularies. None of the plans provided even partial coverage for all of these drugs. That means that for each plan, certain patients would be forced to foot the entire bill for their medicine. What patients spent wouldn’t count against their deductible or out of pocket limits. One of the insurance plans covered 11 of the drugs; three of the plans covered 10 of the 12 drugs; and four of the plans covered only nine of the drugs. Aetna AET +0.96%, on the whole, was the best insurer.

Of the remaining 12 health plans; three covered just eight drugs; three covered only seven drugs; and another three covered just six of the drugs used to treat Multiple Sclerosis. Of the remaining two health plans, one of the plans only provided coverage for four drugs; and the final plan provided coverage for just three of them.

In almost all cases, when the plans did cover these drugs, they put these medicines on their fourth or fifth drug tiers, meaning that consumers were saddled with high co-insurance and would, in most cases, end up maxing out their deductibles and hitting their out of pocket limits (which averaged more than $13,000 across the different plans. This spending would come on top of what people paid in premiums)."

The Affordable Care Act has had the unintended conseuence of forcing payors and PBMs to  screw sick patients to stay afloat financially. Similarly, drug companies have cut deals with PBMs to exclude any number of medicines in exchange for deep rebates.  In some cases, such as psoriasis and psoriatic arthritis, patients are being denied access to safer new medicines and being forced to try other drugs that have more side effects.

This is insane.   Long term, every company in the business of helping patients get better needs to devote more time and effort to providing the most effective treatment for each patient.   And we need to continue to reduce the time and cost required to develop new medicines.  

We need precision medicine. And fast. 


  • 12.09.2015

From the pages of ...

New Compounded Drug Renews Safety Concerns

Last week, Express Scripts announced it would begin processing prescriptions for Imprimis Pharmaceuticals’ drug compound for patients suffering from toxoplasmosis in response to a recent price hike by the makers of the only FDA-approved medication for toxoplasmosis, Daraprim.

“We believe we now have a safe, high-quality and extremely cost-effective way to provide access to a Daraprim alternative,” said Dr. Steve Miller, Senior Vice President and Chief Medical Officer of Express Scripts, one of the country’s largest pharmacy benefit managers (PBM) with over $100 billion in annual revenue.

But the safety and efficacy of compounded drugs have raised questions in the healthcare community and among regulators, and at least two of Imprimis’ compounding facilities have been cited by the FDA for Common Good Manufacturing Practices (CGMP) violations.

Back in 2012, a meningitis outbreak that sickened more than 700 people and killed at least 50, was traced to a compounding facility in Massachusetts setting off a wave of heightened concern and regulatory oversight. Separately, Imprimis’ facilities in New Jersey and Southern California (July 2014 and June 2015) have been issued letters from the FDA citing violations that could call into question the safety and efficacy of the drugs compounded there.

Imprimis says that they did not own the facilities at the time of the violations. The California facility was acquired earlier this year and has not yet been reinspected. The New Jersey facility was inspected in September, and Imprimis says there were “three minor observations noted on the report, all of which have been responded to with no further comments from the FDA.”

But Peter Pitts, former FDA associate commissioner and president of the Center for Medicine in the Public Interest, expressed concern, “just because a facility changes ownership doesn’t mean that existing quality problems can be discounted.”

In testimony before the House Energy & Commerce Committee, Dr. Scott Gottleib, resident fellow of the American Enterprise Institute, said that compounded drugs let “physicians customize drugs to individual patients,” noting that “traditional pharmacy compounding is performed on a small scale.”

According to the FDA’s website, compounded drugs are not generally approved by the FDA and therefore the “FDA does not verify the safety, or effectiveness of compounded drugs.” Additionally, the FDA warns, “[t]here can be health risks associated with compounded drugs that do not meet federal quality standards. Compounded drugs made using poor quality practices may be sub- or super‑potent, contaminated, or otherwise adulterated. Additional health risks include the possibility that patients will use ineffective compounded drugs instead of FDA-approved drugs that have been shown to be safe and effective.”

When Congress passed a new law in 2013 that provided the FDA with greater authority over compounding facilities, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, expressed some concern that the law didn’t go far enough. “While the new law doesn’t provide the FDA with all the additional authority it sought, these provisions are definitely progress,” she said.

Now with this latest announcement from Express Scripts, Imprimis is set to provide patients a compounded drug comprised of two FDA-approved drugs, pyrimethamine (the active drug in Daraprim) and leucovorin, even though the two have never been approved by the FDA to be used together.

The president of research and development for the manufacturer of Daraprim, Turing Pharmaceuticals, Dr. Eliseo Salinas said, “Daraprim remains the only FDA-approved treatment for toxoplasmosis encephalitis when used conjointly with a sulfonamide. Patients and physicians are likely to assume the compounded product is as safe and effective as the FDA-approved drugs pyrimethamine and leucovorin, even though its safety and efficacy profile is unknown.”

Mark Baum, the CEO of Imprimis, questioned that characterization. “The idea that FDA is not involved in nearly the entire drug supply chain of what is produced by our company is just simply not true.” He says the partnership with Express Scripts speaks to the safety of their practices. “Express Scripts is not going to partner with a company that does things the wrong way,” explains Baum. He says Imprimis is now in talks with other leading PBMs, and these companies won’t partner with a compounder that is putting patients at risk.

Pitts, offered words of warning for doctors treating patients with compounded drugs. “Physicians are not pharmacologists. They do not take medical school courses in drug compounding. And since this is not their area of expertise, they should not be deemed ‘experts’ and asked to make a therapeutic choice.”

He added, “the FDA approves innovator and generic medicines based on the benefit/risk/quality equation. It’s a dangerous precedent for a PBM [Express Scripts] to decide on its own to use cost as the sole factor in reimbursement policy. It is irresponsible at best and dangerous at worst.”

There also remains some question as to the legality of Imprimis distributing its unapproved compounded drug widely. Gottleib, who many consider a potential nominee for senior FDA position should a Republican win the White House, said later in his testimony, “but once pharmacies begin manufacturing and shipping medicines on a wide scale, and do so in a way that isn’t in response to a valid prescription, these firms often become ‘drug manufacturers’ and fall squarely under the FDA’s extensive authority.”

A spokesperson for the FDA declined to comment when asked about the Express Scripts-Imprimis announcement and the use of a compounded drug when an FDA-approved drug is available.

Baum argues that an unintended consequence of current policy is to encourage drug companies to engage in monopolistic behavior for some drugs that have no generic competitor, in part because it is so difficult to get new drugs approved by the FDA. “I really believe the future of compounding is in 503B outsourcing facilities. It is in making as many drugs that are compounded as possible,” Baum said.

However, Pitts, the former FDA associate commissioner, said: “The way to drive prices down is not to promote the unapproved use of unapproved compounded medicines. A more effective route is to inject competition into the marketplace. Competition, in this case, coming from additional FDA-approved generic pyrimethamine products.”

I have noted previously that "to create a social movement for cures, the prevailing pessimism must be overcome. This enterprise is critical to progress because social and political movements are essential to sustaining medical innovation.  In the past, progress occurred because social movements overcame the pessimistic resistance of the time and turned a demand for cures into a national strategy."

Perhaps such Partners for Better Care is such a movement.  The organization has 6 objectives.  Most important (at least in my opinion) is this statement:

"We believe patients should have access to adequate formularies that do not discriminate against any medical conditions and ensure patients have affordable access to prescription drugs, devices, and other therapies. Tiering and pre-authorization limitations are becoming more common in formularies, and problems persist with access to devices and allied health professionals such as physical therapists."

I am not usually a joiner beyond my shul and gym.  But I just joined PBC.  You should too. 


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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