Differential naming for biosimilars? NORD on board

06/04/2014 01:00 PM |

NORD URGES FDA TO CONSIDER RARE DISEASE TREATMENT IMPLICATIONS WHEN SETTING BIOLOGICS NAMING POLICY

WASHINGTON DC,  June 4, 2014 – In a letter submitted today to the U.S. Food and Drug Administration (FDA), the National Organization for Rare Disorders (NORD) urged Commissioner Margaret Hamburg to give serious consideration to the concerns of the rare disease community when setting policy regarding official names for biologics, including biosimilars.

With over 7,000 rare diseases identified and 30 million Americans affected, the patient population represented by NORD is extraordinarily heterogeneous, the letter notes. Without thoughtful and consistent naming protocols for biologics, there is the potential for significant confusion among treatment options and increased adverse events, both of which could jeopardize patient safety. Distinguishable naming of all biologics is imperative for health care professionals to deliver the degree of customized care that is routinely required for patients with complicated, uncommon and less well-studied diseases.

“Every patient deserves the care best suited for their medical situation and most likely to give them the best outcomes,” said NORD President and CEO Peter L. Saltonstall. “Biologics are often the most advanced and effective treatments for patients we represent and everyone in the treatment continuum should be able to readily identify the specific drug product a patient was given.”

The letter raises a number of concerns specific to rare disease patients. Rare disease patients usually have unique treatment courses and, while similar medications might work equally well, such a judgment can only be made through tracking of outcomes made possible through distinguishable names.

According to the letter, distinguishable names for biologics would:

* Support the medical community’s vital post-approval learning curve regarding which medicines are best for their rare disease patients;
* Support surveillance and tracking of adverse events given that rare disease patients often do not respond to medications in the same way as other individuals might; and
* Reinforce a critical distinction in the biosimilars law between biosimilars (similar not identical) and interchangeable biosimilars (similar but demonstrated to have comparable clinical results).

Next up: Vote at the AMA House of Delegates.

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OpenFDA? Well, maybe ajar

06/03/2014 08:13 AM |

The FDA has publicly released a huge amount of data on drug side effects that it hopes will lead to new applications and research.

Under its open FDA project, the agency has released more than 3 million reports on adverse drug events and medication errors recorded between 2004 and 2013. These kinds of reports were only available before through lengthy Freedom of Information Act requests. 

Before releasing the information, the agency removed patient identification and other sensitive information. It has also been formatted to let researchers, mobile applications and Web developers easily analyze the data and present it in a way that can help improve how people take drugs.

Eventually the agency plans to release more reports on recalls and labeling, as well as other information it thinks can be useful to developers and researchers.

The move to make medical data more transparent isn’t limited to the FDA. Several drug makers working with the National Institutes of Health have begun releasing clinical trial data in a limited fashion to help find new uses for old drugs. 

Obvious by its absence is any mention of greater clinical trial transparency. But that's a whole other can of worms. (For more on this issue, see "Cry Havoc, and let slip the Dogs of Data Transparency.")

A good next step would be for the FDA to be the coordinating body for all relevant e-tized information from both public and private sources. But that’ll take resources. It would be money well spent.

Speaking of transparency – how about an OpenFDA program for the agency’s risk/benefit decision-making process?

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Off Label on the Table

06/02/2014 07:46 AM |

There’s a difference between off-label communications and off-label marketing – and it’s more than a finesse. It’s one of those 800-pound gorilla issues we’ve been pussyfooting around for too long. And now, at long last, it’s time for a serious conversation.

Here’s a bit of outreach send out by PhRMA. It’s well said. It’s brief. And it's a call to action. Take it seriously.

FDA Restrictions on Medical Communications Can Negatively Impact Patient Care

Some of the regulations and guidances of the Food and Drug Administration (FDA) have a more direct impact on patient care than others.  The FDA’s restrictions on biopharmaceutical companies’ ability to share authoritative, regulated data about prescription medicines limits healthcare professionals’ access to information that can help them make informed decisions based on their patients’ individual healthcare needs and preferences.

Biopharmaceutical companies have the most complete and up-to-date information about the medicines that they research, develop and manufacture for use by patients.  However, companies are often unable to proactively share valuable information about their medicines, especially for information that is not contained in the FDA-approved prescribing information (the package insert you often receive with a prescription), with physicians and other healthcare providers.

To get the best possible health outcome for patients, FDA should revise its regulations to allow companies to share truthful, scientifically accurate, and data-driven information with healthcare professionals to inform treatment decisions.  Some examples of this kind of information include:

·         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.

·         Pharmacoeconomic 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.  As the National Cancer Institute states, “Often, usual care for a specific type or stage of cancer includes the off-label use of one or more drugs.”^[1] Healthcare professionals help patients by applying new uses of approved drugs in “every specialty of medicine.”^[2]  When patients are being prescribed medicines off-label, they deserve to know that their healthcare professionals have the latest information on these uses.

You Can Help.  Patients need their healthcare professionals to have timely, authoritative, FDA-regulated information about available medical treatments.  Currently, the House Energy and Commerce Committee is soliciting comments from patients, providers and other stakeholders about how they learn about new treatments and cures.^[3]  If you believe that physicians and other healthcare professionals should have access to sound, evidence-based information that biopharmaceutical companies have about their medicines in order to help patients make informed healthcare decisions, please send a comment to cures@mail.house.gov by June 13, 2014.

[1] See National Cancer Institute, Off-Label Drug Use in Cancer Treatment, available at http://www.cancer.gov/cancertopics/druginfo/offlabeldrug.

[2] Christopher M. Wittich, et; al., Ten Common Questions (and Their Answers) About Off-label Drug Use, Mayo Clinic Proceedings, available at http://www.mayoclinicproceedings.org/article/S0025-6196(12)00683-0/fulltext#sec3.

[3] See

http://energycommerce.house.gov/sites/republicans.energycommerce.house.gov/files/analysis/21stCenturyCures/20140516PatientsWhitePaper.pdf

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Pharmacovigilance: Trust but Verify

05/30/2014 06:40 AM |

It seems that every day there’s another headline about a serious issue involving generic drug quality. And how to improve the agency’s evaluation of these products drugs was a top priority when the agency recently compiled its regulatory science goals.

In a new Broad Agency Announcement (BAA), the FDA has announced a roadmap that will be funded from a pot of up to $50 million, and it reveals some of the difficulties facing the agency as it works to get a handle on an industry riddled with unanswered questions as companies start to produce more-and-more complex products.

In the BAA, the FDA lays out five broad areas (Post-market Evaluation of Generic Drugs; Equivalence of Complex Products; Equivalence of Locally Acting Products; Therapeutic Equivalence Evaluation and Standards; Computational and Analytical Tools) in which it wants to improve its generic evaluation capabilities and invites organizations to submit proposals detailing how they can help. Many of the specific goals focus on the equivalence between generics and their innovator forbearers. The FDA is particularly interested in methods to compare the bioavailability of complex and locally-acting products. Questions about the bioavailability of generic drugs and its impact on therapeutic effects are as old as the industry itself, but the industry's expansion into new dosage forms--such as sustained release injections and inhaled products--throws up fresh concerns.

Per a report in Fierce Pharma, the FDA is also looking at more human aspects of switching from innovative to generic drugs, with the agency keen to know what patients think about the quality and effectiveness of copycats and how tablet size affects substitution. High-profile quality failings at Ranbaxy, Sun Pharma and Wockhardt could have tainted the public's perception of generics, a possibility the FDA wants to understand while also working to get better at spotting problems early.

Other, less generic-focused aspects of the roadmap also deal with this goal. The FDA wants to develop sensitive, rapid, high-throughput methods to spot microbes, and assess ways other than sterilization to remove such contaminants. The technology is one of several ways the FDA wants to retool its capabilities and those of the industry, with the document also calling for investigations into continuous manufacturing, process analytical technologies and Quality-by-Design.

21^st century pharmacovigilance must also include tighter and more regularly monitored post-approval bioequivalence measures. Recent recalls of products such as Budeprion (Wellbutrin) and Metoprolol (Toprol) offer vivid examples. "We are losing control over what people are swallowing," said Dr. Harry Lever, a cardiologist at the Cleveland Clinic. It’s a new and difficult task and calls for better validated methodologies for both data collection and signal prioritization.

Another key regulatory question is the appropriate role of regulators in coordinating input from crucial partners such as physicians, nurses, pharmacists, disease organizations, patients, and pharmaceutical manufacturers. “Real World” event monitoring must become as specific and informing as in a clinical trial environment. To borrow a term from the nuclear disarmament discussion, 21^st century pharmacovigilance must work with its various colleagues to “trust, but verify.”

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Can there be more than one level of drug quality?

05/29/2014 07:15 AM |

From the pages of the Orange County Register:

Foreign meds, quality control

In the past year, several major foreign pharmaceutical companies have been forced to recall thousands of medications sold in the United States. The problems with their products were myriad, including packaging defects, dosage errors, and bacterial contamination. In one especially egregious instance, epilepsy medications were found in a bottle of diabetes drugs, resulting in the recall of more than 2,000 bottles produced by a company based in India.

Given these dangerous errors, it's little wonder that American physicians are growing increasingly worried about the safety of prescription medications imported from foreign pharmaceutical companies. Compromised medications jeopardize the health of their patients.

We must strengthen America's "pharmacovigilance." The federal government should bulk up its drug import oversight apparatus and implement a tracking system that monitors the entire life cycle of medications.

Right now, 40 percent of America's over-the-counter and generic drugs come from Indian suppliers. The World Health Organization has estimated that around 20 percent of the drugs manufactured in that country are counterfeit.

As the New York Times recently noted, at one hospital in Kashmir, fake drugs likely lead to the deaths of hundreds of infants. In January, the Indian health ministry identified at least 32 medicines being sold in Indian stores that didn't meet basic safety and quality standards. Earlier this year, the FDA's commissioner, Margaret Hamburg, expressed her dismay about "recent lapses in quality at a handful of [Indian] pharmaceutical firms.

To protect against dangerous drug imports, the FDA has established the Office of Pharmaceutical Quality, which will more meticulously monitor the quality of brand-name, generic, and over-the-counter drugs.

Congress also enacted legislation in 2012 mandating that foreign pharmaceutical manufacturers be subjected to more intense scrutiny. This bill lead to 160 FDA-conducted inspections at Indian drug manufacturers in 2013, an enormous increase over the number of site visits in previous years.

What American inspectors discovered was often profoundly disturbing.

For example, at one plant owned by the Indian pharmaceutical manufacturer Ranbaxy, the FDA found flies "too numerous to count." Ranbaxy has since been hit with half a billion dollars in fines and has plead guilty to felony charges.

These developments are all the more discouraging once situated within the broader context of the global economy. Pharmaceutical manufacturing is a $14 billion industry in India. When its firms are permitted to push sub-par medications into the U.S. health care market, they often end up displacing American companies.

Such displacement can hurt our economy. Drug firms currently support 810,000 jobs throughout the United States. More than 20 percent of the sector's domestic sales are directed back into local research and development projects.

The American pharmaceutical industry has already proven its commitment to ensuring the quality and safety of the medicines it produces. It has vigorously pushed for the federal adoption of a track-and-trace system, which would monitor a drug's journey from manufacturer to packager to distributer to pharmacy and, ultimately, to patients.

Such a system would significantly strengthen the security of America's drug supply chain.

In contrast, India is simply shrugging off its gross failures in drug production. The Indian Medical Association's secretary-general recently said: "Our drugs are being sold in many countries and being accepted, so we have no issues. How do I know that Western drugs are better than our drugs?"

That casual attitude is unacceptable. American consumers are being put at direct risk by India's malfeasance. If Indian authorities won't take responsibility, the United States must step in and ensure that proper vigilance is in place throughout the entire life cycle of a drug.

A global pharmaceutical market benefits consumers only when the appropriate safeguards are in place. The recent spate of recalls should prompt renewed dedication to pharmacovigilence.

For the sake of both American drug companies and American patients, federal regulators must work harder to ensure that all drug imports meet basic standards for quality and safety.

Peter Pitts, a former FDA Associate Commissioner, is president of the Center for Medicine in the Public Interest.

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340B nixed for non-orphan Orphans

05/28/2014 06:28 AM |

According to report in BioCentury, the U.S. District Court for the District of Columbia vacated HHS' July 2013 final rule that discounted Orphan drugs when used in non-Orphan indications under Medicare's 340B program. The court said HHS lacked authority to make the rule.

The 340B program requires manufacturers to deeply discount outpatient drugs to hospitals and clinics bearing the brunt of healthcare for low income and other special populations. In 2010, Congress amended 340B to exclude Orphan drugs from discounting, but the law was unclear on whether the exclusion applied when the drugs were used for non-Orphan indications. In 2013, HHS issued the final rule saying the drugs were to be discounted when used in non-Orphan indications, and the Pharmaceutical Research and Manufacturers of America subsequently sued to challenge it.

In the decision, the court said that while the rule "seems like the most reasonable way for implementing the orphan drug exclusion, unfortunately Congress did not delegate to HHS broad rulemaking authority as a means of doing so," noting Congress limited HHS's 340B rulemaking authority to three purposes -- establishing a dispute resolution process, setting methodology for price calculations and imposing monetary civil sanctions. Plaintiff PhRMA said in a statement it is "extremely pleased" with the ruling.

The 340B program has been scrutinized for expanding margins. In June, HHS' Health Resources and Services Administration (HRSA) plans to publish a proposed rule addressing eligibility criteria. HRSA declined to comment on implications of the decision on that rule.

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Thinking about the FDA? Context Matters

05/27/2014 06:41 AM |

Part two of my interview from Context Matters:

Anti-Infectives

In 2010, Representative Henry Waxman voiced concern about non-inferiority trials – but when he was confronted with the science he backed down. That’s a good thing. When politicians start to dabble in science, they generally get badly burned.

Today the FDA is trying to expedite reviews of anti-infectives. The need for these products and that in itself changes the benefit / risk profile. And that will allow for approvals based on less data – and in an expedited fashion.

There are multiple ways to get an important new therapy to market quicker – but that has to be based on a public health need, not a marketing strategy.

Pediatric Trials

Pediatric trials bring both public health and IP benefits, but they are hard to design, hard to recruit for, and hard to field. They’re especially important for anti-depressants and anti-psychotics. We also will be seeing more precise clinical trials in minority and genotype populations. From a perspective of companion diagnostics we’re developing more medicines for small, more precisely identifiable patient populations – clearly the wave of the present and this will continue for the foreseeable future. It’s all about personalized medicine.

The best way to address benefit/risk profile is to make sure that the right patient gets the right medicine in the right dose at the right time. That will result in more positive clinical outcomes and huge cost savings. That’s where you’re going to see the greatest increase in adaptive clinical trials, whether in children, pregnant women, certain genotypes, women, men, African-Americans, Asians, etc.

The benefit/risk profile of a product that’s proven to be more beneficial within an identifiable sub-population is a key for expedited review, because you can more precisely define who it works for and, just as importantly, who should not be using it.

Conditional Approval

As far as so-called “conditional approval” goes, I wouldn’t look for it any time soon in the US. The last time I spoke with senior members of the FDA, I heard comments like, “What does that even mean?” And, then again, do drug developers really want conditional approval? You invest a lot of time and money to get a conditional approval and then the agency decides to take the product off the market? Is that something to roll the dice on?

Unless and until the FDA can ramp up its pharmacovigilance prowess, any kind of provisional approvals will remain problematic. At the moment, the FDA doesn’t have an eye in the sky.

Political Impact

And there’s the issue of Congress politicizing the FDA process. Plan B, Avandia, Zohydro. As Mark McClellan used to say, “If people are saying we’re approving drugs too slowly, and others are saying we’re approving drugs too quickly. We must be doing something right.”

That’s my story… and I’m sticking to it!

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What Bern knows that Pretoria doesn't -- but should

05/23/2014 02:17 PM |

Facts that don’t reinforce your cognitive mapping are pesky things. 

When it comes to the value of innovative medicines, keywords such as welfare impact, cost-effectiveness, innovative drugs, economic evaluation, quality-adjusted life year are often used to explain why both licensure and reimbursement is deferred or denied.

The opposite is true.

In fact, those very key words are tagged in a new Frontiers in Public Health article, Estimating the potential annual welfare impact of innovative drugs in use in Switzerland

In this new study, Swiss academics have estimated that the introduction of innovative pharmaceuticals provided substantial welfare gains to Swiss patients and the health system.

The authors find that "The introduction of innovative pharmaceuticals since 2000 onward to the Swiss market led to a potential welfare gain of about CHF 781 million in the year 2010."

Here’s the abstract:

Expenditure of health care systems are increasing from year to year. Therefore, this study aimed to estimate the difference in costs and benefits of innovative pharmaceuticals launched 2000 onward compared to standard treatment on the national economy of Switzerland in 2010. The approach and formula described in the pilot study by Tsiachristas et al., which analyzed the situation of welfare effects in the Netherlands, served as a model for our own calculations. A literature search was performed to identify cost–utility or cost-effectiveness studies of drugs launched 2000 onward compared to standard treatment. All parameters required for the calculation of welfare effects were derived from these analyses. The base-case threshold value of a quality-adjusted life year was set to CHF 100,000. Overall, 31 drugs were included in the welfare calculations.

The introduction of innovative pharmaceuticals since 2000 onward to the Swiss market led to a potential welfare gain of about CHF 781 million in the year 2010. Univariate sensitivity analysis showed that results were robust. Probably because of the higher benefits of new drugs on health and quality of life compared to standard treatment, these drugs are worth the higher costs. The literature search revealed that there is a lack of information about the effects of innovative pharmaceuticals on the overall economy of Switzerland.

Our study showed that potential welfare gains in 2010 by introducing innovative pharmaceuticals to the Swiss market were substantial. Considering costs and benefits of new drugs is important.

Nations such as South Africa (where the Medicines Control Council is taking 4-5 years to approve medicines that are globally commercialized) should take notice.  If innovative medicines aren’t even licensed within months of their globalization, talking about prices is just a hypothetical exercise.

Imagine all the mortality, morbidity and … costs that could be avoided if people had access to innovative medicines.

Facts do not cease to exist because they are ignored. -- Aldous Huxley   Read More & Comment...

A Better Way To Bring Medicines To Market

05/22/2014 11:28 AM |

Recently I was honored to co-author a letter  to the editor of JAMA with Eric Topol, MD and Stuart Kauffman, PhD,MD in response to an article calling for more randomized trials.   The letter was to have been an article and had other co-authors, but JAMA requested a response which by their editorial guidelines understandably limits co-authorship.    Here is the response to the article (below) and a link to the article itself.   

Study Design and the Drug Development Process
To the Editor

A Viewpoint by Dr Djulbegovic and colleagues1 claimed not only that randomized clinical trials (RCTs) aremore ethical but that greater use of randomized designs throughout the drug development process would “improve the efficiency, ie, enable faster development ofnew, successful treatments.”  However,RCTs are outdated for several reasons. First,RCTs are inadequate to evaluate cancer therapies. Genomic analysis is uncovering the tremendous heterogeneity of what previously were considered single diseases. Genomic analysis of cancers of individual patients is disclosing the large number of mutations, and thus targets, within one person. Developing RCTs for targeted therapies would be difficult and timeconsuming, prolonging the wait for effective treatments.
Second, RCTs are a less efficient and accurate method of establishing which treatments work.

A recent study demonstrated that RCTs fail to predict or improve outcomes when evaluating multicausal diseasenetworks or treatments orwhen assessing which particular interactions are relevant.2 Rather than increase the use of RCTs, we propose an increase in the use of N-of-1 studies, which are based on simulations that rapidly sort through billions of possible interactions
at the clinical, genomic, and biological levels to arrive at predictive models of multicausality. This approach has identified candidate markers, which have been successfully used in clinical trials.3 These studies also have predicted the most effective treatments for patients based on a particular genotype
and medical history when RCTs have not.4 Increasing the use of RCTs would add to the cost and time required to developand use new products. Other analytic methods more quickly and precisely match patients to treatment.

1. Djulbegovic B, Hozo I, Ioannidis JPA. Improving the drug development
process: more not less randomized trials.JAMA. 2014;311(4):355-356.
2. Eppstein MJ, Horbar JD, Buzas JS, Kauffman SA. Searching the clinical fitness
landscape.PLoS One. 2012;7(11):e49901.
3. Wu C-C, D’Argenio D, Asgharzadeh S, Triche T. TARGETgene: a tool for
identification of potential therapeutic targets in cancer.PLoS One.
2012;7(8):e43305.
4. Garnett MJ, Edelman EJ, Heidorn SJ, et al. Systematic identification of
genomic markers of drug sensitivity in cancer cells.Nature.
2012;483(7391):570-575.  Read More & Comment...

CMS: To Protect and D-fend

05/22/2014 01:03 AM |

Per a report in Inside Health Policy:

CMS Holds Off Changes To Protected Rx Classes, Preferred Pharmacies, Limits On Plan Offerings

CMS kept its promise to put on hold key pieces of its proposed drug and Medicare Advantage proposed rule: the final regulation unveiled Monday does not rescind protected drug classes, does not open preferred pharmacy networks and does not limit the number of plans that insurance companies may offer.

CMS' proposed changes to regulations for Part D and Medicare Advantage plans were controversial on several fronts, and both parties attacked the rule, although sometimes over different provisions. After proposing the rule Jan. 6, CMS received more than 7,500 comments. In an unusual move, CMS Administrator Marilyn Tavenner told Congress in March that the agency would indefinitely put some of the most contentious measures on hold.

The strongest bipartisan opposition was against the agency's proposal to take away the protected status of three drug classes. Lawmakers, patient advocates and others argued that all drugs in those classes must be available because not all of the drugs in those classes work for all patients.

The final rule states that, although some commenters praised CMS for trying to apply criteria for drug categories or classes of clinical concern, no one supported the actual proposed criteria. Conversely, CMS did receive significant opposition to our proposed criteria.

"We are not finalizing any new criteria and will maintain the existing six protected classes," the rule states.

CMS received a lot of opposition to its proposal to open up preferred pharmacy networks, although that opposition came primarily from Republicans, who complained that CMS was opening the door to government interference between plans and pharmacy contracts, and the drug makers and pharmacy benefit managers that negotiate those contracts. Smaller community pharmacies, which usually are left out of preferred pharmacies, lobbied for the measure.

Preferred pharmacy networks provide lower cost sharing to beneficiaries who buy from those preferred pharmacies. The pharmacies agree to lower cost sharing in return for the greater volume of sales they get by offering lower prices. CMS proposed to allow beneficiaries to get the same cost-sharing at nonpreferred pharmacies. CMS thought that would simply give lower cost sharing to more beneficiaries, but others, including congressional Medicare advisers, warned that it would end the very preferred pharmacy networks that CMS was trying to expand upon.

"This lower cost sharing was subject to certain conditions that seemed straightforward to us at the time, but which have proven to need clarification," CMS states in the final rule.

Instead, CMS is exploring restrictions on preferred pharmacy networks in a separate document, called the call letter. Primarily, CMS wants to require that preferred networks reduce drug costs paid by plans in order to prevent Medicare from paying more for what intuitively should reduce Medicare spending.

CMS also is holding off on its proposal to limit the number of plans offered by sponsors of stand-alone drug plans. The final rule makes a case for restricting insurance companies to one basic plan and one enhanced plan per coverage year and for limiting the type of coverage offered in those two plans.

"Nevertheless, the comments have given us reason to conduct further analysis of this issue and continue our close observation of the developments in the Part D market," the regulation states.

However, CMS is following through with the proposed rule's measure to limit parent organizations to one prescription drug plan sponsor contract per region.

What the final does do:

•       It requires Part D prescribers to enroll in Medicare. "CMS is requiring that physicians and eligible professionals who prescribe covered Part D drugs be enrolled in Medicare, or have a valid record of opting out of Medicare, in order for their prescriptions to be covered under Part D. Requiring prescribers to enroll in Medicare would help CMS ensure that Part D drugs are only prescribed by qualified individuals," the rule states, adding that it allows extra time, until June 1, 2015, for that requirement to take effect.

•       It simplifies MA risk-adjustment data validation (RADV) audit appeals by combining error rate calculation appeals and medical record review-determination appeals. "The streamlined process will reduce administrative burden on both MA plans and CMS," the rules states.

•       It lets CMS, its antifraud contractors and other oversight agencies the ability collect information directly from pharmacy benefit managers, pharmacies and other entities that contract or subcontract with Part D sponsors to administer the Medicare prescription drug benefit. This provision, which the HHS inspector general recommended, aims to provide faster access to records for investigations of Part D fraud and abuse.

•       It revokes Medicare enrollment from physicians who abuse their prescribing rights.

•       It expands incentives for activities that promote improved health, efficient use of health care resources and prevent injuries and illness.

•       It allows the release of more privacy-protected Part D data. CMS is releasing to the public more unencrypted, prescriber, plan and pharmacy identifiers contained in prescription drug event records.

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NORD Roared

05/21/2014 09:29 AM |

NORD Representative Is One of Five Experts Invited to Testify Before Key Congressional Subcommittee

WASHINGTON DC; May 21, 2014-----Frank J. Sasinowski, representing the National Organization for Rare Disorders (NORD),  testified yesterday before the U.S. House Energy and Commerce Health Subcommittee on advancing the development of treatments for Americans with unmet medical needs.

The hearing was focused on the new 21st Century Cures initiative announced April 30, 2014, by Energy & Commerce Committee Chairman Rep. Fred Upton (R-MI) and member Rep. Diana DeGette (D-CO) to accelerate the discovery, development, and delivery of innovative new medical treatments.

The experts who testified discussed recommendations in the President's Council of Advisors on Science and Technology (PCAST) Report on Drug Innovation pertinent to the new 21st Century Cures initiative.

Sasinowski, a longtime NORD advisor and board member, noted that accelerating the development of safe, effective medical therapies and cures has special significance for people with rare diseases, most of whom have no approved therapy at this time.

"I am reminded daily that the 30 million Americans affected by rare diseases have a vital and urgent need for faster development of therapies," he said.

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FDA's Conditional Response on NBCDs

05/19/2014 07:23 AM |

Let’s talk about Copaxone, Dingell-Grams, and Chevron Deference.

There are many interesting aspects of this issue, not the least of which is the FDA’s pathway to predictably address the many regulatory issues surrounding nonbiologic complex drugs (NBCDs) – such as Copaxone.

And the FDA issues have a crucial impact on patient care – specifically therapeutic interchangability. Payers are watching.

As the agency has stated (most recently in a response to a letter from Representative John Dingall):

FDA believes that it is possible for manufacturers to develop generic versions of complex large-molecule drugs that can be demonstrated to have the “same” active ingredient as the reference listed drug and meet the requirements for generic approval under section 505(j) of the FD&C Act and FDA regulations … FDA currently believes that it may be possible, with some complex products, for an applicant to demonstrate that its proposed drug product meets the standards for approval as a generic drug under section 505(j).

‘It is possible.” “May be possible.”  Now that’s a real conditional response.

Importantly, the agency notes, “It is important to note that analytical methods, data analysis, and pharmaceutical manufacturing capability continue to evolve.”

As far as human trials are concerned, the FDA writes that, “in appropriate cases, FDA can ensure that a generic version of a complex large-molecule product approved under section 505(j) is therapeutically equivalent to the reference-listed drug without clinical safety or efficacy data because the product has been shown to satisfy the statutory sameness standard and other requirements of section 505(j).

Clearly not every case with every NBCD is identical (Lovenox certainly comes to mind), but greater clarity on how the agency review process is certainly needed. Each circumstance – although unique – cannot be forever de novo.

And the policy precedents for biosimilars are also important to consider.

On legal front, the FDA is being given chevron deference by the courts.

Per www.fdalawblog.net …

In a May 14, 2014 Order following a hearing earlier that day, Judge Ellen Segal Huvelle of the U.S. District Court for the District of Columbia granted on ripeness grounds FDA’s Motion to Dismiss a lawsuit brought by Teva Pharmaceutical Industries Ltd. and Teva Neuroscience, Inc. (collectively “Teva”) alleging that FDA’s May 2, 2014 denial “without comment” of a December 2013 Citizen Petition (Docket No. FDA-2013-P-1641) concerning COPAXONE (glatiramer acetate injection) violates the FDC Act and the Administrative Procedure Act.  At the same time, Judge Huvelle denied as moot Teva’s Motion for a Preliminary Injunction.

As we previously reported, Teva filed the lawsuit seeking declaratory and injunctive relief after FDA denied “without comment” several citizen petitions Teva submitted to FDA since 2008 concerning the approval of ANDAs for generic COPAXONE and considered by FDA under the citizen petition procedures added to the FDC Act at Section 505(q).  According to Teva, “FDA’s tactics make it virtually impossible for a court to provide aggrieved petitioners with meaningful relief before they are harmed irreparably.”  Each patent listed in the Orange Book for the 20MG/ML strength of COPAXONE is set to expire on Saturday, May 24, 2014.  After patent expiration, FDA could make ANDA approval decisions.

The D.C. District Court almost immediately denied Teva’s Motion for a Temporary Restraining Order after it was filed, and scheduled a May 14th hearing on Teva’s Motion for a Preliminary Injunction.  Teva pitched its requested relief as follows:

The relief Teva seeks could be structured in either of two ways.  First, this Court could simply enjoin the FDA from approving any purported generic version of Copaxone® until the Court has conducted an expedited trial on the administrative record defined by Congress and ruled on the merits of Teva’s petitions.  In the alternative, this Court could employ a variant of the procedure Judge Bates first crafted in the Hi-Tech case, permitting the Agency to finally offer its views on the issues Teva has raised on a negotiated timetable—though whatever views the Agency might offer would be, by the law’s plain terms, outside the administrative record and thus entitled to no deference—but enjoining the Agency from acting to approve any purported generic version of Copaxone® until this Court can provide meaningful judicial review of the critically important matters Teva has raised.

The so-called “Bates procedure” in Hi-Tech Pharmacal Co. v. FDA, Case No. 08-cv-1495, was established by Judge John D. Bates, who has been particularly critical of FDA’s handling of exclusivity decisions, to give the parties (i.e., FDA and a drug manufacturer) a chance to sit down in court where FDA would reveal an exclusivity decision, thereby allowing a potentially aggrieved generic manufacturer the opportunity to challenge that decision (see our previous post here). 

FDA, in the Agency’s Motion to Dismiss, argued that Teva’s lawsuit should be dismissed for a litany of reasons.  According to FDA:

Not only are Teva’s claims unripe and unjusticiable for want of standing, but Teva has not established that it will suffer certain, great, and irreparable injury in the absence of a preliminary injunction.  If Teva ever suffers the loss that it claims it will here, such loss will be a small percentage of its multibillion dollar portfolio of generic and brand drugs, and thus would not threaten or even seriously injure the business.  And finally, the balance of harms weighs against the entry of preliminary relief because Teva’s desire to further delay generic competition does not outweigh FDA’s interest in the thoughtful and careful exercise of its generic approval decisions without premature judicial interference.

FDA’s efforts to get Teva’s lawsuit tossed were backed by briefs (here and here) filed by Intervenor-Defendants Mylan Pharmaceuticals Inc., Sandoz Inc., and Momenta Pharmaceuticals, Inc., which reportedly have ANDAs pending at FDA for generic COPAXONE. 

After a hearing that went on for over three hours, Judge Huvelle rendered her decision: granting FDA’s Motion to Dismiss and denying Teva’s Motion for a Preliminary Injunction.  Her decision was grounded in previous decisions in Pfizer Inc. v. Shalala, 182 F.3d 975, 980 (D.C. Cir. 1999), AstraZeneca Pharmaceuticals v. FDA, 850 F. Supp. 2d 230 (D.D.C. 2012), and Mylan Pharmaceuticals Inc. v. FDA, 789 F. Supp. 2d 1 (D.D.C. 2011), where ripeness was a central issue to deciding the cases.  Judge Huvelle also refused to employ the “Bates procedure;” however, she did ask for a 24-hour “heads-up” from FDA on ANDA action.  According to Judge Huvelle at the May 14th hearing:

What we have here is a fact-specific complicated, complex scientific issue that has to be determined; and it hasn’t been determined yet.  To force them to decide the really difficult scientific issues at this time, I don’t have the power to do so, and it has to wait until there is a concrete application of the requirements for bioequivalency and sameness.  When that is determined, then Teva has the right to have a review of the administrative record and a speedy decision, and they can fight at that point about whether they're entitled to a preliminary injunction.  That is the only protective-window ability the court has.  Although if, in fact, we have an approval of an ANDA and this case comes back to this Court, I can assure you the FDA will have a matter of days to get together the administrative record because that is the only thing that holds us up. . . . 

Your right here is to get a final agency action.  That doesn't mean that it has to be the final agency action on what you want.  They have said that we need to take it up in the context of a specific ANDA.  That is an action.  We haven’t got to that point yet.  You cannot force us to take a premature action on this.

The Court rests on jurisdictional grounds and will grant the motion to dismiss, deny the [Preliminary Injunction].  To the extent that anything is going to happen, I am requiring the FDA . . . to give the Court notice so that we’re available to decide the difficult issues that come up here.  I’m not in the position of doing what Judge Bates did because you don’t have a deadline, you’re not in that position, but I certainly think that as a courtesy to all people, you should give us 24 hours’ notice before if you’re going to issue anything . . . just to let us know.

The 24-hour notice from FDA is apparently intended to allow the Court to adequately prepare and schedule for what may be the next Teva lawsuit – this time challenging an FDA decision to approve ANDAs for generic COPAXONE.  That decision could come any time after May 24th.

Stay tuned.

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EFPIA Goes Mobile

05/16/2014 08:30 AM |

According to the European Federation of Pharmaceutical Industries and Associations new “Manifesto for an Integrated Life Sciences Strategy in Europe,” drug manufacturers in Europe are missing out on opportunities for growth and patient outreach because they are failing to understand the value and potential of mobile health applications.

Per EFPIA’s director general Richard Bergström, “This is going in the direction of better patient compliance, adherence and motivation as well as an emphasis on health literacy and mobile apps … We need to find a way to unlock both the perceived and real regulatory hurdles, because I am not sure that the regulatory barriers are that high, and I think we are just being held back by conservatism.”

Bergström’s views are supported by the EU’s executive European Commission, which launched a Green Paper and consultation on mHealth in April this year. Its purpose is to examine existing barriers and issues related to mHealth deployment and help identify the right way forward to unlock its potential inside the 28-nation system.

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Safe Hands Across the Ocean

05/15/2014 06:29 AM |

Dear GO, CDER, and CBER staff:

We are pleased to announce an initiative to further our goal of ensuring that the public has access to quality pharmaceuticals. This initiative aims to deepen our reliance on trusted regulators outside of the United States who provide equivalent public safety and quality protection. This work is critically important and requires a dedicated FDA team to collaborate with our colleagues in European institutions and member states.

Managed jointly by GO, CDER, and CBER, this initiative will build upon our existing relationships with the European Medicines Agency (EMA) and member states of the European Union (EU), the European Commission (EC), and the European Parliament. It will complement the ongoing work of CDER, CBER, ORA, and OIP to enhance pharmaceutical quality through international collaboration, and also FDA’s work in implementing the FDA Safety and Innovation Act.  

Dara Corrigan to Lead Initiative as Senior Counselor for Global Operations and Policy

Effective May 18, Dara Corrigan will lead this mutual reliance initiative. She will leave her position as director of FDA’s Europe Office, but remain in Brussels, in the role of senior counselor for global operations and policy. Dara will report directly to Howard Sklamberg, deputy commissioner for global operations and policy.  She will provide strategic advice and counsel to the FDA Commissioner and other FDA senior executives. Don Prater, DVM, will serve as acting director, FDA Europe Office.

Dara brings a wealth of experience and knowledge of U.S. and EU laws and regulations that govern pharmaceutical products. Before serving as director of FDA’s Europe Office, she was FDA’s associate commissioner for regulatory affairs, overseeing one of FDA’s largest operating units and managing FDA’s inspection program. She also has held a variety of senior positions in HHS, and served as an attorney with the U.S. Department of Justice and at the law firm of Arnold & Porter.

CDER OCOMM’s Julie Zawisza and CDER OC’s Helen Saccone to Join Team

Dara will oversee a team that will be dedicated to mutual reliance activities and that will report to GO, CDER, and CBER. The team will include Julie Zawisza, who has served as director of CDER’s Office of Communications since 2008, and Helen Saccone, who has been a special assistant in the Office of Manufacturing and Product Quality (OMPQ) in CDER’s Office of Compliance since 2011. 

Julie holds a master’s degree in international science, technology, and public policy from the George Washington University and has more than 14 years of FDA experience. Before working in CDER, she worked in communications at CBER and was the head of FDA’s press office in the Office of the Commissioner. Julie also has worked for health professional and industry associations in communications and advocacy roles, and as a medical technologist at major medical centers in Washington, D.C. and Ann Arbor, Michigan.

Helen Saccone, Pharm.D., has worked in FDA for six years. Before coming to FDA, she worked as senior manager for education at the American Pharmacists Association and as a pharmacist for the D.C. Department of Health, conducting pharmacy and hospital inspections, as well as providing technical assistance on D.C. regulations. She holds a doctoral degree in pharmacy from Rutgers University. The team also will draw upon the work of other experts in CDER, CBER, ORA, OIP, and OCC.

We are delighted that these seasoned and accomplished individuals have agreed to lead the charge, and we have every confidence that the program is in very capable hands going forward. We invite you to congratulate Dara, Julie, and Helen, and offer them your support.

Building on Existing Pharmaceutical Quality Efforts

We want to thank our FDA staff members who continue to work so diligently on improving pharmaceutical quality and safety for the American public. The initiative announced today builds on the Agency’s ongoing efforts to enhance collaboration between FDA centers and ORA, and to bolster our resources around drug quality.

We are very excited about this programmatic direction and its potential to leverage our relationships with our European partners and capitalize on our shared interests as regulators to strengthen mutual reliance and ensure pharmaceutical quality for the U.S. market. 

In the coming months, you'll hear more about all of this as the team embarks on its first set of activities.  A special town hall will be scheduled soon to give FDA staff an opportunity to ask questions about this initiative and how it fits in with the Agency’s pharmaceutical quality efforts.

Howard Sklamberg, Deputy Commissioner for Global Regulatory Operations and Policy

Janet Woodcock, Director, Center for Drug Evaluation and Research

Karen Midthun, Director, Center for Biologics Evaluation and Research

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A Biosimilar Hierarchy

05/14/2014 06:48 AM |

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Spread the wealth and advance the health

05/13/2014 06:36 AM |

At the May 6th House Energy and Commerce Committee’s 21st Century Cures Initiative roundtable, participants were asked what steps Congress could take to expedite bringing new treatments and cures to patients.

Francis Collins, director of the NIH, said that what is needed is a “steady trajectory of support” so that scientists are willing to take risks. But what does that mean?

Collins said that over the past 10 years, the NIH has lost 20 percent of its purchasing power. His belief is that this loss has cost jobs and caused a lack of enthusiasm in our investigators, he said.

20%? That sounds like a statement worth investigating – because the NIH budget has grown significantly over the past decade.

“If we could have confidence of a stable trajectory for support, that would mean the world for an enterprise that is currently flagging,” he said. Not sure precisely what that means but, again, perhaps a study of how NIH is spending it’s current budget would help identify the strengths and weaknesses of its allocations – and the strategy behind them. After all, every dollar counts.

Janet Woodcock, director of the Food and Drug Administration's Center for Drug Evaluation and Research (CDER), said one issue affecting biomedical innovation is the current clinical trials system for drugs.

“The clinical trial system we have is not a system,” Woodcock said. “It takes years and it exhausts investigators.”

Woodcock said the FDA is starting to look at clinical trial networks that are already set up and funded. Testing a new drug in a clinical trial network is faster and “saves a lot of money,” she said.

Additionally, per Dr. Woodcock, since multiple new drugs are studied by the network, “you can do head-to-head comparisons of products.”

She also said there is a lot of innovation in drug manufacturing, and that the FDA will hold a meeting to pursue this avenue in a few weeks.

Another area that the FDA is focusing on is the Critical Path Initiative. Its goal is to bring innovative, high priority therapies to market quickly.

“There is a lot of research that needs to be done on things like biomarkers that would” speed the development of products, Woodcock said.

And, according to Margaret Anderson, executive director of FasterCures (an advocacy group aimed at improving the medical research system that is affiliated with the Milken Institute), “The appropriated dollars that go to the FDA are extremely valuable, and they are not enough.”

This past Sunday, I participated in a point/counterpoint in the pages of the Chicago Tribune with Dr. Kenneth Polonsky, Dean of Biological Sciences Division at Pritzker School of Medicine, and executive vice president, medical affairs, at the University of Chicago.

Dr. Polonsky’s perspective was, more or less, the same as Dr. Collins’, “more money equals more cures.” If only it was so simple. My view (IMHO) is somewhat more nuanced.

Here is Dr. Polonsky’s commentary.

And here’s mine:

Outside Opinion: Federal funds should go to medicine-makers

By Peter J. Pitts

Is more federal funding for the National Institutes of Health the best bang for the buck when it comes to using precious tax dollars to advance public health? No.

The NIH budget is about $30 billion. But what does that buy? Where do discoveries that advance public health really come from? Some do come from NIH-funded research — but not nearly the majority. The engine of innovation is the biopharmaceutical industry, which spends in excess of $50 billion annually on research and development. It's not a competition; the NIH and industry complement each other's efforts. But context matters.

The NIH focuses on basic research, the study of fundamental aspects of phenomena without specific applications. The biopharmaceutical industry addresses most of its R&D toward clinical research, science focused on the actual development of new medicines. The NIH provides grants to academic institutions. Industry employs the scientists who do the work and, increasingly, funds academic research.

But there's a problem. While universities love NIH dollars, they are less enamored of industry resources. Why? One reason is that NIH funding counts toward achieving tenure, while similar dollars from biopharmaceutical companies do not. Durbin's legislation would disincentivize more industry-academic partnerships. More government spending is not always the mother of invention.

As the Prairie State's great Sen. Everett Dirksen once (allegedly) quipped, "A billion here, a billion there, and pretty soon you're talking about real money." Some $10 billion annually could be allocated elsewhere to achieve broader access to newer, more targeted therapeutic medicines (and $5 billion could go toward the NIH's good work, hardly a paltry sum). The Food and Drug Administration should be No. 1 on the list to get more money.

The FDA regulates more than 25 percent of the U.S. economy, yet operates on an annual budget of $4.7 billion (about $2 billion generated by industry user fees). The budget's federal funding portion is about one-tenth the NIH's. Why hasn't Durbin proposed additional tax dollars for the FDA's programs on advancing regulatory science, expedited review pathways or more ready access to experimental medicines for desperately ill patients? The FDA doesn't even need $10 billion a year for 10 years to become our nation's leading force in health care innovation. Some $1 billion a year would do the job quite nicely. As to the remaining $9 billion, the line forms to the left.

Alas, headlines for hyped and misleading "NIH-funded cures" are far sexier than those for "more money for drug regulation." They may not be inversely important, but they are equally urgent in advancing 21st-century American health care.

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What does Beijing know that Washington doesn't?

05/12/2014 07:15 AM |

China is adopting a free market solution to drug shortages.

China will scrap caps on retail prices for low-cost medicine and is moving toward free-market pricing for pharmaceuticals, after price controls led to drug quality problems and shortages in the country.

The Wall Street Journal reports that Chinese leaders want health care to be more accessible and affordable, but there have been unintended consequences in attempting to ensure the lowest prices on drugs. For instance, many pharmaceutical companies registered to sell the thyroid medication Tapazole have halted production in recent years after pricing restrictions squeezed out profits, experts say, creating a shortage.

The lesson for US lawmakers is clear – artificially low prices are the major cause drug shortages.

Perhaps its time for our lawmakers to revisit the legislative solution proposed in Senator Orrin Hatch’s Patient Access to Drugs in Shortage Act. There are three key codicils:

1. Price Stability

The Hatch bill would change the Medicare reimbursement rate for generic injectable products with 4 or fewer active manufacturers from ASP + 6% to Wholesale Acquisition Cost in order to achieve market price stability.

2. Medicaid/340B Rebate Exemption

The bill exempts generic injectable products with 4 or fewer active manufacturers from Medicaid rebates and 340B discounts in order to achieve market price stability.

3. Extended Exclusivity

Manufacturers who hold an approved application for a drug that would mitigate a shortage can extend by 5 years any period of exclusivity, even if the drug is eventually moved from drug shortage designation.

It’s embarrassing that the world’s leading free market economy (that’s us) hasn’t learned the Econ 101 lessons our friends in China are now implementing to solve the problem of drug shortages.

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Protecting Sustainable Innovation

05/09/2014 09:20 AM |

HEP, HEP, Hooray!

CDER Director, Dr. Janet Woodcock. responding to criticism about the high price of breakthrough drugs, said that the agency is working towards approving more effective treatments for diseases like cancer and hepatitis. Reacting to controversy around the price of the breakthrough Hepatitis C drug Sovaldi, Dr. Woodcock discussed the potential decrease in societal costs and increase in patients' quality of life.

"I think we have to in some ways think about this as a transition period," she said during a panel discussion about the breakthrough designation. "We may have to put a big down payment down now to get something really good."

She highlighted the cost to society and burden on patients in dealing with the side effects and morbidity of having Hepatitis C. "I really do believe we need to drive toward curing, but you have to have a transition period, she said. "We are driving toward a cure with hepatitis."

Woodcock further advocated getting these drugs on the market so they could be combined with other products to drive toward cures. "In cancer, I think we have to recognized this is version 1.0, but we're going to get there," she said. "And to get there we can't hold back. We can see that cure."

 The battle for the heart and soul of 21st century health care is the battle over innovation. And nothing short of victory is acceptable. To borrow an over-used adjective from the world of global climate change, we must protect “sustainable” innovation.

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Timing is Everything

05/08/2014 09:20 AM |

Representative Anna Eshoo (D, CA) and the late Senator Edward Kennedy worked long and hard to write, lobby for, and pass the Biologics Price Competition and Innovation Act.

Unlike many of her congressional colleagues, Representative Eshoo has the creds to ask some tough questions of the FDA. She’s also smart enough to know the right questions to ask.

Unlike some of her fellow members who are swinging their political heft, trying to lobby the FDA on science-based questions, Ms. Eshoo is asking for clarification on the timing of a decision.

That is an appropriate and important question.

Representative Eshoo, in a letter to FDA Commissioner Hamburg asks (among other things) that the agency …

“Share with me the FDA’s timeline for the release of the draft guidance on naming and interchangeability.”

That’s a fair question from a member of Congress who deserves a prompt answer.

Observe due measure, for right timing is in all things the most important factor.

Hesiod

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Putting "vigilance" back in pharmacovigilance

05/07/2014 06:46 AM |

I’ve just returned from Riyadh, Saudi Arabia where both the Saudi FDA and the Ministry of Health are embroiled in the current MERS (coronavirus ) crisis.

It’s already cost the Minister of Health his job and many citizens are questioning the ability of the government to protect their wellbeing. It’s also an international news story that does not reflect well on the Kingdom.

Another reason to reexamine the state of overall health preparedness – and not only in Saudi Arabia.

A good place to start is with a serious conversation on 21^st century pharmacovigilance. Let’s start with definitions.

According to the WHO, “Pharmacovigilance is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.”

Okay as far as it goes. But this is a very 20^th century perspective. Perhaps a more progressive view comes from our regulatory cousins at the MHRA, “Assessing the risks and benefits of medicines in order to determine what action, if any, is necessary to improve their safe use.”

The significant difference is that most regulatory officials still view PV through the lens of adverse events. The MHRA definition, however, broadens the conversation to include safe use. That’s 21^st century pharmacovigilance.

What does this have to do with the coronavirus?

It speaks to the need of public health officials to be both the guardians of the public health as well as the watchmen. And that takes more than vigilance – it takes resources. It also takes a village – a public health village – comprised not just of public officials, but physicians, nurses, pharmacists, hospitalists, patients, and caregivers.

And it’s got to be more than MedWatch.

How much sooner could the coronavirus been identified and dealt with if the Saudi Ministry of Health had a more robust mechanism for post-market surveillance that went beyond adverse events?

But it’s not just the Saudis.

The FDA is establishing an Office of Pharmaceutical Quality to improve the agency’s scrutiny of brand-name, generic and over-the-counter drugs, CDER Director, Dr. Janet Woodcock said at the Bloomberg health-care summit. The FDA is talking with the industry to develop data that may signal which manufacturing plants are straying from standards and need inspection, she said.

The agency 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. “We want to use leading indicators. These people aren’t in trouble yet but they could be.”

Forewarned is Forearmed.

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