The Same Game

• 01.20.2009

A final FDA rule (effective July 15^th) will require ANDA applicants to submit data from all bioequivalence studies conducted on a generic drug product formulation filed for approval, rather than just those that successfully demonstrate bioequivalence to the reference listed drug.

Currently, applicants submit studies demonstrating that the rate and extent of absorption of a generic drug meets bioequivalence limits, but additional bioequivalence studies conducted on the same formulation typically are not submitted. These include studies that failed to meet passing criteria, as well as multiple successful studies. The agency infrequently sees this additional data and is generally unaware of the existence of such studies.

Applicants also must submit data in an annual report on all post-marketing bioequivalence studies for an approved drug product formulation during the annual reporting period.

SCRIP World Pharmaceutical News reports that, “The agency notes that if it receives failed bioequivalence studies for a given application, it might make a different decision about whether to approve the generic than if it had received only the pivotal passing study.”

The FDA is limiting the additional studies to those conducted for the "same drug product formulation,” rather than requiring submission of all studies conducted with developmental formulations. "Same drug product" is defined as the formulation of the product submitted for approval, and any formulations that have minor differences in composition or manufacturing method but are similar enough to be relevant to the agency's bioequivalence determination. The FDA intends to issue draft guidelines giving specific examples of formulations it considers to be the same drug product.

Attention must be paid to the issue of bioequivalence -- particularly by those at the WHO and elsewhere who are toying with the idea of "clinical equivilence" for follow-on biologics.

Will Innovation Survive This Administration?

• 01.19.2009

Forgive me for raining on the inaugural parade.   

I regard the incoming administration with trepidation.  Not because of it's agenda because on first, second and third glance it seems to have none.  But rather, it seems to worship at the altar of being perceived as effective.  What did Nick Carraway say about Tom Buchanan in The Great Gatsby being a "series of successful gestures."  Exactly. 

No permanent allies. No permanent friendships.  Just permanent interests. 

And to maintain it's interests the administration will toss biomedical innovation to the wolves.  Not because they want to but because the way it is done, in bits and pieces and in the dark of night and couched in cost containment and consumer protection it will be really easy to make it harder and harder to produce and bring to market any innovation.   Want your votes on the stimulus bill it will cost you a change to allow an override of pre-emption.  Want expanded SCHIP coverage?  Allow CMS to establish reference pricing for breakthrough drugs or special rebates.  Want more NIH funding?  Be prepared to require that anyone receiving NIH funding be allowed to collaborate with industry.  More funding for the FDA?  Be prepared to saddle the agency with regulation of tobacco, TV ads and drug importation.

Can we expect the media to analyze the impact of all this?  Not at all.  The journalists who believe that "science should not be for sale" and who work at newspapers that can't be given away have led the way in making people believe that the commercialization of medical discoveries is essentially a criminal enterprise no different than the one Madoff concocted.  

Sadly, many of those in the crosshairs appear oblivious or believe they can survive by engaging in accomodation or seeking what is known as a "seat at the table."

Ask the biotech industry in the UK and Europe if that's a recipe for success and prosperity.

There's an awful lot of something in Brazil

• 01.19.2009

The Executive Board of the World Health Organization meets next week with significant discussion expected on a new secretariat report on counterfeit medical products

According to IP Watch, “The new report on counterfeit drugs released on 18 December also is likely to generate discussion, as some sources are concerned about what they see as contradictions between this report and earlier WHO statements on counterfeit drugs, and others are concerned about what they see as internal contradictions in this report.”

The counterfeit drugs report will be the “big IP item” on the agenda next week, a developed country source predicted. A developing country source predicted a “very difficult discussion” on the document.

Several nongovernmental sources have expressed concern over the use of the term “counterfeit” in general - saying that legally speaking it is associated with violations of trademark law, a legal association which is confirmed in international law by its definition in the World Trade Organization Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement relating it specifically to trademark violations. They also say that even statements within the report itself that “legal instruments related to intellectual property rights have a broad scope and are not focused on the protection of public health,” cannot take away the fact that the terminology is focussed on IP and not on healthcare.

A Brazilian delegate agreed with this assessment, saying “we do not want to see WHO as an agency of enforcement related to trademark,” and the use of the word “counterfeit” automatically brings in discussion of IP, especially given its presence in TRIPS. Further, the delegate added, the work of IMPACT was done outside the WHO and therefore “and we cannot simply import IMPACT recommendations without discussion.” It should not be legitimized as though it were an intergovernmental process, the delegate explained.

A meeting of the International Medical Products Anti-Counterfeiting Taskforce (IMPACT) – a taskforce of anti-counterfeiting stakeholders, including pharmaceutical industry associations and drug regulatory authorities, international agencies and non-governmental agencies, and enforcement bodies, launched by the WHO in 2006 – in Tunisia in December 2008, for instance, defined counterfeits in such a way that “disputes about patents” would not be accidentally equated with counterfeits. However, the new report contains the broader statement “recognizing that disputes about IP rights are not to be confused with counterfeiting.” A developed nation delegate said that the patent definition is preferable, but expected disagreement on the issue.

The definition IMPACT agreed on is: “a product with a false representation of its identity and/or source. This applies to the product, its container or other packaging or labeling information. Counterfeiting can apply to both branded and generic products. Counterfeits may include products with correct ingredients/components, with wrong ingredients/components, without active ingredients, with incorrect amounts of active ingredients, or with fake packaging.”

The definition by IMPACT adds that “violations or disputes concerning patents must not be confused with counterfeiting of medical products,” yet there is much concern – particularly on the part of developing countries and non-governmental agencies – that disputes concerning trademarks could still be conflated with counterfeiting.

The International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)’s director general Alicia Greenidge approved of the report, saying it “touches on some key issues concerning the fight against counterfeits, including the appropriate definition of a counterfeit medicine,” and endorsed the IMPACT definition. She added that “generic medicines play an important role in ensuring global health and are unfortunately themselves widely counterfeited, [therefore] it is important to have a definition which provides guidance that authorized generic medicines are not counterfeits and which also assures that patent actions are not confused with counterfeit actions … this will help authorities in both developing and developed countries to identify and address counterfeits of trademarked products, including the many authorized branded generics.” 

Yes we can ... have NICE in the USA

• 01.16.2009

Presented for your edification, a summary of CER provisions in the House Economic Recovery Bill:

APPROPRIATION OF $1.1 BILLION FOR CER RESEARCH

Subtitle B-Health and Human Services, AHRQ (pg. 141)

• $700 million is appropriated to carry out titles III, IX of the Public Health Service Act( establishes NIH, and AHRQ), title XI of the Social Security Act (CERTs program, peer review), and section 1013 of MMA to conduct or support CER. $400 million will be transferred to NIH (leaving $300 million to AHRQ).

• In addition, $400 million will be allocated at the discretion of Secretary of HHS for efforts that:

    o Compares the clinical outcomes, effectiveness, and appropriateness of items, services, and procedures that are used to prevent, diagnose, or treat disease

    o Encourage development of networks that can generate outcomes data

    o $1.5 million will go to the IOM for a report recommending national priorities for CER

• Public Accountability:

    o Secretary shall publish information on grants and contracts awarded with the funds

    o Shall disseminate research findings from grants and contracts to clinicians, patients, and the general public

    o Recipients of funds shall ensure an opportunity for public comment on the research

• Secretary will provide congressional committees an annual report research being conducted/supported and an operating plan for FY 2009 and FY 2010

ESTABLISHMENT OF ‘FEDERAL COORDINATING COUNCIL FOR COMPARATIVE EFFECTIVENESS RESEARCH

• Council shall coordinate and assist government agencies with conducting CER

• Council will advise Congress and President on CER infrastructure, CER funding, and other opportunities

• Council is composed of 15 members all of whom are federal officials/employees with responsibility for health-related programs, appointed by the president. Includes CMS, AHRQ, FDA, VA, DOD

• At least half the members will be physicians (working in government)

• By June 2009, the council will submit a report to the President and Congress detailing recommendations.

What does all this mean?

1. It is, if not a clone of the UK National Institute for Clinical Excellence (NICE), a kissin' cousin.

2. Absolutely nothing in the current legislative language would stimulate the development of measures and studies to advance personalized medicine.

3. There will be inevitable bias towards large randomized trials a la CATIE and ALLHAT.

4. And who will ARHQ rely on for its research? Most likely entities funded by HMOs and other payers with a goal towards cost containment.

5. The underlying assumption is that comparative effectiveness research will deliver improved outcomes via better quality evidence concerning the best treatment, prevention, and management of any given health condition. It assumes that comparative effectiveness research helps patients, providers, and payers of health care to make more informed decisions. But is there any evidence that these assumptions are true?

How about a study to determine whether comparative effectiveness research, compared to other types of research, actually delivers on these lofty goals? How about a meta-analysis to examine how comparatively effective comparative effectiveness research is?

6. And what if such a body swiftly morphs into a New World version of NICE, dictating de facto guidelines for reimbursement and coverage. Doesn't it become an obstacle to access, just like in the UK -- denying patients coverage to innovative uses of new mediccal technologies?

Yes we can ... what? Embrace a healthcare system that is cost-based rather than patient-centric?

No thank you.

Onions on pizza or blood pressure control?

• 01.16.2009

Minefields Along the Innovation Highway

• 01.16.2009

Outgoing Dept HHS Secretary Tevi Troy leaves Washington today for a well-deserved rest (rumors about a Yankee spring training contract can neither be confirmed nor denied) but not without an important parting word about the future of biomedical innovation in America.

This past year Dr. Troy held a series of town hall meetings throughout the country on the future of biomedical innovation. The account of his meetings were published today in a report entitled: Healthcare Innovation in the 21st Century.

He found:

"New and exciting technologies provide hope that pioneering new diagnostics, devices, drugs, and therapeutic interventions will be developed and made available to the public. However, the need to assess standards, clinical utility, safety, and cost all provide significant challenges and delays in translating scientific discovery to a marketable product. Biomedical innovation is fraught with uncertainty, risk, and a high probability of failure. Many new technologies – genomics, nanotechnology, advanced imaging, bioinformatics – offer great possibilities for the development of biomedical innovations. Yet these new technologies have also amplified the risk and uncertainty in the regulatory and payment pathways. Each of these new technologies raises questions about the safety, efficacy, and clinical use of products derived from these technologies. In many cases, the new technologies also challenge existing notions of how a biomedical innovation should be treated if it does not fall into a traditional regulatory or payment pathway, or straddles two existing pathways. In many cases, there may be a long lag between the emergence of a new technology and the issuance of regulatory guidance clarifying the pathway for product approval. Attendees noted that uncertainty can contribute to delays in the development and diffusion of new innovations, and can diminish investors’ willingness to invest in new technologies."

At a time when Congress is pouring buckets of money on failing and floundering sectors of our economy, considering legislation to force banks to issue risky loans (once again) and proposals to restrict access to new medicines while showering tax credits on green technologies some of Dr. Troy's recommendations to remedy these solutions should be adopted:

Requiring that certain funds be set aside for purely
basic research, and that other NIH grants go to basic
and translation research that has a demonstrated or
probable connection to an improved health care
outcome.
􀂾 Moving away from a binary model of safety versus
effectiveness, by having the FDA make sure
consumers have information available to them about
the spectrum of risks and benefit inherent in every
drug, biological, and device – and how these risks and
benefits may vary from person to person.
􀂾 Allowing FDA to approve applications on the basis of
inferences from known biomedical effects, rather than
always requiring clinical trial data on sizeable
populations.
􀂾 Implementing value-based purchasing across different
parts of Medicare, so that Medicare pays providers for
value or outcomes provided to a beneficiary rather
than for each service or good.

Sadly, Congress and the media marches in another direction. That's because they hate innovation...or the innovators to be more precise. And mining the innovation highway to make it riskier and more dangerous to innovate is part of the game plan. Tevi has highlighted the threats to innovation. To the extent that they are turned into policies, we will know who the enemies of progress really are.

Of Mice and Meds

• 01.16.2009

Talk about pharmaceutical direct-to-consumer advertising!

Pfizer has just launched a commercial in British movie theaters  warning about the dangers of counterfeit medicines illegally purchased online .

The commercial, slotted to be shown in 600 theaters across the UK, shows a middle-aged man spitting up a rat after swallowing a pill that arrived in the mail.  (This alludes to the fact that some of the counterfeit drugs seized in the UK contained not API – but rat poison.)

According to an article in the Financial Times,

“The campaign reflects growing safety concerns – and commercial losses for the drug industry – caused by a rise in unregulated internet sales of medicines. It also marks an intriguing extension of the limits on advertising by drug companies to raise their public profile, in spite of tight restrictions on the marketing of prescription medicines to consumers. The film contains no reference to Pfizer’s medicines but shows the corporate logo alongside that of the Medicines and Healthcare Products Regulatory Agency, the UK watchdog that co-ordinates an increasing number of investigations and prosecutions of counterfeiters. It agreed to a pioneering partnership with the company.”

Well jolly good all around.  Now let’s see if Pfizer will reach out to the FDA to pursue a similar program here at home. – and whether the FDA will have the courage to step up to the plate and accept the offer. That’s precisely the kind of pubic interest partnership the world’s biggest life sciences company needs in order to demonstrate that it’s heart – and pocketbook -- are in the right place.  That it's in the public health business first and the selling drugs business second.  And it’s just the kind of unambiguous, bold and innovative messaging the FDA needs to remind the American people – including some of our elected officials -- that drug importation is unsafe healthcare practice and unsound public policy.

To view the commercial, click here.

How big is the problem of counterfeit drugs?  According to CNN:

“Many of the world's bogus drugs originate in Asia, particularly China, according to the U.S. Center for Medicine in the Public Interest. The fakes oftentimes are exported and change hands many times before reaching their unwitting consumers."These are criminal organizations that are manufacturing, distributing and selling counterfeit medicines," says Thomas Kubic, a former FBI agent and president of the Pharmaceutical Security Institute, a group funded by drugmakers. The growing trade has been fueled by the growth of Internet drug sales and the lure of lucrative profits. The Center for Medicine in the Public Interest expects global sales of fake drugs to reach $75 billion by 2010.”

The complete CNN story can be found here.

Perhaps the weakest link in the European chain of custody is parallel trade. In Europe, parallel trade (what we call “importation”) is legal between all 25 EU member states. And last year 140 million individual drug packages were parallel imported throughout the European Union — and an independent wholesaler repackaged each and every one. This means that, literally, parallel traders open 140 million packets of drugs, remove their contents and repackage them. But these parallel profiteers are in the moneymaking business, not the safety business. And mistakes happen. For example, new labels incorrectly state the dosage strength; the new label says the box contains tablets, but inside are capsules; the expiration date and batch numbers on the medicine boxes don’t match the actual batch and dates of expiration of the medicines inside; and patient information materials are often in the wrong language or are out of date. Oops.

In the EU there is no requirement to record the batch numbers of parallel imported medicines. So if a batch of medicines originally intended for sale in Greece is recalled, tracing where the entire batch has gone (for example, from Athens to London through Canada to Indianapolis) is impossible. And all the large "legitimate" Canadian internet pharmacies already admit to getting their supplies from Europe. (An interesting and important side note is that these EU-sourced drugs aren't even legal for sale in Canada. So those who say we'll be getting "the same drugs as Canadians" are just plain wrong.)

In fact, parallel traded medicines account for about 20% (one in five) of all prescriptions filled by the same British pharmacies that have had a record numbers of counterfeit recalls. In other words, drugs purchased from a British pharmacy by a Canadian internet pharmacy to fulfill an order from an American cutomer could come from European Union nations such as Greece, Latvia, Poland, Malta, Cyprus, or Estonia.

Caveat Emptor is bad health care practice and even worse health care policy. Safety cannot be compromised, even if the truth is inconvenient.

$1.4 Billion for a Misdemeanor?

• 01.16.2009

Eil Lilly is paying $1.4 billion to settle charges relating to it's off-label promotion of Zyprexa.  The company pled guilty to a misdemeanor... That's an expensive slap on the wrist. 

Meanwhile, I wonder how much of that settlement will go to group such as The Prescription Project, Public Citizen, The Prescription Access Litigation Project, Community Catalyst, etc and trial attorneys as opposed to state governments..  How much will actually go to Medicaid patients instead of bottom feeders and the interest groups that front for them? 

$1.4 billion can buy a lot of research activity for medicines that could save the lives of kids with cancer or seniors with Alzheimers...instead most of it will go to tort lawyers.

Got Guidance?

• 01.15.2009

FDA Issues Guidances for Industry to Improve the Safety of Food, Feed and Drugs

The U.S. Food and Drug Administration today issued three guidances designed to help ensure the safety of FDA-regulated products in the supply chain. The documents issued today include the following:

·       Final Guidance for Industry on Voluntary Third-Party Certification Programs for Foods and Feeds;

·       Draft Guidance for Industry on Submission of Laboratory Packages by Accredited Laboratories; and

·       Draft Guidance for Industry on Standards for Securing the Drug Supply Chain – Standardized Numerical Identification for Prescription Drug Packages.

“The guidance documents reflect the FDA’s continued vigorous efforts to minimize the chances of unsafe products reaching American consumers,” said Jeffrey Shuren, M.D., J.D., associate commissioner for policy and planning.

The Final Guidance for Industry on Voluntary Third-Party Certification Programs for Foods and Feeds discusses the attributes of a third-party certification program that would merit the FDA’s confidence in the quality of the program’s audit. The guidance, finalizing a draft published on July 10, 2008, is intended as one of the steps in the FDA’s future recognition of voluntary third-party certification programs for foods and animal feeds. The document makes clear that it applies to any third-party certification body, including a private entity or a non-FDA federal, state, local or foreign regulatory body. Third-party certification programs can augment the ability of the FDA and the importing community to verify product safety.

The Draft Guidance for Industry on Submission of Laboratory Packages by Accredited Laboratories is intended to enhance the quality and reliability of test results submitted by importers to demonstrate that their products meet the FDA’s requirements. The guidance advises importers how to use accredited -- rather than non-accredited -- laboratories and makes recommendations about the quality and type of test data and information that these laboratories should produce in support of test results submitted to the FDA. The draft guidance is also intended to reduce the likelihood that an importer will select only favorable test results to submit to the FDA.

The Draft Guidance for Industry on Standards for Securing the Drug Supply Chain – Standardized Numerical Identification for Prescription Drug Packages is the first of several guidances and regulations that the FDA may issue to implement Section 913 of the Food and Drug Administration Amendments Act of 2007. This guidance recommends the standards that industry should use for the identification of individual packages containing prescription drugs. These standards will facilitate the adoption of a uniform electronic track and trace system for prescription drugs to further improve their safety and security. Both draft guidances have a 90-day comment period.

All three guidances support the FDA’s import strategy emphasizing prevention of harm, intervention when risks are identified, and rapid response after harm has occurred.

The FDA’s guidance documents do not establish legally enforceable responsibilities.  Instead, guidances describe the agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.

High (Blood Pressure) Gene

• 01.14.2009

People with a common variant of the gene STK39 tend to have higher blood pressure levels and are more likely to develop full-blown high blood pressure, also called hypertension, University of Maryland School of Medicine researchers found.

They identified the gene's role in high blood pressure susceptibility by analyzing the genes of 542 people in the insular Old Order Amish community in Lancaster County, Pennsylvania.

The researchers confirmed the findings by looking at the genes of another group of Amish people as well as four other groups of white people in the United States and Europe.

About 20 percent of the people studied had either one or two copies of this particular variant, the researchers said.

The gene produces a protein involved in regulating the way the kidneys process salt in the body -- a key factor in determining blood pressure, the researchers said.

Yen-Pei Christy Chang, who led the study appearing in the journal Proceedings of the National Academy of Sciences, said the findings could lead to the development of new high blood pressure drugs targeting the activity of STK39.

"What we hope is that by understanding STK39 we can use that information for personalized medicine, so we can actually predict which hypertensive patients should be on what class of medication and know that they will respond well and have minimal risk for side effects," Chang said in a telephone interview.

People with high blood pressure are more likely to develop heart attacks, heart failure, strokes and kidney disease.

While STK39 may play a pivotal role in some people, Chang said numerous other genes also may be involved. Many factors are involved in high blood pressure such as being overweight, lack of exercise, smoking and too much salt in the diet.

Several different types of medications are used to treat high blood pressure, including diuretics, beta blockers, ACE inhibitors, calcium channel blockers and others. Their effectiveness varies depending on the person, and doctors have a hard time knowing which is best for a particular patient.

Chang said the researchers want to determine how people with different versions of this gene respond to the various drugs and to lifestyle interventions such as cutting the amount of salt in the diet.

The Lancaster Amish are seen as ideal for genetic research because they are a genetically homogenous people whose ancestry can be traced to a small group who arrived from Europe in the 1700s. In addition to genetic similarity, they also maintain similar lifestyles in their close-knit rural communities.

(Editing by Maggie Fox and Vicki Allen)