By plotting the differences between genetic variations of 3,000 Europeans in a two-dimensional grid, the researchers were able to reveal a pattern that looks remarkably like Europe. The scientists included researchers from CornellUniversity; the University of California, Los Angeles (UCLA); the University of Chicago; and the University of Lausanne, in Switzerland. The findings appear in this week's issue of Nature.

Fortunately the Critical Path does not require a visa -- but it does require funding -- now!

Reuters reports that, “Expensive advertising of prescription drugs directly to consumers may do little to encourage sales, U.S. and Canadian researchers reported on Monday.”

According to the report, even though companies spent an estimated $3 billion in 2005 on such ads in the United States, they did not appear to result in more prescriptions.

"People tend to think that if direct-to-consumer advertising wasn't effective, pharma wouldn't be doing it," HarvardMedicalSchool's Stephen Soumerai said in a statement. "But as it turns out, decisions to market directly to consumers are based on scant data."

The nonprofit Kaiser Family Foundation has come to similar conclusions in reports on direct-to-consumer ads.

In an April report the foundation found that 91 percent of adults surveyed had seen or heard advertisements for prescription drugs, but just one-third spoke to a doctor about a drug they saw advertised, and 54 percent of them got a prescription for a different drug.

Among doctors, 76 percent said they sometimes recommend a different prescription drug to a patient who mentions a drug ad and 5 percent said they frequently gave patients the drug.

Here's a new article from The Scotsman:

Advertising rules stifle free market for prescriptions
By Peter Pitts

IN EUROPE, it is illegal for drug companies to advertise prescription-only drugs to consumers. But the European Commission (EC) recently announced that it will allow pharmaceutical firms to disseminate "information" on their products over the airwaves, on the internet, and in print.

I think this change can't come soon enough. For too long, European bureaucrats have put cost considerations before patient care, keeping patients in the dark about alternatives that may best address their needs. Officials have, I think, paid lip service to the idea of empowering patients with more information on treatment options.

James Copping, a principal administrator of the EC, said in 2006: "We want a system where patients can be empowered to take an equal part in healthcare decisions." But thus far, no such thing has happened.

Consider the European agencies tasked with weighing the effectiveness of various treatments, such as the UK's National Institute for Clinical Excellence (Nice) or Germany's IQWiG. These agencies exist to provide unbiased medical information to government.

But because they are operated by government, I would say they have a vested interest in keeping costs down and have an incentive to conclude that newer, more expensive medicines are no more effective than older, cheaper ones.

Nice offers an instructive example. In 2001, contrary to expert findings by licensing authorities in 65 countries – including Scotland – it cited "insufficient evidence" for recommending the use of Gleevec in leukaemia patients.

In 2002, US authorities approved Gleevec for the treatment of stomach cancer and it was deemed a miracle drug. It wasn't until 21 months later that Nice authorised the use of Gleevec for English victims of the disease.

IQWiG seems similarly set on depriving German patients of vital treatments. The agency has promoted an "efficiency frontier" as its governing methodology for evaluating treatments. But such jargon is smoke and mirrors, designed to cover for the government's preference for established – and generally less expensive – treatments, and by decreeing the most cost-effective option in a treatment category, these agencies effectively determine what a doctor must prescribe, irrespective of a patient's individual characteristics.

Obviously, pharmaceutical companies have products to sell. But, by allowing them to provide Europeans with medical information, they could serve as a counterbalance to the heavy-handed pronunciations of state-run comparative-effectiveness agencies.

Indeed, a great deal of evidence demonstrates that consumers benefit when drug manufacturers participate in healthcare decision-making.

In the US, for example, a 2002 study by the Food and Drug Administration found that direct-to-consumer advertising of pharmaceuticals improved both patient-doctor discussions and compliance with physician recommendations. The study also found that 88 per cent of patients who asked about a specific drug were afflicted with the condition in question.

A 2003 study in US health policy journal Health Affairs arrived at a similar conclusion. According to the study, ad- inspired doctor visits resulted in the advertised medicine being prescribed in only about 47 per cent of cases. Put another way, patients didn't get a prescription for the medicine they came in to discuss on more than half their visits. Even with advertising, doctors exert appropriate judgment when they prescribe drugs.

On other occasions, according to the study, previously undiagnosed medical conditions get treated – a good thing.

For European bureaucrats, there is reason for concern. If consumers can get additional information on drug options thanks to direct-to-consumer efforts, there's a good chance they'll start to ask the state-run health systems why they can't access certain treatments.

As European Parliament member Jorgo Chatzimarkakis recently argued: "Citizens cannot be deprived of information by their own governments on such crucial issues as one's health."

Government-run systems have demonstrated that they're not interested in spending more money, but armed with new information, consumers may be able to make the case to their leaders that the status quo of rationed, controlled care will no longer suffice.

A recent report published in The Lancet was the first international analysis of cancer survival that provides comparable data across countries. Across all cancers studied, survival in the US was greater than in Europe. For example, 5-year relative survival for women with breast cancer was 84% in the US and 73% in the EU. For men with colon cancer in the US survival was 60% whereas in the EU it was 47%.

The researchers attributed the variation in survival to “differences in access to diagnostic and treatment services.”

Similarly,

Is the conventional wisdom that medicines for the very ill are healthcare budget busters? Not when you consider the facts.

A recent study published in Health Affairs found that for the severely ill, commercially-insured population, the costs of medical services account for more than 75% of health plan costs. Hospitalization costs accounted for half of this amount. In contrast, medications accounted for just over 20% of health spending for this group, whose annual costs are more than nine times higher than the overall plan population. The authors concluded that medication costs “do not seem to be the driver of health care costs for these members.”

Among the 2.5% of members with the highest spending, specialty medicines (defined in this study as "biologic-derived agents that target specific immune processes and proteins”) were used by 45% and accounted for 32% of spending on medicines and just 6.6% of total plan spending.

Pharma is not the enemy – disease is the enemy.

(But that’s not a convenient political sound-bite.)

Let’s not forget the wise words of Aldous Huxley, “Facts do not cease to exist because they are ignored.”

First let’s talk about transparency.

As John Jenkins (aka, “Dr. Wry”) appropriately pointed out, communications the agency has with sponsors is commercial confidential. That’s the law. The agency’s hands are tied. Period.

Why? Many reasons, but the most important is, well, commercial confidentiality. Trade secrets. Intellectual property. And when it comes to drug development, that’s core business, intelligence other companies would love to see.

But they can’t. And that’s appropriate. It’s at the very heart of a market-based system. The system that has driven unprecedented advances in pharmaceutical development.

The alternative, the so-called “patent-free” idea advocated by Jamie Love and Senator Bernie Sanders (aka, “the Senator from Ben & Jerry’s") was last applied in the former Soviet Union -- and it didn’t work. The Soviet experience was characterized by low levels of monetary compensation and poor innovative performance. The US experience isn’t much better. The federal government paid Robert Goddard (“the father of American rocketry”) $1 million as compensation for his basic liquid rocket patents. A fair price? Not when you consider that during the remaining life of those patents, US expenditures on liquid-propelled rockets amounted to around $10 billion.

Intellectual property rights are the fertile soil that facilitates the tree of pharmaceutical innovation to grow in the first place. To borrow an over-used adjective from the world of global climate change -- we must protect "sustainable" innovation. Jamie Love and Company may very well say, "A world without patents, amen." And they're right, because minus pharmaceutical IPR we'd all better start saying our prayers -- because that's the only way we're going to battle disease and improve the health of our global fraternity. That's a Silent Spring we cannot afford.

The question of honesty, however, is a more difficult issue. “Difficult” because honesty is often in the eyes of the beholder.

If you’re a journalist or pundit, you want as much information as possible. If (post August 11th 2008) the FDA issues a “complete response” letter, you want to see it so you can fully understand and report on the issue. If you’re the sponsor, you don’t want to share it because of both intellectual property considerations – but also because of how the contents of the communication might impact (among other things) how Wall Street views the value of your stock.

Which brings us to the issue of “spin.” Since the sponsor controls what is and is not shared, the sponsor controls what is and is not known. And let’s face it, that can quickly slip/slide into spin. Is not telling the whole truth a lie? It depends on which side of the information divide you reside. At a certain point the sponsor has to make a tough call – is less information better? There’s no hard and fast rule. But one rule is crystal clear – misleading information is just plain wrong.

It’s a fine line.

And speaking of honesty, the news out of Parklawn/White Oak is that 2008 is likely to be one of the slowest years for new drug approvals in the last five years.

Some in Big Pharma (and small pharma and biopharma) blame this on the FDA’s renewed “obsession with safety.” But how can the FDA take action on applications it hasn’t received? The real question is whether or not the FDA has helped or hindered new applications.

Going down this path leads to a discussion of the importance of the Critical Path. And, unfortunately, at present that’s more of a political conversation. Hello Ms. DeLauro. FDA can (indeed must!) be a facilitator – but the main responsibility for 21st century drug development resides with innovator companies.

And hence the importance of intellectual property protection and the need for (yep, you guessed it) commercial confidentiality.

What goes around comes around.

Is this the end of the dynamic duo of safety/efficacy and the beginning of a new Holy Trinity that includes comparative effectiveness?

Most reporting went something like this (courtesy of the Washington Post):

“Vanda Pharmaceuticals' stock tumbled 73 percent Monday after federal regulators rejected the Rockville biotech's schizophrenia treatment, saying it was similar to a drug already on the market.” (My italics.)

In fairness, the FDA didn’t actually say anything. This is how Vanda chose to represent the communications it received from the agency.

But rather than looking at this through the lens of comparative effectiveness – perhaps a better way to think about it is via comparative safety. Should inferior performance in some settings (for example if you won't know about it for weeks) be a molecule killer? The debate isn’t only (or primarily) whether it's bad to be worse – but also whether it can be easily monitored.

A tough situation for the FDA and a potential opportunity for those who would exploit this situation to call for a NICE-like system in the U.S. – such as Senators Baucus and Conrad and their “Comparative Effectiveness Research Act of 2008”

But it’s really just the latest example of why dogmatic approaches to drug regulation don’t work -- and why the Critical Path program is so essential.

Nobody said the FDA’s job was an easy one.

But the views offered on the inside were equally stimulating.

A few examples:

Elizabeth Teisberg (Professor, Darden School of Business, University of Virginia):

"Today pay-for-performance" means "pay-for-process-compliance."

Dr. J. Edward Hill (Past President, American Medical Association):

"If we believe in evidence-based medicine, then we should consider the evidence of what government run healthcare provides."

Dr. Hill also posed this interesting question, "Can we really have personalized care provided by the government?"

Dr. Michael McGinnis (Senior Scholar, Institute of Medicine):

"40% of deaths in the US are caused by the behavioral choices we make," led by lack of diet, not enough exercise -- and tobacco.

He also pointed out that "what happens at the intersections of the domains of influence" is what drives both health and care. McGinnis defined the relevant "domains of influence" as Behavioral, Genetic, Social, Environmental, and Healthcare.

There was much heated debate and audience participation -- but the most memorable comment was also one of the pithiest and it came from Dr. Hill who said, "People need to quit being complacent."

And included on that list of people needs to be doctors.

(Yes, doctors are people too.)

I asked Dr. Hill why we only hear from doctors when it's about their payment schedules. His reply was honest -- "I was afraid someone was going to ask me that question."

And that's when he offered the remark about complacency.

This is crucial since the average age of the FDA's work force is 54, and about 30 percent of general staffers already are eligible to retire.

That’s why “a strong FDA” is part of the agency’s five year strategic plan.

FDA’s most proprietary and valuable resource comes through the door each morning. There are almost 1,500 people with PhDs at FDA and well over 400 with medical degrees – and that’s without double counting.

An organization that can keep up with the rapid changes in the industries that it regulates, and that is capable of developing and implementing effective and innovative public health measures, requires a very special workforce. The FDA’s mission depends more than ever on a solid cadre of experienced physicians, toxicologists, chemists, statisticians, mathematicians and other highly qualified and dedicated professionals. Their expertise is essential for making regulatory decisions that are balanced and fair and timely -- and for keeping the agency on the cutting edge of the technology and sciences used by industry.

Agency leadership must make it a priority to encourage creativity, efficiency, and superior performance - an environment that attracts and retains top-quality scientists, and enables them to do top-quality work as part of an effective team.

Commission’s rigorous testing helps ensure interoperability of technology

As Congress takes up the subject of health information technology, it must take great care to enable accelerated progress rather than sending the process back to the starting line.

My vision of health information technology in the United States is a world where medical information can be privacy-protected and managed in a way that produces better quality, lower costs, fewer medical mistakes and less hassle for everybody. Building such a system requires that clinics, hospitals, pharmacies, labs and patients have systems that speak the same language — that are “interoperable.”

Getting health information systems in various parts of the healthcare system to work together requires the adoption of common technical standards. I’ve often compared the problem to the building of railroads. Before the railroads of the East, West, North and South could be interoperable, they all had to agree on one standard track size. A similar process is required with health IT, except that the degree of difficulty is much harder than just agreeing on a track size.

There are more than 200 developers of electronic medical record systems in the United States.

Until three years ago, there was no process for harmonizing and coordinating the standards they used. To remedy this problem, we formed the American Health Information Community (AHIC). It has succeeded, and as time passes we are seeing an accelerating stream of solid and widely accepted health IT standards emerge.

People who buy systems need to know they are making an investment that will connect them with the rest of the medical world. Today, they can buy with confidence.

The Certification Commission for Healthcare Information Technology gives systems a rigorous testing to demonstrate interoperability. Those systems that pass the test are given CCHIT certification. When doctors buy systems with that seal, they know that they are on a pathway to interoperability. This has given many doctors the confidence to buy who were waiting before.

We have seen more progress toward interoperability in the past three years than in the previous two decades. This is because government agencies, the medical family, the insurance industry and the health IT sector are all working together collaboratively. This type of collaboration is hard and requires great effort, but it is working, and its momentum is increasing.

As Congress begins to write a health IT bill, it is critical that it be crafted in a way that does not interrupt this success by imposing government controls. Government has to be at the table as a full participant, but if the bill prescribes the way these standards are to be set, or puts in place a politically controlled process that picks winners and losers, it will devastate a healthy but fragile process and lose three years of maturity and momentum.

I would offer three principles to members of Congress in dealing with legislation:

First, let’s protect the flexibility of those who are working to invent new tools, and let’s not undermine the work on AHIC that is already underway. Writing legislation to bias the process in one direction or another will constrict innovation and slow the process.

Second, let’s not try to solve all the privacy challenges of the 21st century in a health IT bill. We have to be careful to avoid penalizing early adoption.

Third, let’s respect the need for legitimate healthcare communications. We have to find the balance here. It is in the patient’s best interest for doctors and the patient to have information.

The most important thing government can do is adopt the standards ourselves. The adoption of standards by Medicare, the Veterans Administration, the Department of Defense, and Indian Health, is critical.

We’re making progress on health information technology. Let’s make sure that any legislation accelerates the progress already under way, rather than chilling it with requirements that the government dictate one-size-fits-all answers.

True. But numbers are just numbers. The story is somewhat different when you put those numbers in perspective.

According to the Journal story, “Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, denies that the agency has become "more conservative" about drug safety. Rather, she says, the industry's faltering research efforts are mostly to blame for the fewer product approvals. She says the agency continues to base its decisions on science, not outside pressures. New methods, she adds, have helped it become more vigilant about side effects. She attributed the increase in black-box warnings primarily to a few large groups of medicines that were relabeled."

Reality bites.

Bringing new drugs to market has always been a scientifically challenging and expensive proposition – and it remains so. But the big difference today isn’t (gasp!) politics – it’s that, while discovery and development embrace 21st century science, regulatory science lags behind. At present, the FDA is using 20th century tools to review 21st century medicines.

This is why the agency’s Critical Path Program and the Congressionally-mandated Reagan/Udall Foundation are so crucial to our 21st century healthcare future -- as well as to the future of the pharmaceutical industry.

The comments of Schering-Plough CEO Fred Hassan (courtesy of the Journal article) are instructive:

“Mr. Hassan believes an intensifying focus on safety and a diminished tolerance for side effects at the Food and Drug Administration have dramatically lowered the odds that the drugs would make it to market -- at least not without a lot of extra time and money.”

Not so fast. It is today as it has been in the past and must be in the future – the quest for appropriate risk/benefit balance. Side effects are “tolerated” insofar as the benefits are appropriate. As to the “extra time and money” comment – there’s no benefit from wishing for the “good old days.” Time marches on and so does science. Perhaps a better focus would be on more innovative clinical trial designs – and on the FDA’s promised guidance on adaptive clinical trial designs.

The past is prologue.

"What will it take to get new drugs approved?" Mr. Hassan asks. "The point is, we don't know."

Yes we do. Better development science and better regulatory tools for the FDA.

This is not a new idea – but it’s a good one. But it’s often derided as the pharmaceutical industry calling for a policy change for reasons of self-interest rather than public health.

But at the recent BIO convention in San Diego a European Commission representative said that Brussels is seriously considering proposals that would ban repackaging – a move that, if taken would (according to Reuters), “deal a blow to the parallel trade and could also help drugmakers' profits, since companies' revenues are currently eroded by arbitrage dealings in their products across borders.”

Does this mean that the European Commission is in the “pocket of Big Pharma?”

Hardly.

(In fact, it’s humorous considering the way the industry is treated over there.)

What it does mean is that, enfin; the EC is taking seriously what we here at drugwonks.com have been saying for some time – that parallel trade is the weak link in the pharmaceutical chain of custody and a prime target for counterfeit infiltration.

It’s also important to note that what the Europeans call “parallel trade,” we refer to as “importation.” And that Canadian Internet pharmacies get their drugs from Europe. (Note: over 20% of all pharmaceuticals legally sold in the UK are parallel traded into that island nation from other nations within the EU such as Greece, Latvia, Portugal, and Malta and often illegally from places such as Russia and Turkey.

“Safe” importation?

Perhaps in a parallel universe.

CanWest is arguing in the Ontario Superior Court that this prohibition, which is part of the Canadian Food and Drugs Act, places it at a competitive disadvantage to US newspaper and magazines which are sold on Canadian newsstands, because it prevents it from selling advertising space to pharmaceutical manufacturers. The company also points out that Canada does allow OTC medicines to be advertised directly to consumers, even though these products also carry risks.

The case will be heard this month.

One panel I attended was on the future of personalized medicine via diagnostics. A few of the points made were:

* At present, “trial and error medicine” is the standard of care. Not good for providers, patients, nor payers. That’s true.

* What we today call “personalized medicine” will be referred to in the near future as “medicine.” That’s hopeful.

* Diagnostics will deliver personalized care via drug selection, dosing, efficacy, disease status, recurrence risk, and predisposition. That’s exciting.

* Diagnostics lead the league in the price/value proposition – and that’s what will initially drive uptake. That’s reality.

* To that point, there was also discussion of a diagnostics acceptance continuum beginning with “fear” and then moving to “value” and finally “acceptance.”

* And the constituencies moving along that path include pharmaceutical companies, physicians, patients, payers – and regulators.

* Specifically, to more expeditiously sashay down the Critical Path, the diagnostics industry needs industry-wide guidelines for clinical research.

Take-away is that "personalized" medicine is 21st century medicine. And that's a "win" for physicians, payers ... and even patients. As BIO Chairman (and Vertex CEO) Dr. Joshua Boger commented at the opening day's keynote, we must all be "a confederation of optimists."

Who are these critics? What are the agendas? Where does their funding come from? On these questions the Lancet is silent.

The Lancet opines, “Patients' access to quality information is variable across the European Union's 27 member states and the Commission is right to want to address this inequality. But the pharmaceutical industry's obvious financial conflicts of interest mean that drug information provided by them is likely to be prone to bias.”

“Likely to be biased?” On what do they base this rather strong statement? Isn’t solid, unbiased information in the best interests of both sales and the public health? Isn’t there a more inherent “bias” by having payers control what information consumers get to see? And in the EU, “payers” = “government.”

The editorial concludes, “Patients have a fundamental right to access good quality, objective information on medicines. The EC's final proposal, due out later this year, must empower patients and not the drug industry.”

Why not empower the drug industry to empower patients? That’s what the pending EC directive is all about.

And as far as the Lancet stipulating bias, consider the words of Robert Benchley:

"Tell us your phobias, and we will tell you what you are afraid of."

While the “universal” consensus was that ethics are primary – economics came in a very close second. One robustly debated theme was the idea of “an ethical standard based on resources.”

In other words, reality.

We live in the real world where increasing drug development costs and shrinking resources for reimbursement (government-paid in the case of the Europeans) cannot be ignored when it comes to either green-lighting a development program or making an access decision based on healthcare technology assessment (HTA).

One leading consultant suggested that pharmaceutical development program should not proceed beyond Phase II until the company met with reimbursement agencies to gauge the likelihood of a positive coverage decision based on clinical endpoints.

Frightening that such a highly paid consultant could so completely miss the point – that government healthcare systems exist to serve their citizens, not to act as actuarial bean counters. Financial prudence? Cetainly. But not at the expense of the right medicine for the right patient at the right time. That’s a medical decision. That’s ethics.

Many present pointed out that what we really need are better tools to allow smarter development programs that don’t fail in late Phase III (as over 50% do today). In the US that means the Critical Path. In Europe it’s the Innovative Medicines Initiative. Both are predicated on patient-centric care.

But when a healthcare system is a government-pay model, the cost-based versus patient-centric momentum seems unstoppable.

Consider the remarks last week of Thomas Lonngren, executive director of the European Medicines Agency (EMEA),

"It could come to a situation where we are approving a product based on efficacy, safety and quality ... but the patient can't get it because the health technology institute says it is not cost-effective."

Note to Tom – already happening.

Consider Britain's National Institute for Health and Clinical Excellence (NICE) and the series of high-profile disputes in which new drugs for conditions such as cancer and rheumatoid arthritis have been turned down for use on the state health service.

And what’s worse than a bad decision in one country? Correct – a cavalcade of uncoordinated, voodoo cost-based decisions -- with one even less patient-centric than the last. Or, as Lonngren commented,

"… a different decision in each member state (of the European Union) because this is not harmonized.”

Other countries, including Germany, have recently set up their own versions of NICE and
Lonngren said the emergence of such health technology institutes posed a challenge for drug manufacturers since these bodies often required additional research, and he suggested there might be scope for cooperation with the EMEA in designing drug approval programs in future.

Is that a good idea, EU harmonization of HTA? Or is it the camel getting its nose under the tent?

And that, dear readers, is the distinction between “universal” healthcare and “government” healthcare. In short –no difference at all.