The (Clinical) Trial

09/01/2011 08:18 AM |

Life imitates art.  In Franz Kafka’s unfinished story, “The Trial,” a man is arrested and prosecuted by a remote, inaccessible authority, with the nature of his crime revealed neither to him nor the reader.

 

Well – it’s déjà vu all over again -- new Russian regulations making it harder for the Rodina to become an international destination center for clinical trial excellence.  And nobody knows why.

 

As Dr. Meir Pugatch discusses in a new Journal of Commercial Biotechnology article, “The overall, the strength of national pharmaceutical IP environments provide a good estimate of the level of clinical trials taking place in these countries. Accordingly, countries with a more robust level of pharmaceutical IP protection tend to enjoy a greater level of clinical trial activity by multinational research-based companies. In other words, by choosing to improve their level of protection of pharmaceutical IPRs (together with other factors), developing countries may also be exposed to higher levels of biomedical FDI, not least in the field of clinical trials.”

 

(More on Dr. Pugatch’s article can be found here.)

 

This is bad news for Russia.

 

New data shows that clinical trial activity in Russia is still on the decline following the introduction of new regulations last year. The total number of trials approved in the first half of 2011 fell by 36% to just 200, with trials conducted locally by domestic sponsors most affected, falling by around 80%, according to the Russian clinical trials organization, ACTO.

 

The slowdown is mainly due to the law on circulation of medicines, which came into effect in September last year. Among other things, the law incorporated local clinical trials into the drug registration process, introduced new trial approval and insurance procedures, and imposed a ban on the import of registered products for use in clinical trials.

 

Not only is this bad news for international investment – but it also has the unfortunate side effects of making it more difficult for Russian companies to conduct clinical trials in their own country. Russian companies wanting to conduct local trials (as opposed to Russian arms of multinational studies) can do so only as part of a drug registration procedure, not as freestanding studies.

 

According to ACTO Executive Director Svetlana Zavidova, she did not know why this distinction had been made, but it was possible that those drafting the law had simply forgotten to state that local clinical trials were also a freestanding kind of study.

Kafkaesque – and with unfortunate results.

The number of local safety and efficacy studies approved in Russia fell by 78.4% to 19 in the first half of 2011, while bioequivalence studies were down by 84.4% to just seven. According to ACTO, the fall in bioequivalence studies is probably due to two factors: there are no approved requirements for such studies, and in some cases generic manufacturers cannot refer to the originator's pre-clinical trial results and are having to carry out their own tests, thereby delaying the bioequivalence study.

 

These developments are somewhat worrying given that the government has made much of its plans to build up the Russian pharmaceutical industry and reduce the country's reliance on imported medicines. "It is remarkable that the implementation of the law had a particularly tough impact specifically on the innovation activity of Russian companies, which is in direct contradiction with the governmental desire for import substitution in pharmaceuticals," ACTO commented.

“Remarkable?”  Not really.  Predictable?  Absolutely.

On the positive side, sponsors of international trials fared better than their Russian counterparts in the first half of 2011, gaining 163 trial approvals compared with 160 in the 2010 period. Nonetheless, they had their own problems, including the lack of new rules on insurance, which should have been in place on 1 January this year, and the ban on importing registered drugs (for use as comparators in clinical trials of experimental drugs).

 

Bad News: The import ban affected not only new studies but also those already under way where stocks of the approved drug were running short, says ACTO, which notes that some new studies were cancelled and transferred to other countries.

 

Good News: The ban was finally lifted in June this year when the health ministry took over responsibility for the importation of both approved and unapproved medicines, while the insurance question was dealt with by a May decree implementing the amended rules.

 

Bad News: Another factor dampening trial activity has been the fact that the authorities are not adhering to the new, shorter timeframes for trial approvals stipulated in the new law.

 

In fact, according to ACTO, things are even worse than they were before the law came into force: in the first six months of 2011, the total time taken to gain approval for a trial and obtain import/export permits amounted to an average of 160 days. This is "twice as long as the maximum period allowed by law and 30.5% longer than the all-time worst results.”

 

Other problems remain, says ACTO, including the fact that foreign companies still have to conduct a local trial (free-standing or as part of an IMCT) when seeking new drug registration in Russia. "Unfortunately, this problem is still on the front burner for us", ACTO’s Zavidova commented.

 

That must be some big front burner.

 

Considering the importance of clinical trials as a leading indicator of international pharmaceutical investment, perhaps Moscow should seek expert advice on the subject.  After all, as the Russian proverb says, “With a helper a thousand things are possible.”

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The Four Percent Solution

08/31/2011 01:28 PM |

Is 4% a lot or a little?  Well – it depends whether you’re one of the 4%.

 

As the AP reports, “Pfizer Inc.'s just-approved drug Xalkori, the first new medicine in more than six years for deadly lung cancer, proves the value of precisely targeting rare diseases linked to gene variants

The drug was approved Friday in the U.S. along with a companion diagnostic test for just a small subset of lung cancer patients. It is the poster-child for the 21^st century strategy of developing medicines for relatively few patients to replace (as the AP puts it) “blockbusters for the masses.”

 

"This is a paradigm shift," Dr. Paul A. Bunn Jr., a University of Colorado professor and cancer researcher involved in testing Xalkori, told journalists during a conference call hosted by Pfizer. "It used to be that everybody with cancer was treated the same," with surgery and chemotherapy.

 

Xalkori, a pill with relatively minor side effects compared to the hair loss and nausea that chemotherapy can cause, was approved for the roughly 4 percent of patients with advanced nonsmall cell lung cancer who have what's called the ALK fusion gene.

 

About 6,000 Americans a year develop this cancer, Pfizer said. Those patients, called ALK positive, now can be identified with a $250 molecular diagnostic test developed by Pfizer's partner, Abbott Molecular Oncology. The test was also approved Friday.

 

According to Dr. Mark Kris, head of the thoracic oncology service at Memorial Sloan-Kettering Cancer Center in New York, "You're going to be sparing individuals side effects (and) the waste of resources, time and drug that really isn't going to help them."

Cost efficient and patient-centric. Bingo.

 

Personalized medicine, targeted therapy – call it what you will.  It’s real.  And it’s a giant step towards achieving the 4 rights – the right medicine in the right dose for the right patient at the right time.

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PCORI? Memento Mori.

08/30/2011 08:43 AM |

For those of you who missed Latin class that day, memento mori means, “remember your mortality.”

 

It seems that the American Medical Association has (albeit a little late in the game) woken up to that fact and gotten religion.

 

The AMA has invited other healthcare groups to sign onto a letter to the Patient Centered Outcomes Research Institute (PCORI) on the types of research that should and should not be conducted under ObamaCare. The AMA is concerned about its proposal to "investigate ... optimizing outcomes while addressing burden to individuals, resources, and other stakeholder perspectives."

 

They should have read the bill before they so aggressively supported its passage.

 

Why the turnaround? Could it be that America’s physicians worry that including cost in the equation will open the door to rationing down the line?

 

"We seek further clarification toward the Board's intentions regarding this last component and whether this includes cost analysis," states a sign-on letter scheduled to be sent later this week to PCORI executive director Joseph Selby. "If that is the case, we do not believe that it is consistent with the PCORI's enabling statute."

 

The issue, at its core, is physician disempowerment. With first insurance companies and now Uncle Sam telling doctors how to practice medicine (step therapy, restrictive formularies, more strident and cumbersome preauthorization requirements, and academic detailing), it’s no wonder that physicians are mad and that the AMA is doing a volte-face on PCORI and comparative effectiveness.

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Of IPRs and In-Flows

08/29/2011 08:42 AM |

My good friend, Professor Meir Pugatch of the University of Haifa, is one of the world’s most respected experts in the role that robust intellectual protection plays in economic development.

 

In a new paper in the Journal of Commercial Biotechnology, Dr. Pugatch asks a crucial question -- To what extent does the strengthening of intellectual property (IP) environments in developing countries lead to greater in-flows of technology transfer in these countries?

 

According to Dr. Pugatch, there is a growing body of statistical evidence suggesting that a stronger IP environment does contribute to an enhanced level of foreign direct investment (FDI) and technology transfer in developing countries.

 

For example, an OECD study finds that in developing countries an increase of 1 per cent in the strength of patent rights resulted in 1.7 per cent increase in FDI flows, which in turn resulted in the transfer of know-how, that is innovative capabilities. Quite an attractive multiplier.

 

Here’s the official abstract:

 

The strength of pharmaceutical IPRs vis-à-vis foreign direct investment in clinical research: Preliminary findings

 

This article examines the effect of the intellectual property (IP) environment in developing countries on the level of foreign direct investment (FDI) and technology transfer occurring in the biopharmaceutical field in these countries. In particular, it considers the correlation between the strength of IP protection in several developing countries (using the Pharmaceutical IP Index) and the number of clinical trials taking place in these countries (as a proxy of biomedical FDI). The article finds that overall, the strength of national pharmaceutical IP environments provide a good estimate of the level of clinical trials taking place in these countries. Accordingly, countries with a more robust level of pharmaceutical IP protection tend to enjoy a greater level of clinical trial activity by multinational research-based companies. In other words, by choosing to improve their level of protection of pharmaceutical IPRs (together with other factors), developing countries may also be exposed to higher levels of biomedical FDI, not least in the field of clinical trials.

 

The full article can be accessed here.

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Why Vaccine Fears Persist

08/26/2011 08:54 PM |

As the recent Institute of Medicine report concludes the scientific evidence about vaccines benefits and microscopic risks is clear and convincing.   Report: Vaccines Are Safe, Hazards Few And Far Between

Yet, politicians of all stripes have indirectly fed the  the unfounded fear of parents who refuse to vaccinate, thereby endangering the lives of others.   the Obama administration has ducked the issue of vaccine safety instead of addressing the issue clearly..  It has missed several opportunities to promote vaccine safety and have, in the past, caved into anti-vaccine forces.  It has given money to anti-vaccine groups.  At the same time it was unfortunate that Rick Perry backtracked on the issue of requiring HPV vaccination, not because mandatory vaccination is appropriate (it should be used sparingly) but because in doing so he did not reaffirm the importance of the vaccine in eradicating many forms of cancer that are increasing in prevalence.   And Washington State, where parents are refusing to immunize their kids in record numbers, has buckled under pressure for anti-vaccine forces and failed to enact a law making it tougher to bail out of vaccinations.   www.kvewtv.com/article/2011/aug/01/wa-leads-nation-parents-opting-out-immunizations/

For many reasons lots of politicians don't want to say they support a government requirement of any form.  (The battle over the individual health mandate is a case in point.)  And they don't want to confront parents who insist vaccines cause autism.  But requiring people to be immunized is a way of protecting the freedom not to be exposed to vaccine preventable illnesses.  Many, if not most, of those who are infected by vaccine choicers and their kids, are infants or immunocompromised children who rely upon others to protect them against disease and death.  

Freedom is not the unfettered right to avoid the dangers dancing in your head at the expense of the health and life of others.   Living in and benefitting from a free society requires not just meeting obligations  but also abiding by norms of thought and collective action that comport with reason and science.  Thomas Jefferson observed:  "The value of science to a republican people, the security it gives to liberty by enlightening the minds of its citizens, the protection it affords against foreign power, the virtue it inculcates, the just emulation of the distinction it confers on nations foremost in it; in short, its identification with power, morals, order and happiness (which merits to it premiums of encouragement rather than repressive taxes), are considerations [that should] always [be] present and [bear] with their just weight."

 

Politicians and public health officials should stand up for medical science and not contribute to what the National Vaccine Advisory Committee calls "the culture of refusal."

 

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Shuren’uff

08/26/2011 03:06 AM |

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NIH Conflict of Interest Rules Criminalize Innovation

08/25/2011 04:29 PM |

The gang that have produced new rules to prevent even the appearance of conflict of interest in medical research have an agenda. 

They single out any relationship involving any resource or transaction that "may" have a monetary value exchanged between drug or device companies and academics.

But health IT companies, HMOs,  trial lawyers, hospitals,  government bureaucrats who hand out dough for comparative effectiveness research are exempt from oversight.  Apparently there is no possibility for any undue influence from such entities.

The NIH are defensive about the impact these regs will have on innovation.  And they should be.

"We want to emphasize that the revisions are not designed to prevent or hinder relationships among government, academia, and industry. Rather,
the revisions are aimed at facilitating such relationships by increasing transparency and accountability so that the resulting research is considered objective and in the interest of the public."

Given that most scientific misconduct and publication bias is a product of career climbing having nothing to do with industry, the emphasis on industry seems misplaced.

Moreover,  who said that people are concerned about objectivity as defined by the Obama administration?   One person's objectivity is another person's bias.   And the new regs simple open up the process of biomedical innovation to more questions about conflict that have nothing to do with quality of the research -- ultimately measured by whether we can prevent or control diseases more effectively -- but everything to do with the cultural and ideological belief that commercialization inherently benefits large companies at the expense of the rest of us and that the commercialization process is inherently corrupt and corrupting.   

The advocates of the regs claim that more oversight and investigation is needed because industry support for research has increased.  Is it the industry support itself or the magnitude?  Where is the evidence that more money means more corruption?  Isn't the opposite outcome as likely:  That is, people with a financial stake in the outcome of a research are more likely to be more scrupulous about research to protect their investment?   Loss of reputation is a huge price to pay for fudging data for starters.   Do the NIH reg advocates believe that industry funded scientists are more likely to lie about the safety and effectiveness of new products even at the expense of  harming people?

The answer is yes.  This culture of mistrust would have ensnared and persecuted the following individuals who had -- under the new guidelines -- the potential or actual presence of a financial conflict:

Louis Pasteur -- wine and beer maker and recipient of wine industry money
Gertrude Elion    
George Hitchings
Sir James Black
Craig Zello
Phil Sharp
Joseph Goldstein
SIr Peter Mansfield
Judah Folkman

Most are Nobel Prize winners.  All used industry money to commercialize devices and medicines that have extended and improved life.   But according to the conflict of interest priesthood, the research they produced was tainted and therefore the results could be not trusted.   They would be required to "report the name of the company or entity in which there’s a conflict of interest, the value of the interest, why it’s a conflict and “some key elements” of how the institution plans to manage the conflict."  

blogs.wsj.com/health/2011/08/23/new-nih-conflict-of-interest-rules-better-than-the-old-rules/

Note there is no room for arguing there is no conflict.  It's a confict.  Acting as if it isn't is a grounds for investigation.   Your only option is to tell the world just how guilty are are or appear to be.  This makes a forced confession easy by comparison.

Meanwhile Andrew Wakefield, who received cash from trial lawyers and his own patients, would be exempt not only from the new NIH rules but the suspicion of the COI kapos.  

Ditto the groups who pushed for this sort of witchhunt.  Money from George Soros, the IOM (a conduit for ideologically tilting foundations) and others are exempt too.

The new rules are the culmination of an ideological assault by those who believe commercialization is inherently corrupt and corrupting and who ignore the fact that as a result of such innovation,  life expectancy and death rates from cancer, heart disease and other illnesses have declined in direct relation to the industrial investment in treatments for death and disease.


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SEO = Search Engine Oops

08/25/2011 09:56 AM |

Google Inc. has agreed to pay $500 million for carrying advertisements by online Canadian pharmacies targeting consumers in the United States, according to the U.S. Justice Department.

 

The ads resulted in the illegal importation of prescription drugs, the Justice Department said.

That's a big oops.

 

The $500 million represents the money Google made from selling the drug ads, plus the revenue earned by Canadian pharmacies from sales to American customers.

As an FDA Associate Commissioner said back in 2003 (on the front page of the Washington Post), "You can't blame them (Google) for accepting commerce. But they really haven't understood the consequences."

They do now.

Who was that prescient FDA guy?

For the answer to that question and further background on this story, see here.
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Are Guidances Good?

08/24/2011 02:43 PM |

The FDA has unveiled, after much hard work,  several guidances on everything from companion diagnostics, to biomarkers, to what safety data has to be included in pre-clinical and Phase I research.   That's on top of yet another proclamation about how the agency is focused on regulatory science (isn't that a contradiction in terms?) that will speed innovation.  We heard and saw that from the FDA about three other times this year.  And everything said or written is a footnote to the Critical Path report that was ignored after the Vioxx hysteria.  

Guidances are okay but they are no substitute for less regulation and more scienced-based common sense, as evidenced by this account of how farmers may soon have to regulate...dust.

blog.heritage.org/2011/08/20/president-obamas-regulatory-dust-up/
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Obamacare Drug Shortage

08/23/2011 12:04 PM |

Call it Obamacare's Final Destination Tour.   While President Obama rests up at Martha’s Vineyard, people whose lives should be saved by new and existing cancer drugs are driving from hospital to hospital in search of medicines in short supply thanks in part to Obamacare’s implementation.

 

Over the past two years shortages have developed for over 180 drugs, including cancer treatments.  The shortfall is the result stricter FDA regulation, government price controls on already discounted but complex drugs, and policies that discourage the use of new medications.   Companies, facing lower prices, tighter regulation and increasing government control over what drugs will be used when, are exiting the US market and investing in product development in china and India where, sadly, it is easier and cheaper to produce next generation medicines than in America.

 

Stockpiling will only add to people's suffering by replacing market reforms with government micromanagement.  Government planners require months, if not years, to produce regulations, bids and supply estimates that are usually overgenerous to compensate for paltry prices.  Government bungling was behind the failure of the smallpox and H1N1 vaccine program and responsible for billions of dollars in flu vaccines and antibiotics being dumped.

 

The same forces pushing stockpiling also believe commercializing medical discoveries is evil.  It’s part of a larger effort to nationalize the development of medicines that under Obamacare is become institutionalized  

 

Indeed, the drug shortage is a product of a more troubling trend: At a time when medical research could yield breakthroughs in the treatment of obesity, Alzheimer's, diabetes, stroke among others, innovation has all but dried up.   Most of the medicines being used today were developed 30 years ago.   Most of them have generic competition.   They have contributed greatly to increased wellbeing but as the return on generic drugs fall, price controls and regulation have created shortages. 

 

Obamacare is making the commercialization of newer drugs and devices more difficult.

Though new and faster methods to determine a technology's safety and effectiveness exist, Obama’s FDA still demands evidence collected with science and statistical methods developed in the 19th century.   To be sure, in the last two years new medicines for AIDS, cancer, lupus and hepatitis have been developed.   Yet, these products should have been available sooner if not for FDA nitpicking.   

 

And now that they are finally approved, patients are finding it next to impossible to access several new drugs and genetic tests that would transform the quality of life and extend survival for such illnesses as lupus, prostate cancer and organ transplantation.  

 

Provenge, the first cancer vaccine, stalled at the FDA for years.  Once approved, it faced 18 months of additional delay while the Obama administration figured out whether to pay for it.  The gauntlet cancer patients face with Provenge is being extended to everyone waiting for a medical breakthrough under Obamacare:  Before a medical innovation can be used or paid for the government will now demand additional research demonstrating that a new product will be more effective and cheaper than existing technologies.  Since most new products come from small start-ups with limited cash, such a requirement means live saving innovations will not be available at all. 

 

Similar regulations have been used to delay and deny access to cancer drugs in England, Canada and Australia.  Drugs such as Avastin, Revlimid and Herceptin are barely used in Britain's cancer wards because government decided they were not valuable.  The people who could not use them are dead. Those -- mostly in America -- that did are alive. 

 

But now this de facto rationing is coming to America.  Before the cancer drug shortage there was the decision that women under 50 should not get mammograms.  Both Provenge and Benlysta, new treatments for prostate cancer and lupus respectively, are hard to come by because of uncertainty about reimbursement by health plans and government. .  

 

The death and suffering flowing from such delays are the result of policies promoted by those who want to use the FDA and increased government control over medicine to slash access to new technologies.  In their mind, rationing of cancer drugs frees up money to expand the welfare state.  The shortage of old drugs is simply one side effect of this malevolent strategy.  

 

It would be simpler to claw back regulations and let markets work.  But stockpiling is part of a larger effort to centralize the development and use of medical services.  The administration has gone silent on the wonders of obamacare even as it issues regulations and hires bureaucrats to replace free choice with government edict.  But it will emerge as a campaign and social issue.   In America no one should go without medicine because they can't afford it.  And it shouldn’t be a nation where people are denied such treatments because their government makes medicine impossible to produce or obtain. 

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Asking the right question

08/23/2011 09:22 AM |

I am currently attending (and speaking at) the Technology Policy Institute’s annual Aspen Forum.  It’s refreshing to listen to presentations on issues other than healthcare.  But, on the other hand, there are a lot of parallels.

One disturbing similarity was brought to mind by a talk given by FCC Commissioner Robert McDowell. The topic was regulation of the Internet.  McDowell commented that he wasn’t sure when the question of “Should the Internet be regulated?” morphed into “How should the Internet be regulated?

And he was very clear that this was a disturbing “iterative change.”

Sound familiar?  We should be asking ourselves the same thing about comparative effectiveness.  When did “Should we adopt a national comparative effectiveness approach to healthcare?” morph into “How should we adopt a national approach to comparative effectiveness?”

There’s still time and opportunity to robustly debate the former so that we can avoid the latter.

We can, in the words of Commissioner McDowell, “avoid a race to the bottom.”  Read More & Comment...

BioSimilar Fee for All

08/22/2011 09:25 AM |

The Generic Pharmaceutical Association never misses an opportunity to miss an opportunity. They are balking at continuing to negotiate the design of a biosimilar user fee program that is independent of other user fees and has its own baseline appropriations trigger.

 

The disagreement stems from a proposal by GPhA and a representative of potential biosimilar sponsor Momenta Pharmaceuticals that biosimilar reviews remain part of the Prescription Drug User Fee program through fiscal year 2017, the end of the first biosimilar program cycle, according to minutes of a July 18 meeting.

 

The tactic could be a way to lower the cost of a biosimilar application. If the agency is forced to include biosimilars in the PDUFA program, it likely would have a more difficult time arguing it needed a strong funding base to ensure the program functions properly.

 

GPhA said it could not continue “detailed negotiations regarding volumes and metrics without agreement to parity with the PDUFA user fee program.”

 

The position would seem to reverse one taken during a July 11 negotiation. Minutes indicated “industry stakeholders” and FDA agreed to support a flat product development fee of about 10% of the marketing application fee for the fiscal year while a biosimilar product was in the IND stage.

 

It is unclear whether FDA could send a commitment letter to Capitol Hill for approval without support from a major trade group involved in the negotiations.

 

If FDA went ahead with a commitment letter for a separate biosimilar user fee program and GPhA wanted to press the issue, the generic group would presumably need to convince legislators that its interpretation of the 2007 bill creating the new approval pathway was correct.

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Médecins Sans Facts

08/19/2011 06:47 AM |

“Facts are stubborn things” – John Adams

Médecins Sans Frontières (MSF) should be called Médecins Sans Facts.

MSF reports (correctly) that “while countries are rolling out new tests that will enable them to diagnose more patients with drug-resistant tuberculosis (DR-TB), a worldwide shortage of the drugs to treat these patients is likely.”

Not quite.

The news item generating this story comes from South Africa, which has the world's fifth-largest burden of multi-drug resistant (MDR) TB cases. According to Norbert Ndjeka, director of DR-TB, TB and HIV at the South African National Department of Health, the government will replace all microscope-based TB diagnoses with faster, more sensitive GeneXpert testing within two years, making it the world's largest user of the machine.

Good news.  But here’s the MSF spin:

But while more patients may get diagnosed, their access to treatment remains precarious as a limited number of approved drug producers keep many DR-TB prices high and supply uncertain, according to Dr Eric Goemaere, MSF's senior regional adviser.

It’s the familiar refrain from our friends at MSF: Blame industry! Blame international intellectual property (IP) protection! Convenient and consistent – and untrue. Médecins Sans Facts.

 

The truth of the matter is that the fault for shortages lies with all too familiar misguided government policies – in this case the government of South Africa and their myopic focus on lowest price.  Combined with a concerning lack of transparency, utter unpredictability and the exploding processing costs of their regulatory system, it all adds up to delays and drug shortages of not just medicines for TB – but for many other critical healthcare products.

 

Mr. Ndjeka has admitted that South Africa's regulatory Medicines Control Council (MCC) has been laboring for years under a backlog in drug registrations, including those of some fixed-dose antiretrovirals long available in other nations. South Africa now pays a private company to import the drug through a special application to the MCC.

So what does MSF recommend doing beyond their criticism of IP and the innovator pharmaceutical industry? Ignoring Economics 101, they recommend lowest cost "access to essential drugs"  -- which just further exacerbates the medicines supply problem.  

 

Médecins Sans Facts continues to call for countries to avert the looming crisis by “improving drug forecasting, negotiating better prices and accelerating national medicines registrations.”

As Mark Twain said, “Get your facts first, then you can distort them as you please.”

It would be helpful if groups like MSF took a longer term view -- encouraging multiple suppliers of medicines through more stable and predictable pricing versus their usual and customary (and wrong) focus on lowest cost. If MSF really wants to be part of the solution, they should consider combining efforts with industry to help streamline the complicated and costly regulatory process in South Africa (and in many other nations of the Developing World).  Harmonizing regulatory practices to align with evolving global standards (as called for recently by US FDA Commissioner Dr. Margaret Hamburg) and pressing domestic regulatory officials to respect timelines and transparent performance criteria, would make a huge difference for patients in countries like South Africa.

Why can't MSF advocate new drug approvals in places like South Africa within 90 or 180 days for products already approved leading regulatory agencies in Europe, Japan, and North America? Should South African patients really wait 2-5 years for access to promising new medicines that are already licensed for use in dozens of other countries?  Where is the activist outrage about these inexcusable regulatory delays?

Perhaps a better question (at least for starters) is why won’t MSF and their fellow travelers opt for a more collegial and logical agenda?

Perhaps the answer to that question was best addressed by George Orwell who wrote that “All political thinking for years past has been vitiated in the same way. People can foresee the future only when it coincides with their own wishes, and the most grossly obvious facts can be ignored when they are unwelcome.”

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Prior Proper Notification

08/18/2011 08:22 AM |

When I served at FDA we signed an MOU with PhRMA that required its member companies to notify the agency when instances of counterfeit medicines came to the attention of manufacturers.

 

It got the job done – minus additional federal regulation.

 

Today we face a different problem – drug shortages – but a similar decision tree:  regulation or public-spirited public health cooperation.

 

Minus the latter, we will get the former.

 

Senators Amy Klobuchar (D, MN) and Bob Casey (D, PA) have introduced legislation to require drug manufacturers to give “proper prior notification” to FDA when there is going to be a drug shortage.

 

Further, Klobuchar (D, MN) and Richard Blumenthal (D, CT) have formed a bipartisan group to work on the issue of drug shortages.

 

At their request, the FDA will hold a hearing on the matter September 21, and the General Accounting Office will review the problem.

 

It’s time for FDA and PhRMA to get the job done.

 

Legislation takes longer and leads to mission creep.

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Now that's what I call priority review!

08/18/2011 08:17 AM |

BioCentury reports that the FDA has dentified eight priorities in the Strategic Plan for Regulatory Science: preclinical toxicology; personalized medicine; manufacturing; evaluation of emerging technologies; using information sciences to improve health outcomes; food safety; medical countermeasures; and communication with consumers and professionals.

 

The agency is seeking to improve the prediction of product safety through new animal models that consider both disease progression and co-morbidities. The plan also calls for FDA to collaborate with academia, industry and global regulatory agencies to develop and refine clinical trial designs. Such a collaboration would identify and evaluate improved endpoints and related biomarkers for areas where "optimal" endpoints are lacking, such as for osteoarthritis, gene therapy, ophthalmic indications, tumor vaccines and stem cell-derived therapies

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Diagnostic Mission Creep

08/17/2011 08:32 AM |

CDRH has released two draft documents on approval process and guidance on its evolving approval process and planning clinical trials.

The first document explains the Center’s procedures for approving diagnostic and therapeutic devices -- how it weighs benefits and risks, judges the seriousness of a disease or condition, estimates how many people would use a device, and gauges availability of other devices for the same condition.

“Availability of other devices?”  Really?  Shouldn’t Shuren and Company stick to safety and efficacy?  Where’d this third leg come from?

Sounds like insidious mission creep of the comparative effectiveness variety.

The second document explains the agency's expectations for medical device clinical trials, and suggests companies pre-submit protocols for the design of pivotal studies. Both drafts are open to public comment for 90 days, beginning August 15.

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"Temporary" My Aunt Fanny

08/17/2011 08:22 AM |

The IRS has "released what it's calling “temporary regulations” under which brand-name drugmakers must pay fees "to help fund" health-reform law provisions.

This was, as you will recall, part of “the deal.”

The regulations request payments of $2.5 billion in 2011 and are due by September 30^th. Additionally, IRS calls for $2.8 billion in each of '”fee years” of 2012 and 2013; $3 billion for fee years 2014 through 2016; $4 billion for fee year 2017; $4.1 billion for fee year 2018; and $2.8 billion for fee year 2019 and thereafter.

So what’s “temporary?” And what about those who are pounding the podium about rebates for dual eligibles?

Just asking.

According to reporting in Congressional Quarterly, although pharmaceutical companies have to "pay fees," they will garner "far more sales as millions of the uninsured gain coverage."

The requirement applies to companies with annual drug sales of "$5 million or more" to Medicare "Parts B and D"; Medicaid; and Veterans Affairs, and Defense Department and TRICARE programs.

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The Dangers of Shorting Drug Shortages

08/16/2011 01:11 PM |

All of a sudden the Mainstream Media (highlighted by a much ballyhooed New York Times Week in Review op-ed by Zeke Emanuel) has discovered the problem of drug shortages.

 

Except it’s not a new problem.

 

According to a recent analysis, the frequency and impact of drug shortages have risen to critical levels, more than tripling since 2005, and affecting all segments of the healthcare community. In 2010, over 240 drugs were either in short supply or completely unavailable and more than 400 generic equivalents were backordered for greater than five days. In most instances, these did not progress to critical shortages, but point to instabilities in the supply chain that cause national concern. Many of the drugs identified in 2010 remain unavailable or in short supply in 2011.

 

Seventy-seven percent of drugs in short supply in 2010 were sterile injectable products, critical in the acute care setting. Recent media coverage highlights the plight of patients and physicians faced with shortages for cancer drugs, anesthetic agents, and critical care medications that have contributed to delays in treatment and surgery, or changes in care plans. Drug backorders cause patients to receive substitute therapies that add expense to patient care.

 

A major reason for shortages is quality/manufacturing issues. However there are other reasons such as production delays at the manufacturer and delays companies have experienced receiving raw materials and components from suppliers.  Discontinuations are another factor contributing to shortages.  (The FDA can't require a firm to keep making a drug it wants to discontinue.) 

 

It is time not to fix the blame – but to fix the problem.

 

Let’s start with the FDA.

 

In 2010, there were 178 drug shortages reported to the FDA. Is that a solid number?  Hard to say, because current regulations do not require companies to notify FDA of shortages. The only requirement is that companies inform FDA six months in advance for discontinuations of sole source, medically necessary drugs.  

(In 2010, for example there were 38 shortages prevented due to companies notifying FDA voluntarily of potential issues that could lead to shortages and FDA was able to work with the company to avoid a shortage.)

Inside the FDA’s Center Drug Evaluation and Research (CDER) resides the agency’s Drug Shortage Program (DSP). The DSP was established to address potential or actual shortages of drugs that have a significant impact on public health. Through communication, facilitation and negotiation, DSP works with pharmaceutical manufacturers, review divisions, compliance and other components of FDA to manage product shortages.

For example, when the drug shortage is for a generic product (as it often is), the FDA works with other firms making the drug to help them ramp up production if they are willing to do so. Often they need new production lines approved or need new raw material sources approved to help increase supplies. FDA can and does expedite review of these to help resolve shortages of medically necessary drugs. 

But the FDA can't require the other firms to increase (or commence) production.

The agency tries to do the best it can with limited authority, spare resources and shared staff. In addition to direct communication with industry, the DSP also gets reports from healthcare professionals, patients/individuals, or professional organizations using the e-mail address drugshortages@fda.hhs.gov.

But, as you can imagine, there is not a lot of e-mail traffic.  And there is no social media effort to promote either its purpose or existence.

It’s a good start – but it’s not enough.  And you know what they say about good intentions.

The FDA’s Drug Shortage Program is a good start.  But it’s not getting the job done. The problem is getting worse. The FDA needs both more authority and greater resources. In short, more needs to happen.

The Institute for Safe Medication Practices reports that, according to survey of 1800 healthcare practitioners, more than half of respondents frequently or always encounter difficulties associated with drug shortages.

The top three problems fall squarely within the zone of appropriate FDA attention and action:

* Little or no information available about the duration of a drug shortage (85%)

* Lack of advanced warning from manufacturers or FDA to alert practitioners to an impending drug shortage and suggested alternatives (84%)

* Little or no information about the cause of the drug shortage (83%)

Survey respondents felt “unsupported by the FDA and are perplexed regarding why the US is experiencing drug shortages of epic proportion that are often associated with third-world countries.”

(More detail on the ISMP survey can be found here.)

Should the issues of both authority and funding for the FDA’s efforts to mitigate drug shortages be hung on the PDUFA Christmas tree or addressed in separate legislation?  Whether it’s one or the other, it’s an issue that must be addressed with alacrity before it becomes a political question of "Who lost drug shortages?"

And before it becomes a question of American lives.
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The PDUFA Christmas Tree

08/15/2011 11:09 AM |

The EU Innovative Medicines Initiative (IMI), the world’s largest public-private partnership in health R&D, is calling for proposals across seven new health care areas.

 

The areas of focus are linking patients’ data to develop more targeted therapies; using knowledge management of experimental data for translation into drugs for patients; complications of obesity; predicting Alzheimer’s disease and other dementias; drug delivery by nanocarriers; sustainability of chemical drug production; investigating stem cells for drug discovery; and understanding the behavior of drugs in the human body.

 

The EU has agreed to contribute up to €105 million ($150 million) to this latest step in IMI's evolution, a figure that will be matched by "in kind" contributions – staff, access to databases and research activity and equipment – from the European Federation of Pharmaceutical Industries and Associations.

 

The new project phase comes weeks after IMI signed a Memorandum of Understanding with the U.S.-based Critical Path Institute, aimed at increasing collaboration between the two bodies. They have agreed to foster increased information sharing regarding each other’s programs and create a mechanism to exchange knowledge and develop scientific consensus regarding research and testing methods.

 

But, as our European cousins step up to advancing 21^st century medicine, wither our own domestic efforts?  What’s become of the Critical Path?  Where’s the Reagan/Udall Center?

 

Funding for the FDA’s Critical Path program and the Reagan/Udall Center is generally considered a “Christmas Tree” issue relative to PDUFA V. That’s a mistake.  Beyond the agency’s request to fund it’s Advancing Regulatory Science Initiative (ARSI), we are all talk and no action.

 

For many involved in the reauthorization process, one statement that keeps coming up is -- ”The FDA is broken.” But what does that mean? Rather than making blanket statements that cause friction and promote areas of disagreement, one thing everyone can agree to is that the FDA’s must be both ally and accelerator in the advancement of innovation.

 

And that must be within the confines of PDUFA V – and it cannot be accomplished without moving forward the FDA’s Critical Path program and funding the Reagan/Udall Center.

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The Cognitive Dissonance of Disinvestment

08/12/2011 09:39 PM |

Sander Flaum, the grand master of pharmaceutical marketing asks, “If you put the world’s top CEOs together in a room and asked them what challenges kept them up at night, what do you think you’d hear?”

The answer is shocking if not surprising/

According to the Conference Board’s CEO Challenge 2011 Survey – Fueling Business Growth with Innovation and Talent Development, most CEOs in the U.S. and Europe listed Business Growth as their top challenge.

According to Flaum there’s an even bigger concern. “Look down the list of the top challenges.  Where did these leaders consistently rank Innovation?  #3!  And guess what U.S. CEOs collectively viewed as an even more pressing challenge than the need for innovation– Government Regulation!” 

Flaum continues, “A CEO who is more worried about being handcuffed by regulations than coming up with the next big idea needs a priority readjustment. Sure, regulations can be a pain. But they can also be simply an excuse for failure. In Pharma, we’re always contending with the FDA in the struggle to bring innovations to market. And it’s not easy. But doesn’t the need for Innovation come first? If we don’t have something new and important to bring to market, then why complain about the regs?

Top 5 Global Challenges by Region

Rank	U.S.	Europe	Asia
1	Business Growth	Business Growth	Talent
2	Government Regulation	Cost Optimization	Business Growth
3	Innovation	Innovation	Innovation
4	Talent Cost Optimization  (tied)	Customer Relationships	Corporate/Brand Reputation
5		Government Regulation	Sustainability

Wither innovation? This crucial question becomes even more problematic when you consider the issue of “disinvestment” -- the processes of (partially or completely) withdrawing health resources from existing healthcare practices, procedures, technologies, or pharmaceuticals that are deemed to deliver little or no health gain for their cost, and thus do not represent efficient health resource allocation. “Disinvestment” is a more honest (and frightening) term for “comparative effectiveness.”

And leading the disinvestment charge (not surprisingly) is NICE.

Over the past 10 years NICE has identified over 800 clinical interventions for potential disinvestment. But, in the July 27^th edition of the British Medical Journal, Sarah Garner and Peter Littlejohns (both of NICE) report that although disinvestment will increase the opportunity for cash saving is unlikely to provide ways of controlling costs without cutting quality of care.

The authors write:

There is general agreement that stretched health services budgets should not be used to fund low value services. However international experience has shown that identifying and removing those services can be problematic and controversial.

Are you listening AHRQ?

Many suggestions for total disinvestment are based on a “social judgment” about whether it is appropriate for the NHS to fund the intervention rather than evidence of poor clinical or cost effectiveness. Others relate to “experimental” use of technologies outside their indications and evidence base.

Are you listening Dr. Berwick?

Opponents of a total disinvestment approach highlight the methodological flaws of using average estimates of effect drawn from populations; they argue that an intervention may be beneficial for an individual patient and should be an option, even if a last resort. An alternative strategy is optimal targeting: identifying subgroups in which an intervention is most clinically and cost effective.

Are you listening Dr. Pazdur?

Disinvestment is part of a broader agenda to improve efficiency and quality focusing on public health and prevention and ensuring that patients receive the right care at the right time in the right way.

Are you listening PCORI?

Although this approach releases resources in the long term, it may entail investment in the short term. It is very important to make the distinction between improving the efficiency of care and saving money.

Aha!

Without data, it is also difficult to identify the subgroups necessary to fully understand variation in care and therefore determine realistic potential savings.

Did somebody say “personalized medicine?” Did somebody say, “more and more targeted molecular diagnostics?”

The author’s conclude, “However, current evidence suggests that disinvestment is unlikely to achieve the huge savings required to meet tightened NHS budgets.”

We would be wise to learn from honesty of our transatlantic cousins.

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