Latest Drugwonks' Blog
Subsequent to the July adcomm on Avandia, the FDA asked GSK to send a letter to doctors detailing what took place.
The first question is … why didn’t the FDA do this itself? It was, after all, an FDA event. Was a written synopsis, perhaps, too hot to handle for the folks at White Oak?
To nobody’s surprise, a certain agency employee is unhappy with GSK’s letter.
“This summary is biased, misleading and not truthful,” Dr. Graham told the New York Times. “The whole purpose of this letter is so that they can reassess whether this is an ethical trial going forward, but the step-by-step ethical flaws and problems with the Tide trial are not even referenced.”
Some panel members agree with Dr. Graham. Panel member Dr. Curt D. Furberg, described the letter as “very Avandia friendly. Panel member Dr. Sanjay Kaul, disagreed, saying the letter “faithfully reflects the deliberations of the Avandia advisory meeting.”
Erica Jefferson, an F.D.A. spokeswoman, said that after ordering GlaxoSmithKline to send a summary of the hearing to the Tide trial investigators, the agency had relied on the company to provide a balanced account. “F.D.A. did not pre-clear or approve the content,” she said.
Mary Anne Rhyne, a GlaxoSmithKline spokeswoman, said the company had only one week to write the 10-page summary, which was necessarily brief. But the company and the leader of the Tide trial agreed that the letter “reflected the science and data discussed at the advisory committee meeting,” Ms. Rhyne said.
Avandia? Controversy? Who could have guessed?
Why didn’t the FDA write this letter?
"Please give me some good advice in your next letter. I promise not to follow it."
-- Edna St. Vincent Millay
If we learn nothing else from BP’s recent unpleasantness, it’s that being able to identify an obvious problem (like when oil is gushing uncontrolled into the Gulf of Mexico) is one thing. Identifying that there is a potential problem is tougher. And toughest of all is designing a solution that addresses a need early in the curve.
Case in point, Alzheimer’s Disease. As Gina Kolata writes in today’s New York Times, “The failure of a promising Alzheimer’s drug in clinical trials highlights the gap between diagnosis — where real progress has recently been made — and treatment of the disease.”
Alzheimer’s Disease is a healthcare oil spill of draconian proportion.
Recent significant steps forward in early diagnosis of the disease are important. And frustrating -- because there is still precious little that can be done when this devastating condition is identified either late in the game or in its nascent stages.
To say that the science is “hard” (while true) is not particularly helpful. What needs to be addressed are the twin issues of drug development and regulatory science. Both are lagging. Biomarkers notwithstanding, more needs to be done. We need better tools. Too many programs (almost 50%) are failing in late Phase III. Too many programs are mired in regulatory treacle. The economics are unsustainable from a corporate R&D standpoint and the impact of Alzheimer’s Disease on patients, their families and American healthcare economics is devastating.
Better, more current and predictable scientific research and standards must be developed and devoted to streamlining the critical path. Investment in basic research is not enough. Specifically new development tools are needed to improve the predictability of the drug development cycle and to lower the cost of research by helping industry identify product failures earlier in the clinical trials process.
25 years ago, the success rate for a new drug used was about 14%. Today, a new medicinal compound entering Phase 1 testing—often after more than a decade of preclinical screening and evaluation—is estimated to have only an 8% chance of reaching the market. For very innovative and unproven technologies, the probability of an individual product’s success is even lower. We have got to work together to turn that around.
When Thomas Edison was asked why he was so successful he responded, “Because I fail so much faster than everyone else.” Consider the implications if FDA could help companies to fail faster. Using the lower end of the Tufts drug development number ($802 million):
* A 10% improvement in predicting failure before clinical trials could save $100 million in development costs.
* Shifting 5% of clinical failures from Phase 3 to Phase 1 reduces out of pocket costs by $15-$20 million.
* Shifting of failures from Phase 2 to Phase 1 would reduce out of pocket costs by $12-$21 million.
Investment in basic research is not enough. Specifically new development tools are needed to improve the predictability of the drug development cycle.
For all that modern science has to offer, developing new treatments is still very much an art—in which hunches, intuition, and luck play a critical role. The odds are long. For medicine that is affordable and innovative, we need more well-understood science and we need regulatory predictability. And that’s precisely the mission of the FDA’s still moribund Reagan-Udall Foundation.
To quote the late Senator Ted Kennedy, the Reagan-Udall Foundation “will make new research tools and techniques available to the entire research community, shortening the time it takes to develop new drugs and reducing costs for patients.”
Shortly before his death, I had the privilege of a private meeting with Nobel Laureate Joshua Lederberg. The topic of conversation was the future of the FDA and the agency’s Critical Path initiative. We talked about the state of applied research and “the texture” of the agency, the prioritization of development science, biomarkers and a host of other future-oriented issues. He talked. I took a lot of notes. At the end of the meeting he put everything into perspective in a single
I hope so and so should we all. Innovation = Hope.
The Florida Medical Association decided Sunday after two days of heated debate not to break off relations with the American Medical Association, officials and delegates said at the conclusion of the event.
Instead, FMA will send AMA a letter describing just how unhappy it is with the national group’s actions on health reform.
In a formal written statement, Executive Vice President Timothy J. Stapleton said that the FMA letter will convey a vote of “no confidence.” “The FMA House of Delegates strongly believes that the American Medical Association has failed to represent practicing physicians on the issue of health care reform.”
One of the delegates, Tampa surgeon Michael Wasylik, said, "Doctors are really, really, really upset with the AMA. Doctors are so angey they can't see straight.
And not seeing straight is a bad place for a surgeon to be.
marketplace.publicradio.org/display/web/2010/08/16/am-fda-may-revoke-breast-cancer-drug-q/
German authorities have filed charges against pharmacies in the north of the country that have been suspected of purchasing cheap and illegal active ingredients, which they have used to manufacture in-house cancer treatment preparations and then sold them to the general public.
Frank Keller, chief investigator of the Technician's Health Insurance Fund (TKK), as saying that the fund had been tipped off that a Danish wholesaler had been supplying German pharmacies with an unauthorized active ingredient for the preparation of an infusion used in cancer treatment. Some 100 of the 400 pharmacies authorized to manufacture the preparation in-house are suspected of having purchased the cheap, illegal product from the wholesaler.
Separately, Alexander Retemeyer from the Office of Public Prosecution in Osnabruck, revealed that he had tracked a local wholesaler, which had sourced illegal products from Eastern Europe and then sold them to pharmacies.
In the latest revision to the Pharmaceutical Act, the German government has put in place measures to sanction those who introduce counterfeits into the health system. The European Union is also concerned about the increase of falsified medicines emerging in the Member States. Figures from the Directorate General for Taxation and Customs show that counterfeit medicines accounted for 10 percent of goods seized upon entering the EU. Almost 75 percent of these were shipped from the United Arab Emirates.
In April, the European Parliament's Environment Committee approved the European Commission's proposal for fighting counterfeit medicines. The committee added a stipulation to the draft, which insists that in addition to preventing counterfeits from entering the legal supply chain and introducing mandatory safety features for prescription medicines, the legislation should prohibit internet sales of “detrimental products.” The EU Parliament will vote on the draft proposal in October.
Per the FDA’s approval of the 5-day emergency contraceptive ella, some perspective. When the FDA reviewed (and reviewed and reviewed) moving the Plan B “morning after” pill OTC in 2003 it was reported as “political interference.” Well it wasn’t true then and it isn’t true now with the approval of a new improved (safe and effective) Rx alternative. The FDA reviews the science and makes it’s decision. The agency is often imperfect and sometimes contentious. But it never lacks for passion or intellectual honesty.
Read more here.
Why, you ask, is it important to pursue the advance of 21st century regulatory science?
Rare Sharing of Data Leads to Progress on Alzheimer’s Disease
By
GINA KOLATA
In 2003, a group of scientists and executives from the
National Institutes of Health, the Food and Drug Administration, the drug and medical-imaging industries, universities and nonprofit groups joined in a project that experts say had no precedent: a collaborative effort to find the biological markers that show the progression of Alzheimer’s disease in the human brain.
The complete New York Times story can be found
Fund Reagan/Udall now!
"While physicians and the life science industry have done little to advance the use of testing for drug-gene interactions, now the pharmacy benefit managers (PBMs) Medco and CVS/Caremark, which collectively administer the employer prescription plans for nearly 100 million Americans, are stepping up. They are introducing wide-scale genotyping for certain drugs, like Plavix or Tamoxifen, and many anti-cancer medications.
- Scripps Health
Why are the PBMs leading the charge? On one hand, the hope is for more efficient use of prescription drugs to get the right drug, right dose and right individual in alignment. But also, since PBMs compete, they want to have an edge beyond simply mailing prescriptions to the large population of constituents they serve. It has caught the medical community by surprise, but may be just the thing that is needed to bring the marked progress in genomics forward for patients."
Understatement of the year.
In his Science article Topol describes as clinical inertia and academic squabbling over methodology continues, PBMs are setting up the infrastructure for the routine use of genetic testing:
There is a simple way to confirm and quantify the extent of platelet response to clopidogrel, using a variety of point-of-care platelet function tests, each of which has been clinically validated to predict long-term prognosis. Furthermore, the information is highly practical, because patients who do not respond to the antiplatelet drug can have their platelet suppression achieved by using higher doses of clopidogrel or prasugrel (Effient) or by using alternative antiplatelet agents that are expected to be approved in the months ahead. Still, the medical community takes no initiative in routinely genotyping patients who are taking clopidogrel. In March 2010, the U.S. Food and Drug Administration (FDA) put a “black box” warning on clopidogrel that addresses the issue of risk in “poor metabolizers,” as defined by genotyping (8). However, months after this action was taken, it remains exceptionally rare for a patient receiving clopidogrel to undergo genotyping. The lesson here is clear: The medical community is unwilling to change clinical practice and wants more evidence, even in the wake of a significant regulatory body warning.
This reluctance on the part of clinicians has left the door wide open for PBMs. These companies can pitch to their clients—large employers—that they are benefiting their employees by avoiding the use of a drug that won’t work or isn’t being administered at an effective dose. For the exceptionally common clopidogrel medication, which costs $4 to $5 per day, the rationale for more precise use and the avoidance of major adverse outcomes seems attractive. In the next year or two, this medication will become generic, so that routine determination of genotype and, if necessary, platelet responsiveness could provide marked cost savings by avoiding the use of a proprietary drug when unnecessary.As Eric notes, commercialization carries pluses and minuses, the balance of which could have been enhanced in favor of patients if doctors and researchers had not been engaged in nit-picking and grant seeking.
"Promoting the right drug, the right dose, and the right cost for patients may well improve the competitiveness of PBMs.
But the potential benefits for PBMs go far beyond this pitch. Under the pretext of personalized medicine, these companies potentially may charge patients or insurance companies for genotyping services—for which the market has doubled over the past 5 years —while at the same time also profiting from the drugs prescribed and sold. This may represent a conflict of interest or at least the potential perception of double- or triple-dipping. It will be important for PBMs that pursue such initiatives to be transparent about their genotyping strategies and drug recommendations."
Still, as Topol notes, it is the PBMs and large health plans -- and the DTC firms in their own haphazard way -- making personalized medicine mainstream. And the long term benefit or externality may be what Ralph Snyderman has envisioned: the regular use of pharmacogenomic data from the sequencing of our own genome to promote prospective and personalized medicine for specific illnesses. Unfortunately it seems that clinicians, regulators (now most particularly the comparative effectiveness crowd) and academia (that see their grant receiving status threatened in some strange way by clinical adoption of gene testing) are way behind the curve and out of sync with patients, payors and entrepreneurs. As Topol notes:
"The lack of alignment will probably be further exacerbated in the next phase of genomic medicine, in which whole-genome sequencing becomes commonplace. The first clinically annotated sequence, albeit requiring a team of 30 investigators and 600 person-hours, demonstrated 63 pharmacogenomic variants of clinical relevance . As more information becomes available from genome-wide association studies that provide actionable data, such as recently reported regarding interferon therapy for hepatitis C , the era for routine pharmacogenomics may finally shift into high gear. In the end, we may ultimately view the surprise movement by PBMs and drugstores as having helped catapult genomic medicine forward. "
Read the full article here.
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
