Latest Drugwonks' Blog
“Generic” does not equal “identical.” That’s why the FDA wants to tighten certain bioequivalence standards.
Generic-drug makers will have to meet tighter standards to prove that “critical dose drugs” such as blood- thinners and anti-seizure treatments, work as well brand-name products. And it’s about time.
The FDA, responding to complaints that some copies don’t work as well as the originals, is writing guidelines for limits companies must follow that include how fast active ingredients are absorbed in the bloodstream.
Critical dose drugs have a narrow therapeutic index, meaning that small changes in blood concentration have the potential to result in serious therapeutic failures and/or serious adverse drug reactions.
The FDA is outlining its plans to companies after patients and employees of generic-drug makers complained to regulators that some of the medicines don’t work as well as the originals.
And, according to Lawrence Yu, deputy director for science and chemistry in the agency’s Office of Generic Drugs, “Ideally, they should start using them now.”
Currently, the "sameness" of a brand product and a generic version is evaluated based on two-treatment crossover study to prove bioequivalence, the aim being to show that the 90 percent confidence intervals of the geometric mean test/reference ratios for both maximum plasma concentration and the area under the plasma concentration-time curve fall within a range of 80 percent to 125 percent. The agency is now requiring a rate between 90 percent and 111 percent for narrow therapeutic index drugs.
A generic drug’s potency will also have to fall within 95 percent and 105 percent of the original. Currently, drugs can fall within a range of 90 percent to 110 percent.
The FDA plans to release guidelines on the stricter standards, Yu said, declining to say when. Well, the sooner the better -- because a confused public wants to know.
A Consumer Reports poll of 1,226 adults in June showed 39 percent of respondents had concerns or misconceptions about generics while 21 percent thought the copies weren’t as effective as brand-name products. Twenty-one percent didn’t trust generics as much as brand-name drugs and 14 percent said they didn’t think the products were as safe.
Pharmacists “hope that FDA tightening the standards does in fact help alleviate some consumer skepticism about generics,” said Chrissy Kopple, a spokeswoman for the National Association of Chain Drug Stores.
Rx-to-OTC switch questions that FDA asked advisory committees over the past 10 years can help guide future sponsors to success, says the lead researcher in an analysis of the agency's switch actions.
The journal SelfCare has published "an essential blueprint for designing and implementing any Rx-to-OTC drug development program," says lead author Bill Soller, professor and executive director of the Center for Consumer Self Care at the University of California, San Francisco, School of Pharmacy. Well, maybe not essential -- but certainly intriguing.
Soller and his colleagues list questions - "OTC Considerations" - based on switch principles FDA set in 1990 and 1998 and questions to post-2002 advisory committees that evaluated first-in-class switches.
The analysis recommends 11 primary questions about the Rx fundamentals of a drug, its "OTCness" and overall risk vs. benefit.
1- Has the Rx product been on the market for a sufficient time and extent to enable full characterization of the drug's safety profile?
2- Can the condition be adequately self-diagnosed or is there a need for physician diagnosis?
3-vIs the minimally effective dose known?
4- Are there efficacy studies needed to support the intended OTC use of the switch candidate?
5- What are the patterns of diagnosing, prescribing and patient use in the Rx setting related to OTC intended use?
6- Are the studies supporting OTCness generalizable to the intended OTC target population?
7-Do consumers understand key communication objectives of the label, relating to directions for use, contraindications, in-use warnings and precautions?
8- Do consumers show they would be likely to be able to assess and take action on the treatment effect (e.g., take appropriate action if the drug is not working, serious side effects emerge, or self-monitoring is needed)?
9- Do consumers demonstrate successful self-selection and de-selection of the product under conditions (or simulated conditions) of actual use?
10- Does the pattern of actual use support that the label can be successfully used in practice?
11- Do the benefits of OTC availability outweigh the risks?
The list reflects materials FDA provided advisory committees and presented at meetings on first-in-class switches from 1992 to 2011. The latest was in 2007.
The authors say FDA "uses its discretion to select areas of concentration for advisory committee discussions on switch." Factors influencing the agency's questions for advisory committees include the novelty and uniqueness of a proposed OTC indication or Rx active ingredient; intrinsic and extrinsic toxicity of a switch candidate; and robustness of published and NDA-derived data and worldwide post-marketing surveillance evaluations, according to the article.
The analysis in SelfCare comes a month after FDA published a draft guidance on designing self-selection studies in support of OTC switches. The draft states FDA's interest in greater insight into consumers' thought processes and says study sponsors should follow up with medical history questions and additional open-ended queries.
What about the potential of Behind-the-Counter (BTC) arrangements? Well, according to Eric Brass, a physician, director of Harbor-UCLA Center for Clinical Pharmacology and a professor at David Geffen School of Medicine at UCLA, "The statement that a company will voluntarily impose such a restriction cannot influence the regulatory decision, as the second company to market could not be held to the same restriction.” Good point. And, further, “If pharmacist assessment is required for safe and effective use by the consumer, I think that the drug would not be appropriate for OTC status today." Brass added that no public health benefit from expanding consumers' access to medicines through pharmacists has been established.
Maybe it’s time for the pharmacy community to step up to the plate and commence that conversation.
Bloomberg reports that Eli Lilly & Co., which has spent $135 million since 2003 training seven generic drugmakers to make treatments against drug-resistant tuberculosis, plans to spend $30 million over the next five years helping patients to get access to the pills.
Lilly plans to work on improving availability of treatment for people in China, India, Russia and South Africa, and to train health-care workers from 2012 until 2016.
There were about 9.4 million cases of tuberculosis globally in 2009, according to the World Health Organization. Of those, almost 4 percent were a form of the disease that isn’t cleared by the two frontline drugs used against it, requiring treatment with costlier medicines. Lilly’s funds will help make second-line medicines available to those who need it, Chief Executive Officer John Lechleiter said. He traveled to western China in March to observe the Lilly Foundation’s work.
“The impression that that left me with is the scarcity of resources available to health-care providers,” Lechleiter said. “By that I mean simple things like posters and brochures that would make people aware of the disease, how to prevent it, how to seek treatment.”
That’s a consistent message. On September 16th, at the Washington Post’s “Sharing the Responsibility” event on non-communicable diseases, Lechleiter commented, “There is no substitute for the power of partnership.”
Amen.
With the Food and Drug Administration Amendments Act (FDAAA) of 2007 barely in the rear view mirror and the Prescription Drug User Fee Act V reauthorization rapidly approaching, drug safety, risk evaluation and mitigation strategy (REMS), and pharmacovigilance in the United States are about to undergo significant changes.
Meanwhile, the United Kingdom is forging ahead with its most significant pharmacovigilance legislation since 1995, with serious implications for applicants and holders of European Union marketing authorizations.
What will these changes mean for the pharma industry worldwide?
Please join the Center for Medicine in the Public Interest (www.cmpi.org) and FDA News for the 4th Annual Risk Management and Drug Safety Summit: Building an Effective Global Risk Management and Drug Safety Program, scheduled for Nov. 1–2, 2011, in Washington D.C.
Keynote speakers:
• Peter Pitts, co-founder, president, Center for Medicine in the Public Interest (chair)
• Edward Fotsch, M.D., CEO, PDR Network LLC (chair)
• John Lechleiter, Ph.D., CEO, Eli Lilly & Co.
• Janet Woodcock, M.D., director, Center for Drug Evaluation and Research (CDER), FDA
• Sir Alasdair Breckenridge, chairman, Medicines & Healthcare Products Regulatory Agency, UK
• Ravi Deshpande, vice president, McKesson Specialty
• John Jenkins, M.D., director, Office of New Drugs, CDER, FDA (invited)
• Ankur Makadia, PharmD, risk management plan leader, Global Clinical Safety & Pharmacovigilance, UCB
• Jane Axelrad, associate director for policy, CDER, FDA (invited)
• Deborah Autor, deputy commissioner, Globalization & Regulatory Operations, OC, FDA
• Josephine Torrente, director, Hyman, Phelps & McNamara (invited)
• Vaishali Patadia, Ph.D., director, head, Pharmacoepidemiology, Astellas Pharma (invited)
• Timothy Franson, M.D., senior vice president, health and life sciences sector, B&D Consulting; president, U.S. Pharmacopeia Board of Trustee; former vice president, global regulatory affairs, Eli Lilly & Co. research laboratories
Click here to see the full agenda.
But setting aside the dislocations deep recessions, burst bubbles and depressions cause in household income (the right metric for measuring disparity in my opinion) is the gap between rich and poor – in America and elsewhere – has been declining over the past two centuries, not increasing. By any measure, the Gini ratio in particular, the gap between rich and poor declined from 1967 to 2010. And the cause for this change in which everyone’s incomes rise is mainly medical innovation that allows billions of people to live longer and healthier lives. Nobel Prize winning economist Robert Fogel comments on the effect of what he calls the “technophysical evolution” of the human race on inequality:
“In every measure that we have bearing on the standard of living, such as real
income, homelessness, life expectancy, and height, the gains of the lower classes have been far greater than those experienced by the population as a whole, whose overall standard of living has also improved. If anything sets the twentieth century apart from the past, it is this huge increase in the longevity of the lower classes.
The fact is that government transfers were incapable of solving the problems of beggary and homelessness during the eighteenth and much of the nineteenth centuries, because the root cause of the problems was chronic malnutrition.
Even during the most generous phases of the relief program, the bottom fifth of the English population was so severely malnourished that it lacked the energy for adequate levels of work (It was the huge increases in English productivity during the later part of the nineteenth and the early twentieth centuries that made it possible to feed even the poor at relatively high caloric levels. Begging and homelessness were reduced to exceedingly low levels, by nineteenth century standards, only when the bottom fifth of the population acquired enough calories to permit regular work. The principal way in which government policy contributed to that achievement was through its public health programs. By reducing exposure to disease,more of the calories that the poor ingested were made available for work.”
http://www.ekh.lu.se/seminar/presentation/Fogel.pdf
In our time, longer life and the increased participation of women in the workforce have contributed an increase in income and wealth among married households who are 45 and older. By contrast, households headed up by a single women are likely to be poorer and experience slower growth in income.
Income inequality is a function of education and life expectancy. The healthier people are the more they are likely to think about the long term and as a result, more likely to invest time and money in education and health care. Much of the inequality in income – over the decades -- is still due to barriers to regular work. Education can remove many of those obstacles, but reducing exposure to mental and physical diseases will be required to achieve greater growth and productivity. Thus the key to reduce disparities and promoting prosperity is consumption of new medical products.
http://www.census.gov/compendia/statab/cats/income_expenditures_poverty_wealth.html
My guiding principle is this: Guilt is never to be doubted. – Franz Kafka
Will Par Pharmaceutical Inc.’s First Amendment suit against FDA result in a new approach to battling government allegations of off-label marketing?
Par contends that the government is criminalizing it’s speech to healthcare professionals about the on-label use of its appetite suppressant Megace ES (megestrol acetate) in settings where doctors prescribe the drug for both approved and unapproved uses.
Par’s complaint, filed Oct. 14 in the U.S. District Court for the District of Columbia, seeks a preliminary injunction against government enforcement of FDA labeling regulations on the grounds they are harming Par’s First Amendment rights by chilling protected speech.
Par’s suit states that physicians more frequently prescribe the drug to treat wasting in non-AIDS geriatric and cancer patients and that the majority of prescriptions for the drug are for off-label uses.
Par also seeks a declaratory judgment that it may speak about the approved use to physicians who could prescribe it for that use, even if they are more likely to prescribe the drug for off-label uses.
“Common sense dictates that the government cannot justify censoring a broad swath of truthful and valuable speech regarding lawful activity out of a desire to prevent other lawful activity,” a memorandum in support of the motion for preliminary injunction states. “And it is absurd to think that the government may imprison a person for engaging in truthful speech about a lawful activity that the government itself subsidizes.”
At issue in Par’s suit are provisions in the Food, Drug, and Cosmetic Act concerning “intended use” of a drug and misbranding.
“If a manufacturer speaks about the on-label use of its drug in a setting where the manufacturer knows that physicians prescribe the drug off-label, the government interprets the FDA’s ‘intended use’ regulations to deem the manufacture to be expressing an ‘objective intent’ that physicians prescribe the drug off-label,” Par’s memorandum states.
Par says the government has advised the company that manufacturers should only talk to physicians in an off-label setting if there are “a sufficient number of patients being treated for whom the drug could be prescribed on-label,” but that the government has not provided any guidance as to what would constitute a sufficient number of on-label patients.
“The regime is also Kafkaesque. Manufacturers have no way of knowing whether, under the FDA’s regulations, they may speak to physicians who, for instance, prescribe the drug 20% on-label and 80% off-label, or to physicians with the reverse prescription ratio.”
In a press release announcing the suit Par said it hoped to “elicit tailored and constitutionally permissible regulatory guidance to ensure that physicians may be kept abreast of valuable, on-label information about prescription drugs to aid in their provision of quality and informed patient care.”
Atlas was permitted the opinion that he was at liberty, if he wished, to drop the Earth and creep away; but this opinion was all that he was permitted. – Franz Kafka
BioCentury reports:
FDA is seeking to clarify language in Orphan drug regulations and propose areas of minor improvement, according to a proposed rule issued Wednesday. The changes are intended to eliminate sponsors' confusion, which is evident in that 124 (38%) of 324 requests for Orphan drug designation in 2010 were denied or stayed so that the sponsor could submit additional material to respond to deficiencies.
The rule clarifies that a compound under development for a subset of a non-rare disease will not be considered for Orphan designation unless the company demonstrates that the compound would not be appropriate for use in the broader population of patients with the non-rare disease. The agency said 24% (79) of requests for Orphan drug designation in 2010 were denied or stayed because they did not identify a medically plausible subset of a non-rare disease.
The rule also clarifies that a compound could receive multiple Orphan drug exclusivities for multiple subsets of the same underlying Orphan disease, and that a drug approved for any indication could still receive Orphan drug designation for an unapproved use. The rule proposes that FDA may consider a designation request to be voluntarily withdrawn if the sponsor does not respond to a deficiency letter within one year, but the agency anticipates granting extension requests for sponsors who need to develop data supporting a designation request for a subset of a non-rare disease. Comments on the proposed rule are due by Jan. 17, 2012
Trade and health: a new agenda for the WTO
Featuring a discussion with Fredrik Erixon,
Director of the European Centre for Political Economy
Thursday 8th December, 12:45-2:00pm,
Hotel Intercontinental, Geneva
RSVP - philip@cgwg.co.uk
Globally, healthcare systems are facing financial huge pressures as a result of ageing populations and increases in the costs of new technologies. Some of this pressure could be relieved if countries opened up their healthcare systems to cross border trade and exchange. But in most countries healthcare remains a closed market, accessible only to local companies.
The Center for Medicine in the Public Interest (www.cmpi.org) is pleased to host a high-level policy round table featuring Fredrick Erixon, economist, international trade expert, and director of the European Centre for International Political Economy, who will put forward the case for special WTO trade deal for healthcare services, medical technology and pharmaceuticals.
It was an honor to be on a panel of " doers" -- people who are actually working on making health care more personalized and convenient -- and to be able to listen again to those who raise the capital and create the conditions necessary to commercialize new treatments.
I spoke mainly about the negative impact comparative effectiveness research is having on innovation, life expectancy and economic growth. I emphasized the value of medical progress to our nation in the centuries ahead. Ironically, the demand for leisure time and longer life that medical innovation generates and more efficient production of food, housing and energy allows has reduced the number of workers per retirees worldwide. Even china ( especially china, because of its birth control policy) is likely to ' run out' of workers in manufacturing to pay for government health and pension programs. As I noted, health care will be the leading industry of the 21st century meaning it will be the source of economic growth just as energy and manufacturing was in the 20th. But if the united states does not do it, no one really will. Russia is too corrupt, China is too strategic and commited to rationing, Singapore too small, India too parochial, Europe too wedded to welfare statism and unable to resist the rise of Islam.
There are many things that Americans can do to accelerate commercialization. However, most of them are opposed by a culture and a politics hostile to that enterprise at every important step. This oppositon is bi-partisan and reflects the belief that technology is used to pollute, displace and disrupt traditional relationships and nature purely for profit. The number of organizations that promote the view that commercialization deepens disparities and enriches corporations at the expense of the public's health, wealth and safety has steadily increased, as have the number of law firms that sue on the same basis. There have been a proliferation of laws, rules and regulations that add time and cost to the process of innovation to erode the inequalities commercialization creates.
If we organize medicine in America to suppress health care spending, innovation and demand for innovation it will harm our civilization for generations to come and leave us weaker than we already to defend democracy. This may sound overwrought, but it's only because I am being brief. What if America had not invested in the military might or the medicines Europe and the developing world relied on the past half century? Would another nation done so if it were able? ( Britain perhaps. Or Israel) But it is largely because of American leadership in both spheres democracy has spread and inequality has declined.
What I took away from the Aspen conference and why it is so valuable was the importance of something Milton Friedman said: “I do not believe that the solution to our problem is simply to elect the right people. The important thing is to establish a political climate of opinion which will make it politically profitable for the wrong people to do the right thing. Unless it is politically profitable for the wrong people to do the right thing, the right people will not do the right thing either, or if they try, they will shortly be out of office." The conference was a step towards establishing the sort of climate change Friedman thought necessary.
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.
