Latest Drugwonks' Blog
The Pink Sheet reports that “An international group of regulators and drug companies have agreed in principle to a framework that sets out eight steps for assessing a drug’s benefits and risks and could set the stage for a global approach to evaluating drugs.”
The framework will not result in uniform decisions across countries, but rather will provide a structure for the benefit-risk assessment process as a number of efforts are underway to make the exercise more methodical and to develop systematic ways for regulators and sponsors to present, communicate and discuss drug data.
Methodologies to reach decisions may vary, but “if everybody follows those same basic eight steps, … any new method that you come up with to develop or to assess benefit-risk should be internationally acceptable because they follow these general eight-step principles,” Lawrence Liberti, executive director of the Centre for Innovation in Regulatory Science, explained in an interview.
The Eight-Step Benefit-Risk Assessment Framework can be found here.
A task force of representatives from eight regulatory agencies and six international pharmaceutical companies, organized by CIRS through its Unified Methodologies for Benefit-Risk Assessment initiative, endorsed the framework following a June 21-22 workshop held in Washington, D.C., to discuss global harmonization of the benefit-risk assessment process. FDA Senior Advisor Murray Lumpkin and GlaxoSmithKline Inc. Senior VP-Global Clinical Safety and Pharmacovigilance Frank Rockhold co-chaired the workshop of regulators, academics and industry representatives.
The CIRS-mediated effort is separate from the International Conference on Harmonization, a long-standing initiative to coordinate regulatory standards between the U.S., Europe and Japan. FDA recently put ICH periodic benefit-risk evaluation standards into draft guidance for post-market safety reporting
While the eight steps coming out of the CIRS effort create structure, the methodology for benefit-risk decision-making will not be uniform soon, if ever. A common lexicon should be developed, according to a synopsis of the meeting, which was not open to the public. But agencies vary in their weighting of benefit-risk parameters and there are regional differences in regulatory and cultural viewpoints, making uniformity difficult.
With general agreement on the framework, stakeholders now can focus their attention on developing those methodologies. “Time should be allowed for pragmatic methodological approaches to be developed, including adequate timing for feedback on best practices to emerge,” the synopsis says.
Four agencies that make up the Consortium on Benefit-Risk Assessment – Swissmedic, Health Canada, Singapore’s Health Sciences Authority and Australia’s Therapeutic Goods Administration – pilot-tested the methodology using information from applications for a drug they previously approved.
The BRAT process was pilot-tested by 13 companies during various stages of drug development. A case study of its application to evaluate Johnson & Johnson/Bayer HealthCare AG’s rivaroxaban found that such methodology can add rigor and transparency to decision-making and is easily used in regulatory settings, such as advisory committee meetings, according to the workshop synopsis.
FDA is field testing its benefit-risk framework with six products. With the FDA approach, reviewers list evidence/uncertainties and conclusions/reasons for five decision factors in a grid format and then analyze the implications. The factors are severity of condition, unmet medical need, clinical benefit, risk and risk management.
(FDA committed to a structured benefit-risk assessment framework for the drug review process as part of PFUFA V.)
Among FDA initiatives in this area is a basic roadmap to be used by patient groups interested in development of patient-reported outcome measures in a specific disease area.
The European Medicines Agency has a benefit-risk assessment methodology that it considers a simple qualitative tool. PrOACT-URL identifies the problem, determines the objective, considers the alternatives and their consequences (presented in tabular form) and makes tradeoffs through swing-weighting of the events. Sensitivity analysis determines the level of uncertainty.
On the developer’s side of the table, Diana Hughes, a vice president in Pfizer Inc.’s primary care business unit, suggested industry form a consortium with the mission of gaining a perspective on unmet medical need and patient experience. Companies should continue collaborating with advocacy groups and develop patient educational programs to elicit information on the most relevant aspects of a disease and advance a common approach to valuing and weighting benefit and risk, she said.
Workshop participants concluded that rules of engagement must be set to avoid any misperceptions of conflict-of-interest during interactions with patients, and that such interactions are consistent, scheduled and balanced. Patients would benefit from education on the inherent nature of uncertainty in benefit-risk decisions, according to the workshop.
If you’re among the 21% of American adults who have tattoos, you might be surprised to learn that there’s no law or regulation that requires tattoo inks to be sterile. The FDA, which has oversight over the inks, treats them like cosmetics and says only that ink manufacturers must use ingredients that have received pre-market approval.
How about healthcare evolution through personal responsibility?
Increased adherence to non-insulin hypoglycemic drugs in diabetes patients can reduce hospitalizations or emergency room visits by nearly 13%, according to a large observational study conducted by researchers at Harvard and Express Scripts and published in the August issue of Health Affairs.
The researchers estimate that improved adherence to diabetes drugs could save nearly $5 billion annually across the U.S. health care system.
The study analyzes medical and pharmacy claims from 2006 through 2008 for approximately 136,000 patients with diabetes who were continuously enrolled in a private health plan or covered through a self-insured employer during that time.
In 2006, approximately 40% of patients in the study were non-adherent to their diabetes medication. Of that group, 32% (or 17,279) became adherent in 2007. After adjusting for underlying differences in co-morbidities and socioeconomic factors, the researchers found that “increased adherence was associated with nearly 13% lower odds of being hospitalized or visiting an emergency room.”
Conversely, “losing adherence was associated with nearly 15% higher odds of being hospitalized or having an emergency department visit in the following year.” In addition, “we found that those who remained adherent had the lowest rates of hospitalizations or emergency department visits” across all groups, at 27%.
Using census data, the authors found that “for patients from zip codes with high percentages of minority populations and for those from poor areas, the benefits of increased adherence were more substantial than they were for patients with zip codes with smaller minority populations or higher average incomes.”
The researchers extrapolated their findings to national medical data to estimate the potential financial benefits of improved adherence. They project that approximately 700,000 emergency room visits and 341,000 hospitalizations could be averted annually if all non-adherent patients with diabetes became adherent.
Quantifying the dollar savings that could result, the researchers estimated that the U.S. could save $3.95 billion in hospitalizations and $735 million in emergency room visits each year, for a total savings of $4.68 billion annually across the health care system.
In addition, 1.6 million Medicare patients lose their adherence in any given year, the researchers reported. And “preventing those losses of adherence would yield an additional $1.71 billion in savings per year to the Medicare program, leading to a potential total benefit of $3.93 billion to Medicare alone.”
The article mentions that such drugs can command a high price. In point of fact -- and this is something worth studying -- most companies that have developed new orphan or targeted therapies underwrite the cost for patients or substantially discount the price. I don't think this is sustainable because eventually all new medicines will be targeted and likely to be taken orally rather than injected. The most interesting piece of information in the study is the observation that orphan drugs are more likely to be approved more quickly, have a higher degree of success in getting FDA approval and are more likely to be adopted more quickly. The reduction in risk and uncertainty is likely to be more valuable to companies than launch price. Moreover, the shift to oral therapies is probably associated with increased compliance and increased survival.
You ask Amicus CEO John Crowley about why his firm is determined to turn infusions for Pompe's, Fabry's and Gaucher's diseases into pills and he will tell what it's like to have to spend a day and a half transporting his children to a hospital when they could be taking a pill and be monitored at home through sensors or online tools.
Indeed, I think were are now in the age of personalized medicine. The use of biomarkers and sophisticated analytical tools to weed out toxicities specific to subpopulation is becoming standard operating procedure. Rather than just jumping into development with a target that is biologically active, companies large and small are engaging in what my colleagues and mentors Frank Douglas and Steve Paul have described as value-driven proof of concept.
Additionally, people can now monitor their health at home, through apps and sensors that collect and analyze data in real time and in less time than it takes to check email or text messages. And people are know sharing information about their 'consumer' experience, opinions that can shape their care and future product development. If companies will listen.
As Josh Lederberg often said: science is not linear in its progression. Lederberg also noted that for innovation to flourish, social and economic institutions had to change with medical progress as well. For the most part, despite pushback from those who warned about a 'tsunami' of new biologics that would devour every dollar spent on health care, the future is here. These new biologics are more targeted and more effective. They extend life and reduce more expensive hospitalization. They are solutions that make staying healthier and living longer easier and cheaper to do. We seek out such products for the same reason smart phones and notebooks are crowding out conventional PC sales: They make doing what we want easier and more enjoyable. They enrich life. We need more articles that track these benefits and more companies that use these values to design and produce new medical products. And companies will or should be more savvy in how they launch these products in countries where the middle class is growing along with life expectancy.
Point of care and personalized diagnostics, tools to prevent disease and targeted therapies that ultimately 'cure' by shutting off every avenue of escape for degenerative illnesses that are widely commercialized across the planet. I think we are getting there.
On several measures, the NHS came out the worst of all the systems examined. For example, it ranked worst for five-year survival rates in cervical, breast and colon cancers. It was also worst for 30-day mortality rates after admission to a hospital for either hemorrhagic or ischemic stroke. On only one clinical measure was it best: the avoidance of amputation of the foot in diabetic gangrene.
This hardly seems like a cause for national rejoicing, yet according to the report, the British were the most satisfied with their healthcare of all the populations surveyed. They were the most confident that in the event of illness, they would receive the best and most up-to-date treatment; and they were the least worried that their personal finances would prevent them from receiving proper treatment.
So, how is it that the population most confident that it will receive treatment of the highest possible standard, featuring the latest medical advances, actually has the worst survival rates in precisely those diseases that require the most up-to-date treatments?
One explanation is ignorance. The average Briton or Swede is unlikely to know that the five-year survival rate for colorectal cancer is 51.6% in Britain but 59.8% in Sweden, or that the 30-day fatality rates for myocardial infarction in those two countries are 6.3% and 2.9%, respectively. (The figures for the United States are 65.5% and 5.1%.) By contrast, the average Briton knows that if he suffers a heart attack, he will be taken to the hospital and connected to a lot of machines, from which he concludes that he is having the best possible treatment.
In my youth, I often heard the refrain that the NHS was "the envy of the world," and people in Britain are still inclined to believe that, even though they probably have never met anyone who envied the NHS and, indeed, probably know Continental Europeans residing in Britain who hurry home as soon as they require medical treatment, horrified by the prospect of subjecting themselves to a British hospital.
That said, there are some strengths the system can claim. Medical care is coordinated, for example, by means of a universal (and compulsory) system of family doctors. The lack of such coordination in the United States leads not only to a high rate of medical error but to duplication of effort.
The American rate of polypharmacy (the taking of four or more medicines daily) is twice the British rate. This difference is unlikely to reflect genuine need; the American polypharmacy rate is also 21/2 times the Swiss rate, and whatever one might think of British medical care, few would impugn the quality of care in Switzerland.
Read the full piece here.
The Pink Sheet reports, “Congress and the public should get an updated and extensive look at FDA performance over the next few years thanks to the many studies included in the FDA Safety and Innovation Act, although the additional work may tax agency personnel.” PDUFA V calls for more than 30 reports and studies.
That which gets measured gets done. But whose going to do the work? The FDA isn’t getting any additional funding or staffing to accomplish this important reportage – so what’s going to get prioritized?
That’s easy. Anything that is required by Congress gets done first – and that means PDUFA dates take a back seat.
More Congressional accountability for the FDA without additional funding?
Be careful what you wish for.
If you can’t measure it, the saying goes, it doesn’t count. But what if you’re measuring the wrong things?
The Access to Medicines Index (www.accesstomedicineindex.org) is an attempt to measure and compare the corporate social responsibility of both innovator (20) and generics (7) companies based on a number of different (and often quixotic) indicators. It was developed by Netherland's-based non-profit Access to Medicines Foundation (ATMF) with funding from the Dutch Ministry of Foreign Affairs, the UK Department for International Development and The Bill & Melinda Gates Foundation. It was launched in 2008, and comes out every two years.
The Index analyzes the following seven technical areas across four pillars:
Pillars:
1) Commitment (30% weight)
2) Transparency (30% weight)
3) Performance (30% weight)
4) Innovation (10% weight)
Technical Areas:
1) General Access to Medicine Strategy and Governance
2) Public Policy and Advocacy
3) R&D for Index Diseases
4) Patients & Licensing
5) Equitable Pricing & Registration
6) Technology Transfer (Capability Advancement)
7) Drug Donations and Philanthropic Activities
The Index concentrates on the global list of Low and Medium Development Countries based on the UN Human Development Index and World Bank Country Income level categories. The Index has historically covered 33 diseases including: WHO Neglected Tropical Diseases; the top 10 infectious diseases based on DALYs (Disability-Adjusted Life Years) from the WHO Global Burden of Diseases for the Low Development and Medium Development Countries; and the top 10 chronic diseases based on DALYs from the WHO Global Burden of Diseases for the Low Development and Medium Development Countries. The next index will likely broaden the disease scope to additional categories including NCDs, women’s health and some cancers. They also plan to place increased weighting on companies’ actual performance (vs. their commitments).
According the Access to Medicine Foundation, the index “aims to help poor people in developing countries gain access to medicine by encouraging the pharmaceutical industry to improve its commitments and practices related to this issue.” Since it’s a comparison, the theory is that competition among companies will drive desirous “socially responsible” behaviors. That’s a noble goal, but the devil is in the details.
As Goran Tomson, professor of international health systems research at Karolinska Institute points out, the Index’s methodology cannot be reproduced, hence it cannot be considered statistically valid.
There are also troubling issues relative to the index’s metrics for success. According to the Index’s methodological designer, Afshin Mehrpouya (an assistant professor of accounting and management control at the Paris-based HEC international business school) recently said, the only current measurements are “web hits and media coverage.” That’s not very exciting, plausible, or helpful from a health policy analysis perspective.
Another metric is the opinion of patient groups. When asked why certain patient groups were chosen (they are not named in the Index), the answer was that groups were chosen based on their “credibility.” That’s code for groups who do not accept funding from the pharmaceutical industry or may share the anti-private sector bias of the party line. At minimum, it’s a dubious selection bias.
Karolinska’s Tomson also pointed out that the index’s “review committee” consisted almost entirely of “familiar faces,” thus creating an issue of normative bias.
In other words, when did you stop beating your wife?
To offer better balance and some reference, shouldn’t the Index create a parallel metric that measures the policies and political environments of low and middle-income countries to determine whether they facilitate or hinder their citizens’ access to healthcare? How about creating an index that addresses the lack of transparency in the LDC public sector and (the 800 pound gorilla in the room) corruption. These are all polite ways of saying that the design criterion stacks the deck. But, hey, doesn’t the end justify the means?
Karolinska’s Tomson put the discussion about the index—as well as the entire ICIUM enterprise—into perspective when he said the index lacked for “higher ambitions.”
“Higher ambitions” requires that the Index do more than read its own press releases and talk with its friends in NGO-Land. “Higher ambitions” requires honesty beyond one’s own cognitive mapping.
According to Index CEO and Founder Wim Leerveld, “Today all companies have teams to deliver us the requested data as they see the relevance for them.”
Maybe. Maybe not. Interviews with participating companies showed much displeasure with both the Index questionnaire, the volume and type of information being requested by the Index and the “normative bias” of the ATMi staff. In some cases, participating companies are spending hundreds of hours to collect, verify and prepare final submissions. Is it worth it?
Here are some tough questions the Indexers must ask themselves:
Q: Is the Index moving the needle? Is there evidence that this is worth the effort that companies put into it and does it justify donor funding? Have they had an impact on financial investment patterns? Web hits and press clippings don’t cut it.
Q: What work has ATMF done to validate that their metrics are in fact the right drivers to improving access? Are they selecting an agenda being pushed by activist constituents without assessing a more full-bodied picture of what is happening in the real world?
To take one glaring example, the Index operates from the assumption that the innovator pharmaceutical industry can improve access to essential medicines. But, when you examine the WHO's model Essential Drug List, very few of the 400 or so drugs deemed essential are new, or patented or were ever patented in the world's poorest countries. In category after category, from aspirin to zithromax, in almost every case and in almost every country, these medicines have always been (or have been for many years) in the public domain. That is, the medicine is fully open to legal and legitimate generic manufacture.
There are important implications for the world's poorest patients. If these patients had reliable and affordable access to these several hundred essential medicines, all available theoretically as multi-source, that is from generics companies, then global mortality and morbidity might be cut as much as 10-20% -- a huge gain for populations around the world. Strangely, the Index gives a pass to the world's largest producers of generics drugs in India and China. Those companies are not being asked to spend hundreds of hours assembling data on their contributions to medicines access. Given the potential hugely positive impact on access to medicines, any reasonable person might ask why?
Q: Is it time to reassess the Index’s bias for certain mechanisms and tools? Its fixation on the medicines patent pool, for example unfairly demoting companies that aren't in negotiations. This doesn't seem fair. The pool is only one part of a broader landscape of what's happening around access to HIV and other treatments and it's unfair to use one tool as a measure of companies' commitment when there are other things happening that are very relevant and important.
There are ideological and activist assumptions within questionnaire’s section on tech transfer question. Is the Index looking at tech transfer as a measure of access to medicines or are they promoting industrial policy? Why isn’t in-country capacity building measured? What about efforts to fight counterfeiting? If ATMi is an ideological exercise, then innovator pharmaceutical industry should question the usefulness of the proposition.
Q: How does the Index ensure each company answers the questions in the same way to allow for an apples-to-apples comparison? Is the Index able to objectively compare companies? According to one corporate participant:
“Some of the questions were just too difficult to understand and required too much interpretation. In the Pricing & Distribution section, (Q1.9) we’re asked to provide product-specific registration status. When I asked for clarification, our Index contact told us to indicate if the product is patented in the countries in which it's registered. This is not inherent in the question. Also, we think it would be useful for the Index to know where we have filed for registration but where the application may be stuck in a bottleneck since the speed of registration is highly dependent on the speed and efficiency of local countries' regulatory processes. But our contact indicated this information was not necessary.”
The concern among participating industry is that the Index is getting increasingly arbitrary and opinionated. This is exacerbated by the fact that (per ATMi staff bios on its website) – many of the Index staff has worked for NGOs such as Médecins sans Frontières and other like-minded anti-pharmaceutical industry groups.
Industry wants the Index. They value being recognized for their good work – and the competitive rankings are appreciated (and flaunted). But the agenda isn’t appreciated. Pushing TRIPS+ and penalizing intellectual property rights trivializes the nature of the program. Perhaps it’s inaccurate to say that industry wants the Index. Maybe a better statement is that industry wants an index.
Recognizing the inherent flaws and bias of the ATMi – but also the importance of measuring industry’s commitment to social responsibility and access, Business for Social Responsibility’s (http://www.bsr.org/) Healthcare Working Group has launched an effort to provide an industry-wide lens on this important issue. The Working Group’s efforts center on the group’s acknowledgement that solving this challenge is a human need, and a business priority that requires a close collaboration with other actors from industry, public and NGO sectors.
It will be interesting to see how these two programs compare – and which one survives.
First there was CATIE then, earlier this week, AHRQ reported (in the August 14th Annals of Internal Medicine) that second-generation antipsychotics are not much better than the earlier incarnations at treating positive symptoms associated with schizophrenia. That's just Son of Sham.
Now here’s some important news.
According to research published in Nature Neuroscience, scientists have discovered a molecular mechanism for resistance to antipsychotic medications. Researchers from the Mount Sinai School of Medicine in New York City found that "long-term administration of atypical antipsychotic drugs selectively upregulates expression of the enzyme histone deacetylase 2 (HDAC2) in both mouse and human frontal cortex." That "epigenetic change, which is dependent on serotonin 5-hydroxytryptamine 2A (5-HT2A) upregulation, leads to lower expression of the metabotropic glutamate 2 receptor (mGlu2), thereby limiting the therapeutic effects of atypical antipsychotic therapy, often leading to a recurrence of psychotic symptoms."
Personalized medicine anyone?
Talk about qualified health claims!
In a letter dated February 14, 2012 (published online on August 14,) the FDA warns Hershey's that its labels for "Hershey's Syrup+Calcium" and "Hershey's Syrup Sugar Free with Vitamin and Mineral Fortification" are misbranded because they don't meet the nutritional requirements to make such claims.
The FDA has distinct definitions of "plus" and fortified" and doesn’t “consider it appropriate" to fortify snacks or sugary foods and carbonated beverages with vitamins and minerals. The FDA also said that Hershey's Syrup Genuine product was not an appropriate reference food for the other two types of syrups, because it does not include any of the added ingredients declared on the other products.
The labels now read as Hershey's Syrup with Calcium and Hershey's Sugar Free Chocolate Syrup.
Here’s the regulatory quandary – If you pour Hershey’s Syrup with Calcium over cholesterol-lowering Cheerios, is it a combination product?
The passage of the Generating Antibiotic Incentives Now (GAIN) provisions in the latest PDUFA agreement is being applauded for adding incentives like an additional five years of market exclusivity and priority review for qualifying antibiotics – but they may not be the game-changing incentives as some in the industry hoped.
High development hurdles for antibiotics, the availability of low-cost generics and reimbursement challenges for pricey new antibiotics are likely to keep most investors on the sidelines at least until big pharma starts to show more interest in the space.
The pharmaceutical industry, particularly at the top tier, has largely abandoned the therapeutic area because of development, regulatory and commercial challenges.
GAIN, which had been a pending stand-alone bill for years, was created as a partial solution to the dilemma, driven by groups like the Infectious Diseases Society of America, the Robert Wood Johnson Foundation and the Pew Health Group’s Antibiotics and Innovation Project as well as major companies in the space – what one lobbyist called the perfect storm of academia and industry, with industry using the thought leaders’ support to make it happen on the Hill. GAIN is intended to encourage development of new antibiotics as part of an effort to combat growing antibiotic resistance by providing incentives to companies developing drugs that target resistant pathogens.
One of the key challenges facing antibiotic drug developers is uncertainty in the approval pathway for antibiotics. One of the provisions in GAIN requires FDA to review antibiotic guidelines and update them where appropriate. The agency already has been working to update guidance for industry by type of infection, as required by the previous round of PDUFA, and has turned its efforts to complicated urinary tract infections, acute bacterial skin and skin structure infections, and community- and hospital- acquired pneumonia. Nonetheless, the clinical trial requirements, statistical analyses and endpoints in some cases are considered overly burdensome by many in the industry.
A more dramatic change to FDA’s approval requirements for antibiotics could spark a sea change in antibiotic R&D. Industry had pushed Congress to consider more aggressive changes that would reduce the clinical trial requirements for new antibiotics by allowing drug makers to study new drugs by pathogen rather than by indication, or only in the most severely ill patients, which would raise the threshold for safety and create a market for antibiotics similar to that for orphan drugs, where high-priced treatments are used in only a small subset of critically ill patients. IDSA asked Congress to consider such an approach, which it calls the Limited Population Antibacterial Drug mechanism.
Beyond the regulatory hurdles, generic antibiotics are widely available, posing reimbursement challenges for expensive new brands that do reach the market. Antibiotics for resistant pathogens are mainly used in hospitals so they face the added pressure of needing to secure placement on hospital formularies. On top of all that, antibiotics are prescribed for short-course therapy, generally just a matter of days, which limits their sales potential compared to chronic treatments, and in turn, limits a company’s return on investment.
The increasing prevalence of drug resistant pathogens means there is a clear need for new agents – and a significant market opportunity for drugs that can fight resistant strains and demonstrate a compelling pharmacoeconomic value story in the process, mainly by reducing the length of time patients are required to stay in the hospital. Almost two million Americans per year develop hospital-acquired infections resulting in 99,000 deaths, according to the Centers for Disease Control and Prevention. Sepsis and pneumonia alone killed nearly 50,000 Americans in 2006 and cost the health care system more than $8 billion.
How much antibiotic developers will benefit from the GAIN provisions depends on the molecules in development. The five years of additional market exclusivity, which comes on top of the five years of exclusivity already granted to brand manufacturers through Hatch-Waxman, is a big incentive but only in cases where patent protection doesn’t run in parallel.
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.
