Latest Drugwonks' Blog
For all the talk about a predictable and appropriate FDA pathway for biosimilars, where’s the thinking about what happens after approval?
Since patient safety and product efficacy will be a justifiable cause of angst to wary physicians, how will biosimilars be detailed? And who will do the detailing? Will biosimilar manufacturers need to develop patient assistance programs? What about REMS issues (both IP and implementation)?
Can you say, “authorized biosimilars?”
(And what will Congress and the FTC have to say about that?)
I am an EMR geek who isn’t so thrilled with the direction of EMR. So what, I have been asked, would make EMR something that is really meaningful? What would be the things that would truly help, and not just make more hoops for me to jump through? A lot of this is not in the hands of the gods of meaningful use, but in the realm of the demons of reimbursement, but I will give it a try anyhow.
Read his list here.
The bad news is that solanezumab (Eli Lilly’s experimental Alzheimer's treatment) failed to meet its primary endpoints in two late-stage clinical trials in patients with mild to moderate levels of the disease. The good news is that investigators saw positive signs in some analyses of the studies.
According to Lilly, after combining the results from the total of 2,050 participants in both trials, it found statistically significant signs that the drug slowed memory loss in some patients, many with mild cases.
"We're encouraged by the signals we see here," said David Ricks, president of Lilly Bio-Medicines. He said the solanezumab findings validated the company's heavy investment in Alzheimer's treatments. Lilly plans to discuss the findings with regulators before determining how to proceed with the drug.
Happy talk or hopeful hypothesis? Generally, combining the data from the two trials—aren't considered conclusive but are used to generate hypotheses that require further study and validation.
Importantly, the results from the pooled solanezumab data are to the first from any late-stage Alzheimer’s studies to suggest a benefit from an anti-beta amyloid compound.
Full data from the studies, based on an independent analysis by an academic national research consortium called the Alzheimer's Disease Cooperative Study, will be presented in October at scientific conferences in Boston and Monte Carlo, the company said.
As the Wall Street journal reports, “Much will depend on how regulators interpret the data. Usually the U.S. Food and Drug Administration makes decisions based on how experimental therapies perform in meeting the primary goals of pivotal trials.”
The Journal continues, “In the case of solanezumab, the FDA will have to weigh the potentially limited cognitive benefits against the lack of effective treatments, experts said. The agency could ask Lilly to do additional studies exploring further whether solanezumab does indeed slow down Alzheimer's progression in certain patients.”
True – but an even more important issue is understanding – and rewarding – incremental innovation. “Limited cognitive benefits” is in the eyes of the beholder, but the impact is anything but limited when it comes to our nation’s healthcare wallet.
As the prevalence impact of Alzheimer’s grows, so does the cost to the nation.
One in eight people age 65 and older (13 percent) has Alzheimer’s disease. Nearly half of people age 85 and older (45 percent) have Alzheimer’s disease. Of those with Alzheimer’s disease, an estimated four percent are under age 65, six percent are 65 to 74, 44 percent are 75 to 84, and 46 percent are 85 or older.
If Alzheimer’s Disease was a tradable stock, the demographics of the Baby Boom generation would make it a “must buy.”
The direct and indirect costs of Alzheimer’s and other dementias amount to more than $148 billion annually, which is more than the annual sales of any retailer in the world excluding Wal-Mart.
Is there value in slowing the progression of Alzheimer’s Disease? Certainly.
According to a study in Health Affairs (“Alzheimer's disease care: costs and potential savings”), monthly savings of $2,029 in formal services are possible if disease progression can be slowed. Annual institutional cost savings of $9,132 also are achievable if alternative residential settings are used.
Sometimes the biggest success stories rest on the foundations of failure. The solanezumab trials may have missed their primary endpoints – but they have succeeded in advancing our knowledge of Alzheimer’s Disease and provided a possible new and innovative option for patient’s (and family members) of this draconian disease.
Alas, solanezumab will not be the magic bullet that eradicates Alzheimer’s Disease from our lexicon of suffering – but it may yet be an important addition to our pharmacological armamentarium.
As FDA and then CMS decide on the value of solanezumab, it’s important to remember that innovation is slow. As any medical scientist will tell you, there are few "Eureka!" moments in health research. Progress comes step-by-step, one incremental innovation at a time.
Harvard University health economist (and Obama healthcare advisor) David Cutler has noted: "Virtually every study of medical innovation suggests that changes in the nature of medical care over time are clearly worth the cost."
The battle for the heart and soul of 21st century health care is the battle over innovation. And nothing short of victory is acceptable.
To borrow an over-used adjective from the world of global climate change -- we must protect "sustainable" innovation.
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.
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.
