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In Vitro Veritas
A renegotiation of the EMA (European Medicines Agency) medical devices directives is imminent. Our spies tell us that, for in vitro diagnostics, a line will be drawn between tests used as companion diagnostics -- where clinical evidence of their applicability will be required -- and other in vitro tests such as PSA for prostate cancer -- where no such evidence will be required.
Uneasy lies the head that wears a crown
Eric Abadie, the chair of CHMP (The Committee for Medicinal Products for Human Use) has resigned -- another victim of L’Affaire Mediator (the French anti diabetic /anti obesity drug remained questionably available in France and killed somewhere on the order of 5000 patients from pulmonary valve disease). The French Agency sacked him and the EMA opted not to pick up his salary.
Meanwhile on our own placid shores
Here’s an excellent article from the April edition of Nature Biotechnology on some of the key policy questions facing the US biotech sector pending PDUFA and presidential politics.
Part of the FDA’s promise for PDUFA V is a more patient-centered approach to risk/benefit analysis. A timely new analysis provides a closer look at how much cancer patients value hope --with important implications for how insurers value treatment, particularly in end-of-life care.
The analysis by Darius Lakdawalla, director of research at the Schaeffer Center at USC and associate professor in the USC Price School of Public Policy, surveyed 150 cancer patients currently undergoing treatment, and is part of a special issue on cancer spending from the journal Health Affairs.
Lakdawalla and his co-authors found the overwhelming majority of cancer patients prefer riskier treatments that offer the possibility of longer survival over safer treatments: 77 percent of cancer patients said they would rather take a “hopeful gamble” — treatments that offer a 50/50 chance of either adding three years or no additional survival — to “safe bet” treatments that would keep them alive for 18 months, but no longer.
“Consumers tend to dislike risk, and researchers and policy makers have generally assumed that patients care about the average gain in survival,” Lakdawalla said. “But patients facing a fatal disease with relatively short remaining life expectancy may have less to lose and be more willing to swing for the fences. This analysis points to the larger ideal — that value should be defined from the viewpoint of the patient.”
Reaching the wrong conclusion only makes a problem worse. Witness drug shortages and a bill pending in Congress that would require drug manufacturers to notify federal officials of a disruption to a drug supply six months in advance.
In theory, such a requirement would give the FDA an opportunity to prevent the shortage, notify health-care providers and develop a contingency plan. In reality, that’s not the problem.
“What we’re trying to find out is whether there’s a pattern behind the shortages that we can address,” comment senator Richard Durbin (D, IL). “We’ve got to get down to what is really behind it and try to solve it.”
Precisely.
While earlier and more robust communications between drug manufacturers (largely generic manufacturers of hospital injectables) and the FDA is important – lack of such interaction isn’t the major cause of the problem. The issue at hand is that that, because of the way hospitals purchase medicines, there is no incentive for drug makers to update manufacturing facilities or build new ones. Hence, when a facility goes off-line due to quality concerns (the major cause of supply line disruption) or is retooled for a different (and more profitable) use – shortages can occur. In such an instance, should a manufacturer advise the FDA of potential shortages? Certainly.
But that’s not the real problem. The unreported problem is the role of Group Purchasing Organizations (GPOs). GPOs control the purchasing of more than $200 billion in drugs, devices, and healthcare supplies annually for some 5,000 private, acute care hospitals nationwide. And they keep costs low. That’s the good news. The bad news is that they are also permitted (by law) to charge a fee to hospital suppliers based on percentage of sales volume for a particular product. And sometimes it’s a hefty one – often as high as 35-50%. That certainly throws a spanner in the supply-and-demand proposition. Six months supply at ever-lower margins becomes a non-starter for many companies – further exacerbating the problem rather than solving it.
GPOs are a monopsony (a buyer’s monopoly) dominated by six firms that control about 90% of the goods purchased by hospitals via GPOs. The power of these organizations is such that they can often dictate which drugs, devices and supplies are used in hospitals – and which companies are allowed to sell them.
These practices have created a concentrated market that excludes other existing and would-be suppliers and distributors. So, with no other suppliers able or available to fill the gap, increases in demand for generic drugs have resulted in shortages and surging prices. It is no coincidence that the problem is generally limited to generics sold to healthcare facilities through GPO contracts rather than directly to consumers through retail pharmacies.
GPOs have their critics. Among them is former Wall Street Journal reporter Phil Zweig who writes that, “GPOs have concentrated production of generic drugs in a handful of drug makers and have forced some manufacturers to cease production of various lifesaving drugs altogether and distributors to slash inventories to the bone. In a nutshell, these cartels have undermined the laws of supply and demand in this critical industry.”
We applaud Senator Durbin for striving to solve an important problem. We urge him to include not only drug manufacturers and the FDA in potential solutions – but also our nation’s giant Group Purchasing Organizations.
It’s time to actively and aggressively pursue FDA Commissioner Peggy Hamburg’s call for a regulatory Marshall Plan to help build, nation-by-nation, global systems for both quality and safety. A high tide floats all boats.
A new IOM report concludes the FDA should invest in advancing the regulatory capacity of developing low and middle income nations in order to secure the pharmaceutical supply chain and safeguard the American public.
The report, Ensuring Safe Foods and Medical Products Through Stronger Regulatory Systems Abroad, recommends 13 steps FDA and other regulatory bodies can take in the next five years to improve the regulatory systems of developing nations.
Rather than try to inspect all foreign establishments itself—something IOM conceded was unrealistic given FDA’s limited budget—FDA should instead invest in improving other regulatory systems to accomplish its goals of ensuring a safe pharmaceutical supply chain.
After all, as Peggy Hamburg has repeatedly said, ““We can’t inspect our way out of this problem."
The IOM reports, “The FDA should use partnerships to drive improvements in supply chain management. The committee recommends that the FDA work with strong regulators in other countries to plan inspections and pool data. There is no need for American and European inspectors to duplicate each other’s work, especially when a vast number of facilities go uninspected … One promising initiative is the two-year FDA Secure Supply Chain pilot program, which rewards firms that trace their products thoroughly from manufacture to entry into the United States.”
“The report urges FDA and its technologically advanced counterparts in the European Union, Canada, Japan, Norway, Iceland, Switzerland, Australia, and New Zealand to plan a system for mutual recognition of one another's inspections, which would eliminate the wasteful duplication of effort,” wrote IOM in a statement.
FDA, the European Medicines Agency (EMA), Australia’s Therapeutic Goods Administration (TGA) and the World Health Organization have all announced their participation in a global active pharmaceutical ingredient inspection program that might go a long way toward accomplishing IOM’s recommendations—something IOM agrees with in principle.
IOM also called on industry association to “define a reliable way to share internal inspection results among their members within the next three years.
With scare resources, perhaps the best place to start is by committing to common standards for data capture and reporting.
After all, knowledge is power.
It is rare that the words “progress” and “Alzheimer’s Disease” are used (positively) in the same sentence.
Maybe that’s about to change.
Last week the EMA's CHMP adopted a qualification opinion that positive/negative PET imaging of amyloid can be used as a biomarker to identify patients in clinical trials with predementia Alzheimer's disease (AD) who are at increased risk to have an underlying neuropathology. Now an Eli Lilly & Co. diagnostic that detects the presence of proteins in the brain that are related to Alzheimer's disease is FDA-approved.
According to a report in the Wall Street Journal, “The tool could enable clinicians to detect Alzheimer's earlier and more accurately in patients at the earliest sign of memory problems—a potential boon to treatment and developing drugs against the disease.”
A lack of ability to reliably diagnose patients in the early stages of the Alzheimer's disease has hampered research. Some experts believe that investigational drug trials have failed because patients enrolled in such studies already had progressed too far for the treatments to be effective.
Proponents of using florbetapir and similar agents that are being developed have said that such technology will accelerate research by helping to accurately identify people at high risk of developing the condition and to enroll such people in therapeutic trials.
The test uses a chemical called florbetapir, known by the brand name Amyvid, which is a radioactive agent that tags clumps of a sticky substance called an amyloid. Amyloid proteins are hallmarks of Alzheimer's disease. The chemical, which costs $1,600 per dose, then is detected using a brain imaging technique called positron emission tomography, known as PET scans.
The Journal raises an important point, “Some experts have questioned how useful the test is since no treatments are available that significantly alter the course of the disease. But some doctors believe that patients may find a diagnosis helpful for planning purposes or just to know for certain that they have Alzheimer's.”
Question – will payers pay?
If a tree falls in a forest …
BioCentury reports:
EMA backs AD biomarkers
The EMA's CHMP adopted a qualification opinion that positive/negative PET imaging of amyloid can be used as a biomarker to identify patients in clinical trials with predementia Alzheimer's disease (AD) who are at increased risk to have an underlying neuropathology. CHMP also adopted a qualification opinion that the combination of low beta amyloid (1-42) and high tau in cerebrospinal fluid (CSF), and amyloid-related PET imaging, can be used to identify patients with mild to moderate AD who are increased risk of an underlying AD neuropathology. CHMP said the biomarkers are intended to enrich recruitment in trials aimed at studying products to slow the conversion to AD or severe AD.
The Health, Education, Labor and Pensions Committee released a discussion draft of legislation aimed at accelerating patient access to innovative medical treatments for life-threatening diseases.
The bipartisan Drug Approval and Patient Access Plan would overhaul the FDA's Accelerated Approval pathways and create a new "breakthrough" designation to provide more flexibility and certainty for developers of new medicines intended to address serious or life-threatening diseases or conditions.
The draft includes legislation introduced last week by Sen. Michael Bennet (D-Colo.) that would expedite FDA approval and provide more flexibility when a drug or treatment shows dramatic responses early in development.
We called it.
At CMPI’s November PDUFA without the Politics conference, each panelist was asked to bring one ornament to hang on the reauthorization Christmas Tree. Tim Franson (President of the USP Convention and one of the “Fathers of PDUFA”) offered a little lifeboat.
What can we do for those with life threatening unmet needs? One thing, as was done in PDUFA IV, is adding renewal of the Best Pharmaceuticals for Children’s Act. That piece of legislation has done more for pediatric drug development than anything in the past. It’s been good for American children and it should be made permanent. I think the better policy argument is to make it permanent, because companies don’t invest in five-year cycles. (Note to reader: The Act is currently renewable every five years.)
If I’m looking for a return on an investment, I need certainty well in advance of five years on types of studies I should be conducting and I need to know the benefit I’m getting at the end. I think five years is far too short a period of time.
There’s an accumulated body of evidence, of companies fulfilling their commitments. Maybe its time we make it permanent. I think this point of holding up renewal like the Sword Damocles isn’t very persuasive even to sponsors.
Well, a bipartisan House bill now proposes to permanently reauthorize two pediatric-drug statutes that include marketing incentives and clinical-study mandates, which the drug industry supports, while also giving FDA recourse for unfinished pediatric studies and requiring drug sponsors to submit their plans to the agency earlier, measures advocated by pediatricians.
Reps. Ed Markey (D-MA), Anna Eshoo (D-CA) and Mike Rogers (R-MI) introduced the bill to permanently reauthorize the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act.
The bill would require drug makers to submit an initial pediatric-study plan by the end of phase 2 clinical trials. Currently, companies must submit the information when they submit an application or supplement to the agency. FDA must promulgate a rule and guidance on the new timing requirement, according to the bill. The plan should include an outline of proposed studies and any request for a waiver to defer the requirements.
Lawmakers backing the bill said the pediatric laws have led to pediatric studies for 180 new drugs and more than 400 updated drug labels.
“Government and private industry have worked together to fill an important void,” Eshoo said in a statement. “The laws have provided greater transparency and accountability in the programs, while improving communication between FDA and companies. I’m proud of how far we’ve come and look forward to a day when we know how all medicines will affect children.”
Now sponsors are looking for a little HELP.
In recent statements ANVISA, the Brazilian equivalent of the FDA, has put forward the proposition that (relative to raising the level of international drug quality and safety) there isn’t a way forward but rather “ways to move forward based on local situations.
While the solution must fit the problem, this poses an interesting question – can there be a floor and a ceiling for global drug safety and quality? Even as we move toward differential pricing, should we allow some countries to have lower standards than others “based on local situations?”
When it comes to the safety of pharmaceuticals and medical devices, can one man’s ceiling be another man’s floor.
And how does this fit into the debate over trade policy versus trade practice? Should medical products that are determined not to meet any given national standard be allowed to be exported to other countries? Should there be a “good enough for me, good enough for thee” standard for international trade in pharmaceuticals and medical devices?
For example, should Beijing allow substandard API -- illegal for use in the Middle Kingdom -- to be exported to, say, Nigeria?
When Paul Orhii, Director-General of Nigeria’s National Agency for Food and Drug Administration and Control, complained to the Chinese government that China was the origin of many of the counterfeit medicines in Nigeria, he was bluntly told Beijing was not responsible for the quality of medicines in Nigeria.
That’s the unfortunate distinction between trade policy and trade practice. Is this an issue for TRIPS? Should TRIPS Article 61 be amended to include punishments and penalties for those who export medicines and medical devices that do not meet a certain global standard?
While domestic standards are undeniably an issue of domestic sovereignty, shouldn’t there be transparency as to how any given nation defines safety and quality? “Market authorization” means one thing in the context of the MHRA, the FDA, the EMA, and Health Canada (to choose only a few “gold standard” examples), but how are we to judge the regulatory competencies of other national systems? Is that the responsibility of the WHO via a better-developed (and far more transparent) pre-qualification scheme? Or regional arbiters (such as PAHO)? Should there be “reference regulatory systems” as there are reference nations for pricing decisions? Should there be regulatory reciprocity?
All the more reason for “gold standard” nations to undertake a regulatory Marshall Plan to help build global systems for drug quality and safety.
The harmonization of global trade policy and practice is essential to the sinews of international medicines quality and safety.
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.
