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The FTC and biosimilars
Instead of playing name game, it should choose clarity
By Peter Pitts
The Federal Trade Commission (FTC) has started to meddle on a health issue that probably isn’t on the radar of more than a couple of health-policy wonks, but it should be of interest to anyone who treats patients or cares about patient safety.
It’s about a class of medicines called “biosimilars,” copycat versions of innovator biologics — or medicines made from living cells. Most people aren’t even familiar with biologics, let alone biosimilars. Biologics are the fastest-growing segment of the pharmaceutical industry and are primarily used to treat life-threatening or difficult-to-target diseases like cancer, diabetes, multiple sclerosis, lupus, Crohn’s disease, rheumatoid arthritis and epilepsy. Many people aren’t familiar with them yet and only know about traditional chemical compounds, which are vastly different.
Why is the FTC involved? Good question. The FTC’s interest here would be to ensure that “anti-competitive” or “deceptive practices” don’t compromise consumers’ ability to know which product he or she is prescribed, and to ensure it’s the one he or she actually receives. That’s because that’s what “informed consumer choice” is all about — right?
Not in this case. The issue the FTC is actually focusing on is whether any and all biosimilars that follow a particular “reference product” (the innovator biologic) ought to have the exact same name as that reference product. And all current indications point to the FTC is about to concur that they should.
This is no trivial issue. It is a fact that no two biologic products produced by different manufacturers will be the same. A biosimilar can only resemble its reference product. Therefore, how biologics are named will directly impact clarity of information around which products a patient has been using. Greater clarity will obviously occur if biologics and biosimilars have distinguishable names, and that clarity will enable better safety monitoring, “adverse event” reporting and timeliness in managing adverse events if they occur, and can even help us better understand which products work better for certain patients and specific subpopulations.
Let’s employ some common sense here. Suppose parents were to give birth to a set of fraternal twins: would it make sense to name them both “Tim,” on the grounds that it would “level the competitive playing field” as they grow and master their fate? Or do the boys have the right — and the rest of world an interest — in being able to tell them apart? And while we’re on the subject of names, let’s remember that the name “biosimilar” was coined for a reason — as with fraternal twins, who are not identical. (Even if they were — and you wanted to marry one of them — you’d probably want your “choice” to be “informed” by their having distinguishable names.)
In the FTC’s eyes, it seems to come down to clarity of information versus eking out every possible cent of cost savings. It’s not worth the trade-off. Biosimilars have the potential to provide quality alternative medicines and to improve prices in the biologics space. Because of the complexities associated with all biologics (including biosimilars), however, cost savings from biosimilars are not expected to exceed 10 percent to 20 percent over branded products. Chemical compound generics can realize savings of up to 80 percent over brands.
If we go in the direction of non-unique names, and issues arise, we might not have the information we need to quickly understand which among similar products is causing the issue. That can unnecessarily affect trust across a class of drugs and biosimilars as a whole, and that could significantly affect uptake.
Biosimilars are already available in other parts of the world. This gives us a unique opportunity to learn from the experiences of those markets. In Europe, where biosimilars share the same names as the originator product, they’re experiencing an increased number of adverse events, and it can take months for manufacturers to determine if their product is causing the problem.
Thailand also uses nondistinguishable names and rapidly approved biosimilars to treat certain diseases, which has led to both a dramatic increase in the number of cases of life-threatening blood-related adverse events and near futility in efforts to track back to which products are causing the problems. Australia opted for distinguishable codes for all biologics, and they appear to be experiencing successful rollout and uptake of biosimilars.
It’s a universal reality: What’s in a name is a fundamental ability to tell things apart. Nothing more informs American competitiveness and informed consumer choice. No one more than the FTC should recognize that fact — and be its champion.
Peter J. Pitts, a former FDA associate commissioner, is president and co-founder of the Center for Medicine in the Public Interest.
According to the FDA Law Blog:
There’s a hot debate brewing over whether or not a biosimilar biological product licensed under Section 351(k) of the Public Health Service Act (“PHS Act”), as added by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), should share the same non-proprietary name – or International Nonproprietary Name (“INN”) – as its brand-name reference product counterpart. Last Friday, Amgen Inc. (“Amgen”) further turned up the heat when the company announced the submission of extensive comments (89 pages in length) to two citizen petitions submitted to FDA earlier this year requesting that the Agency require that a biosimilar be identified by the same INN as the reference product it relies on for approval.
The first petition (Docket No. FDA-2013-P-1153) was submitted by the Generic Pharmaceutical Association (“GPhA”) in September and requests that FDA “implement its INN naming policy equally to all biologics” such that all biosimilars “share the same INN name as the” reference product (see our previous post here), The second petition (Docket No. FDA-2013-P-1398) was submitted in October by the Novartis Group of companies (“Novartis”) and requests that FDA “require that a biosimilar[] be identified by the same [INN] . . . as the reference product.” (see our previous post here).
According to Amgen:
Contrary to the position of GPhA and Novartis . . . , we believe that a policy of identical non-proprietary names would pose significant public health risks, and is inconsistent with applicable legal requirements. Petitioners fail to take into account fundamental scientific principles of biological products as well as their distinctive posology and methods of administration in clinical practice. We believe that, both as a matter of public health and as a matter of law, biological products licensed under the BPCIA should have distinguishable non-proprietary names—that is, non-proprietary names comprised of common roots and distinguishable prefixes or suffixes, as deemed appropriate by FDA, to achieve the goals of patient safety through effective post-market surveillance, and widespread physician and patient acceptance and appropriate use of this important new class of medicines.
Amgen lays out its case for distinguishable non-proprietary names – and opposition to the GPhA and Novartis petitions – in seven parts, arguing along the way that:
(1) “Biosimilars licensed under the BPCIA are appropriately neither required nor expected to be structurally identical either to their reference counterparts or to each other. Indeed, the product quality attributes for biosimilars may fall outside even the range of variability that is acceptable for the reference product, and differences in both structure and function will become increasingly prevalent as the complexity of the reference products increases. Because biosimilars cannot be—and are not—brought to market through the same abbreviated pathway as generic drugs, the legal requirements applicable to generic drugs (including the requirement that generics bear the same labeling and established names as their reference counterparts) do not apply to biosimilars. This difference in regulatory treatment is both appropriate and critically important to development of biosimilar medicines using state of the art technology.”
(2) “Distinct safety and immunogenicity profiles are found among structurally related biological products. Similar biological products cannot be fully characterized in premarket clinical trials, but instead must be subject to effective post-market surveillance that distinguishes accurately among related products. . . . [I]t is especially important that pharmacovigilance measures account for the possibility of differences in the safety profiles of related biological products. These differences could be intrinsic to products as a result of their distinct methods of manufacture, or they could be emergent as a result of post-approval manufacturing changes.”
(3) “Because FDA’s spontaneous reporting/post-market surveillance system does not encompass the separate tracking of [products] sharing the same non-proprietary name to be separately tracked, biosimilars with the same non-proprietary names but potentially different immunogenic profiles will be difficult to distinguish, hampering immunogenicity tracking and optimal pharmacovigilance.”
(4) GPhA and Novartis include in their petitions “numerous unsupported and erroneous objections to the use of distinguishable names for biological products.”
(5) A biosimilars naming policy that would mirror the naming rules for generic drugs “would create a significant risk of confusion regarding a biosimilar product’s bioequivalence or identity to its reference product. Moreover, given FDA’s obligations under the Administrative Procedure Act to treat like cases alike and to explain any departures from precedent, FDA would need to reconcile any naming policy with its past statements recognizing the potential safety risks of using identical established names for similar biological products, as well as instances in which FDA has required, for safety reasons, the use of distinguishable names for similar products.”
(6) “[T]the need for better pharmacovigilance measures for all drug products does not obviate the need for distinguishable names to facilitate post-market risk management in the context of biosimilars.”
(7) Alternative pharmacovigilance mechanisms, such as those suggested by GPhA in its citizen petition, “are not sufficient to address the need for robust post-market surveillance of biological products.” Efforts to create a federal tracing system “is not capable of ensuring the robust pharmacovigilance systems necessary for biological products if biosimilars are assigned identical non-proprietary names to their respective reference products.”A short missive from White Oak that may portend broader consequences:
“Rachel Sherman has decided to retire after many years of service to both FDA and CDER. We will miss her leadership and guidance as the OMP Office Director and wish her well in future endeavors!”
Wow.
Very few words to announce a very big loss.
While Medicare as a whole is a fiscal basket case -- due to run out of money in 2024 -- Part D has been the very model of a well functioning federal program since its implementation in 2006.
The Congressional Budget Office (CBO) found that, between 2004 and 2013, Part D will cost an extraordinary 45 percent below what was initially estimated. Premiums for the program, meanwhile, are roughly half of the government’s original projections. Part D enrollees pay, on average, $30 a month -- a rate that has remained essentially unchanged for years. It’s no wonder that beneficiaries are so pleased with the program. In fact, 96 percent of those enrolled in Part D say that their coverage works well.
These unprecedented results are largely due to Part D’s market-based structure. Beneficiaries are free to choose from a slate of private drug coverage plans, forcing insurers to compete to offer the best options to American seniors. It’s hardly surprising that the program has led to low prices and satisfied customers.
Through their own negotiations with drugmakers, private insurance plans that operate under Part D have already had great success in keeping pharmaceutical prices down. In fact, the CBO has observed that Part D plans have “secured rebates somewhat larger than the average rebates observed in commercial health plans.”
What’s more, the CBO has said time and again that doing away with the non-interference clause “would have a negligible effect on federal spending.” In a report from 2009, they reiterated this view, explaining that such a reform would “have little, if any, effect on [drug] prices.”
Smart partnerships between government and the free market work. They work at keeping costs low and – most importantly – improving care. As JAMA reported, “Implementation of Medicare Part D was followed by increased use of prescription medications, reduced out-of-pocket costs, and improved medication adherence.” And this, in no small measure, significantly reduces more drastic medical interventions -- which in turn reduces our overall national health care spending.
A new report from the Manhattan Institute, “A Decade of Success: How Competition Drives Savings in Medicare Part D,” details many of the reasons why a free-market approach to healthcare access is not only working – but a model for how to design future healthcare partnerships between Uncle Sam and the private sector.
Here is the report’s executive summary:
National trends are not a sufficient explanation for Part D’s success.
While patent expirations are part of the story—national drug spending as a whole slowed during the period we examine—they are far from the full explanation for large overestimates in Part D spending (indeed, patent expirations were likely captured in the original projections). Instead, the available evidence indicates that private-sector firm-level innovations, including preferred pharmacy networks and aggressive negotiations with drug manufacturers, have played a significant role in keeping the program’s costs below projections. We find that broader market trends (e.g., patent expirations and other changes) account for only about half (56 percent) of the program’s performance. The remainder—44 percent—of Part D’s lower-than-estimated cost savings is attributable to factors not captured in national prescription drug trends, which should include competition between Prescription Drug Plans (PDPs). This is strong evidence indicating that consumer-driven competition in Part D has been critical to the program’s financial success.
Consumer-driven competition is a relatively new tool in the government’s effort to control health-care costs.
In hindsight, government overestimates of Part D’s costs are not surprising, since the program utilizes a model of consumer choice (robust competition among dozens of regional drug plans and Medicare Advantage plans) that has no perfect analogue in other government health plans, such as Medicaid.
Part D is an excellent model for future health-care and entitlement reforms.
Arguably, Part D and Medicare Advantage plans represent the first national health-care exchange (the Federal Employees’ Health Benefits Program [FEHBP] is a close cousin). While the Affordable Care Act (ACA) operates a similar exchange concept, there are important differences. First, Part D plans compete in large regional areas, not states (this creates much bigger risk pools because even large states are incorporated into larger regions), as the ACA exchanges do. Even the federal exchange is layered on top of a state-regulated insurance market. This potentially limits the ability of plans to create economies of scale to bargain with providers and to utilize innovative tools to arbitrage cost and quality differences across state markets (preferred pharmacy and mail-order networks in Part D; telemedicine and medical tourism to “centers of excellence” for health-insurance plans). Notably, while Part D includes higher subsidies for sicker seniors (typically, the low-income subsidy population), it does not penalize healthier seniors through higher premiums, as the ACA’s community rating provisions do. Arguably, a better approach would be to rely more on backdoor (non-cross-subsidized) risk adjustment of plans and larger subsidies for sicker or older patients, while allowing plans to charge actuarially fair premiums to younger enrollees. The cross-subsidies in the Part D approach are more transparent in that sense, since they come from tax revenues rather than from private premiums.
The complete MI report can be found here.
Per a new draft guidance:
While generic formulations of these drug products are required to be both pharmaceutically and therapeutically equivalent to a reference listed drug (RLD), we are concerned that differences in physical characteristics (e.g., size and shape of the tablet or capsule) may affect patient compliance and acceptability of medication regimens or could lead to medication errors. We believe these patient safety concerns are important, and we are recommending that generic drug manufacturers consider physical attributes when they develop quality target product profiles (QTPPs) for their generic product candidates.
This is important and even more significant considering the agency’s recent proposed rule that would permit generic drug makers to update their labels if they received information about potential safety problems.
(For more on this, see here.)
Next up: tighter ranges for bioequivalencyIn Friday’s Washington Post, the editorial page opines that, “… not every problem can or should be solved by federal regulation, and there is still a decent chance that the balance between regulation and liberty that the Affordable Care Act struck will work. If it does, the more rational health-care system that results will have been well worth the price in expanded government intervention in the health-care market.”
That’s the conclusion, but the body of the piece reads like an introduction to a manifesto about why what we really need is a single-payer system. A "rational health-care system" is the the global code phrase for "one-size-fits-all" care. Have a look here and judge for yourself.
Here’s my view on some of the same problems from a different angle (as seen in yesterday’s Des Moines Register).
The devil is in the details.
From: A Message from the Commissioner
Sent: Wednesday, December 11, 2013 02:05 PM
To: FDA-Wide
Subject: Personnel Announcement
Dear Colleagues:
I am deeply saddened to announce that John M. Taylor, Counselor to the Commissioner and Acting Deputy Commissioner for Global Regulatory Operations and Policy (GO), will be leaving the Food and Drug Administration in January 2014 to pursue other opportunities. John has accomplished so much during his two stints at the Agency (from 1991 to 2005 and from 2009 to present) as he served in various ways and touched many lives. From his early days in the Office of Chief Counsel, to his senior roles in the Center for Drug Evaluation and Research, the Office of Regulatory Affairs, and the Office of the Commissioner, John has brought leadership, sound advice, and most of all, good humor to his work. We will all miss his expert knowledge, his innovative thinking, and his uncanny ability to remain calm during times of adversity and matters of urgency. John has proven himself as a leader who epitomizes integrity, dignity, kindness and compassion, and he is widely respected by his colleagues.
Most recently, John has been wearing two hats – Counselor to the Commissioner and Acting Deputy Commissioner for GO. In these two positions over the past year, John has demonstrated flexibility, creativity, and decisiveness that has enabled us to make important forward progress on key matters. John has always stepped up in the times when I have needed him most to take on specific tasks that represent my highest priorities, including those related to globalization, FDASIA, and pharmacy compounding. John has been a catalyst for organizational progress and change while handling and managing the high demands of the Office of the Commissioner. And notably, John agreed to serve as the Acting Principal Deputy Commissioner during a time when the Agency was in a period of transition, for which I am extremely grateful.
I know I speak for all of us when I say that John will be sorely missed. Please join me in thanking him for his distinguished service to FDA and wishing him the very best in his future endeavors.
Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs
In “Personalized Medicine and Responsible Access to Pain Medication” (a white paper based on the Center for Medicine in the Public Interest’s September 2013 Capital Hill conference), Dr. Douglas Throckmorton, CDER’s Deputy Director, for Regulatory Programs and the FDA’s point person on opioids, writes,
We understand that for the millions of Americans experiencing an acute medical need or living with chronic pain, opioids, when prescribed appropriately, can allow patients to manage their pain as well as significantly improve their quality of life. However, we have also become increasingly concerned about the abuse and misuse of opioids. We are challenged with determining how to best balance the need to ensure continued access to patients who need these medications while addressing concerns about abuse and misuse.
FDA must walk a difficult public health tightrope, balancing patient need, medication safety, and (in the case of opioids), the dangers of abuse.
This careful balance is now being called into question by 28 state attorneys general who, in a letter to FDA Commissioner Margaret Hamburg, ask the agency to “reconsider its controversial approval of the powerful new narcotic painkiller known as Zohydro.” The attorneys general are concerned that the medicine lacks “an abuse-limiting formula.”
First let’s consider the rhetoric. Was the approval “controversial?” Well, for starters, the FDA approved the medicine notwithstanding a negative adcomm vote. Is that what makes it “controversial?” No. Adcomm votes are recommendations and the advice (while generally followed by the agency) is in no way binding and there’s plenty of precedent for the FDA going its own way.
No, it’s controversial because the issue of opioid abuse is controversial. And that’s an important difference. Nobody said the FDA’s job was easy.
Noble Prize winner Joshua Lederberg once observed that the failure of regulatory legal and political institutions to integrate scientific advances into risk selection and assessment was the most important barrier to innovation in public health. Lederberg noted that in the absence of such changes, “The precedents affecting the long-term rationale of social policy will be set not on the basis of well-debated principles, but on the accidents of the first advertised examples.” And there isn’t a better perspective-setting proposition when it comes to the issue of Zohydro than that quotation.
Policies and regulations that seek to limit risk are often shaped by the immediate fear of sensational events. This perspective is commonly referred to as the Precautionary Principle, which, in various forms asserts that unless innovators can demonstrate that a new technology is risk free, it should not be allowed into the marketplace. Moreover, any product that could possibly be dangerous at any level should be strictly and severely regulated. But precaution is not always safer than the alternatives.
Pierre Trudeau once said, “There’s no place for the state in the bedrooms of the nation.” But what’s the appropriate place for the state in our nation’s pharmacies and medicine chests? The AGs who are petitioning the FDA see abuse and seek to minimize access to opioids as the solution.
That’s a law enforcement solution. They mean well, but are behaving like a bull in a china shop. Arbitrarily limiting choice is not generally associated with the scientific method. Should regulation be shaped by factors other than science? Or should advances in medicine and digital information be used to right size regulation reduce the excessive reductionism that leads to regulatory overreaction and promote resilience rather than ever increasing regulation.
Which brings us to the second objection raised by the “Opioid-28,” that Zohydro lacks “an abuse-limiting formula.”
Per Doug Throckmorton,
Another important step towards the goal of creating safer opioids, and one that is a high public health priority for FDA is to encourage the development of formulations of these drugs that deter their abuse. This relatively new science of abuse deterrence is exciting and evolving and showing encouraging promise. To guide drug development in this new field, we also issued a draft guidance for industry in January, announcing a flexible, adaptive approach to encourage the development of abuse-deterrent opioids. We believe abuse deterrent products have promise to help reduce prescription drug abuse and improve public health.
The FDA has its eye on the prize. But what’s the game for the AGs? They refer to an “epidemic.” That’s a powerful word. But does it qualify in the case of opioids?
According to the CDC in 2008, there were 14,800 opioid overdose deaths. Half of those, the CDC has claimed, involved opioids and other illicit substances, whether it’s cocaine or heroin, or alcohol. They also mentioned that alcohol was involved in many of those deaths but they don’t actually tell us the numbers. So conservatively, half or 7,400 deaths occurred in 2008 from opioid overdose. The same year from CDC’s own statistics, there were 36,500 suicides. There also were 24,000 alcohol-induced deaths and that doesn’t count other related alcohol deaths like drunk driving. The bottom line is that the opioid numbers do not even come up in the CDC’s list of the top 15 causes of death of Americans
It’s important to add to this “epidemic” perspective, the fact that people suffering from chronic pain are under-served by existing therapies. A recent IOM report that was issued in June of 2011 found that 100 million Americans are now living with chronic pain. That’s a third of the U.S. population. Ten million of those have pain so severe that they are disabled by the pain. The report also said that pain costs the U.S. economy about 600 billion dollars a year in lost productivity and healthcare cost.
And the “Opioid 28” wants fewer pain medications on the market?
The vast majority of people who use opioids do so legally and safely. A subset, approximately four percent, use these medications illegally. In fact, from 2010 to 2011, the number of Americans misusing and abusing opioid medications declined from 4.6% to 4.2%.
And the FDA’s decision was “controversial?” Really?
Rather than dealing with the problem of abuse with sledgehammer solutions (such as those proposed by the 28 AGs), we should focus on potential solutions such as:
* The structure and impact of programs such as the recently instituted by CVS initiative (detailed in a recent New England Journal of Medicine perspective piece) where, through the use of “Big Data”, the chain pharmacy identified outlier prescribers and took appropriate and responsible action.
* The role of the 21st century pharmacist in improving drug safety and medication adherence via more proactive and remunerated patient education? How can pharmacists become better integrated beyond Med Guides into the FDA’s Safe Use of Medicines initiative? When will pharmacy synchronization really kick into gear, and how will states help to jump-start these important initiatives?
* Government and legislative initiatives such as the Stop Act (H.R. 486), which focuses on tamper-deterrent formulations and the continued development of those. Also, Senate Bill 1277 (sponsored by Senator Barbara Boxer, D/CA) which would establish a commission to bring all of the stakeholders together to have discussions about how to approach this issue so that law enforcement, providers, patients, and pharma can debate the issues and reach common ground.
* The appropriate role of tamper-resistant technologies. They are part of the solution, but they’re not the whole solution. We need to develop policy options that focus on the prescriber/patient relationship, and a professional assessment of what’s the risk involving this patient. Is the patient is going to tamper with the medication and potentially expose themselves or others to some danger. We have to do a better job (via CME and other methods) of training physicians and other prescribers on how to do these kinds of assessments.
And, most importantly, we need to keep the needs of patients front and center.
There is no expedient to which a man will not go to avoid the labor of thinking.
– Thomas Edison
As we inch closer to biosimilars in the US, we need to remember that similar does not mean identical – and that means paying close attention to bioequivalence.
MedPage Today reports that FDA-funded studies are underway that may lead the FDA to stiffen its bioequivalence rules for generic anti-epileptic drugs (AEDs) and others with so-called narrow therapeutic indices.
These studies examine drug pharmacokinetics in epilepsy patients and under chronic dosing -- could show that some current generic AEDs vary enough to put patients at risk. My eldest son has Juvenile Myoclonic Epilepsy (JME), and I can attest to the problems with therapeutic substitution from personal experience.
The FDA has shown a willingness to modify its rules if, indeed, the evidence is there, said Barry Gidal, PharmD, of the University of Wisconsin, at a press briefing held at the American Epilepsy Society (AES) annual meeting. "We're bringing the evidence."
Current bioequivalence regulations allow some variation in generic drug pharmacokinetics relative to the original branded drug. In particular, the lower boundary for 90% confidence intervals in measures of bioavailability can be as low as 80% of the mean for the branded drug, and the upper boundary can be as high as 125% of the branded drug mean.
Under current FDA rules, single-dose studies in healthy volunteers are adequate to show bioequivalence. He said that this poses two problems: drug availability and metabolism may be different in patients than in healthy people, and it may also be different with chronic dosing.
The issue of real-world generic equivalence is not confined to AEDs. Immunosuppressants are another drug class with narrow therapeutic indices, and an FDA-funded study of tacrolimus bioequivalence is also underway.
Another view of the bioequivalence issue was provided by another University of Cincinnati study led by Lisa Garrity, PharmD -- a survey of Cincinnati-area pharmacists about their knowledge and experience with generic AEDs.
Garrity and colleagues obtained responses to a one-page questionnaire from 30 retail pharmacists who had a mean of 15.6 years in practice (SD 8.8). Of these, 20 reported having no specific education about possible issues with generic AEDs when switching from one manufacturer to another.
Responses indicated that 22 believed that switching from a branded version to a generic could cause problems, but only 18 said that issues could arise when switching between generic versions of the same drug. Per Garrity, "I think these [types of switches] should be equally concerning.”
Another problem with the current system is the lack of transparency regarding generic drugs' pharmacokinetics. Data from manufacturers' FDA submissions are not readily available.
Can you say INN?
Today's FTC hearing on biosimilars cancelled because of safety concerns (snow day in DC).
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.
