Latest Drugwonks' Blog
From the pages of the Burrill Report …
Cracking the Social Media Code
The U.S. Food and Drug Administration recently issued two long-awaited draft guidances for drug and device makers' use of social media. The first concerns risk and benefit information, and the second addresses correcting misinformation published by others on the web. We spoke to Peter Pitts, president of the Center for Medicine in the Public Interest, about the issues of concern to the agency, why the industry has been slow to embrace social media, and how these new ways to communicate with patients are accelerating broader changes in the healthcare landscape.
Let's ignore the fact that health plans have calculated, down to the penny, that they make more money discouraging people with chronic conditions from using new medicines or enrolling in their plans than they do in performing the mission they claim they pursue: maintaining health and preventing disease. The claims about drug costs skyrocketing are lies. Don't take my warped word for it.. Here's the headline from a news release put out by the IMS Institute for Health Informatics..
IMS Health Study: Cancer Drug Innovation Surges As Cost Growth Moderates..
From the study: U.S. market for oncology drugs has grown at a 3.5 percent CAGR over the past five years, reaching $37 billion last year.
Total revenues of US health plans in 2013 are estimated to be $432 billion. In 2008, total revenues were $346 billion. That's nearly 6 percent a year increase.
Prescription drugs are 15 percent of total health care expenditures paid for by health plans. They are 13 percent of revenue. In 2008, Rx was $46 billion. In 2013 Rx costs were about $56 billion. That's a 4.3 percent increase.
I know how you are feeling after reading that.. my heart weeps for AHIP too...
Meanwhile, back on planet Earth, HIV organizations and the National Heath Law Program are suing four health plans for discriminating against people with HIV. From Brianna Ehley's article in The Fiscal Times:
Obamacare Insurers Hit High-Cost Patients with High Drug Prices
Some insurance companies are finding ways to get around one of Obamacare’s most popular provisions that requires everyone to be covered equally—regardless of any pre-existing condition.
The anti-discrimination rule was meant to guard against insurers who historically charged higher premiums to sick people. But some insurers are still charging certain patients more by passing the extra costs on in the form of higher drug prices.
Meanwhile, the results of a 3 year study show what dozens of others have demonstrated. Use of new drugs reduce other health care costs.. by a lot.
Changing Physician Incentives for Affordable, Quality Cancer Care: Results of an Episode Payment Model
I'll have more on this study later as well as the befuddlement of the authors who can't believe the results clash with the AHIP propaganda...
AHIP's hashtag should be #AHIP4letterwordforlie.
The First Amendment, In Your Medicine Cabinet
No American in 2014 who watches television, reads a magazine, goes online or visits a doctor’s office can escape the ever-present promotion of prescription drugs. Pharmaceutical promotion, both directly to doctors and to patients, has been the backbone of prescription drug sales for decades, with sales driving everything from drug access to stock prices to research and development. So what happens when the third largest industry in the United States changes the way it promotes products? We might find out.
Scott Liebman, head of the FDA Regulatory and Compliance practice at Loeb & Loeb LLP explains, “A confluence of events has primed the life sciences industry for a paradigm shift. First Amendment challenges to restrictions on off-label communications, evolving transparency in pricing and payments, the Affordable Care Act and other key regulatory developments are coming together in a way that could fundamentally change the sales of drugs, devices, and biologics in this country.”
The Promotion Paradigm: “Ask Your Doctor About…”
The United States is one of only two nations in the world that allows direct-to-consumer advertising of regulated medical products. It is no coincidence that we also rank as the world leader in pharma research and the world’s largest market for pharmaceuticals. “In order to protect consumer safety while preserving consumer choice, regulators have developed numerous and rigid standards for promotional communications, especially those related to the marketing or advertisement of drugs off-label, in other words outside of their FDA-approved indication,” says Liebman.
At present, any promotional statements about a prescription product that are inconsistent with the prescribing information in the label are prohibited according to the Food, Drug and Cosmetic Act. Liebman further explains, “Any promotional statement must be accurate, complete, not misleading and balanced with information related to both benefits and risks.” Along with these regulations comes a highly active enforcement system that generates billions of dollars in revenue at the federal and state levels through settlements and penalties.
In reality, many drugs may be effective in treating disease states or patient populations outside their FDA-approved indications, creating the potential for billions of dollars in new sales. The burdensome regulation placed on manufacturer’s speech is not, however, intended to stop doctors from prescribing drugs for any use they believe to be safe and effective. According to a 2006 Stanford study, an estimated 21% of all written prescriptions are for non-primary label use. Dr. Randall Stafford says in his 2008 New England Journal of Medicine article that, “Although off-label prescribing — the prescription of a medication in a manner different from that approved by the FDA — is legal and common, it is often done in the absence of adequate supporting data. Off-label uses have not been formally evaluated, and evidence provided for one clinical situation may not apply to others.” If that is true, however, how are doctors predicating their off-label prescribing decisions?
Off-Label Communications: The FDA Loses Ground In Court
Doctors have access to off-label information from the manufacturers themselves through a legal carve out for scientific communications made in response to an unsolicited request. If a representative provides off-label information without receiving an unsolicited request, however, the communication can be deemed illegal. In 2009, Allergan sued the FDA asserting that the FDA’s prohibition on the dissemination of off-label information violated the company’s First Amendment right of free speech.
At that time, Allergan had allegedly been promoting Botox® for the treatment of migraine and other indications that were not yet approved. The three resulting whistle-blower suits left Allergan facing enormous civil and criminal penalties, so in 2010 it negotiated a $600 million settlement to resolve its liabilities and entered into a Corporate Integrity Agreement that required the withdrawal of its First Amendment complaint.
A mere six weeks later, Botox® received FDA approval for prevention of headaches in adult patients with chronic migraine.
Allergan’s withdrawal left the industry without appropriate jurisprudence to guide decision making about off-label communications. That changed in 2012 when the US Circuit Court for New York decided US v. Caronia, determining that a sales representative for a pharmaceutical manufacturer had the constitutional right to discuss products for off-label uses. The Caronia case raised questions regarding the authority of the FDA, and to date, the FDA has not appealed. “Although only valid in the Second Circuit, the Caronia case opened the door for additional challenges,” says Liebman.
Since the Caronia case, the FDA revised and reissued a draft Guidance document related to the distribution of scientific and medical publications on unapproved new uses for drugs. Echoing Allergan’s 2009 complaint, the Washington Legal Foundation, a prominent public interest law and policy center, has submitted a comment challenging the Constitutionality of this draft Guidance.
How Much Does That Cost?
Several sections of the Affordable Care Act (ACA) address the cost of healthcare services, including prescription drugs. On the highest level, the ACA intends to shift from a fee-for-service model to a value-based outcomes model. In addition, the law mandates the disclosure of vast amounts of pricing and outcome information. The ACA drew attention to the issue of transparency around the pricing and usage of drugs, such as the costs associated with promotion of regulated products. Further, the FDA recently requested comments regarding use of comparative price information in direct-to-consumer and professional prescription drug advertisements.
“Because of new reporting requirements, a shift toward insurers reimbursing for value to the patient and the ability to make information publicly available online, consumers have an unprecedented amount of information available to make healthcare decisions,” explains Liebman. The New Consumer
Today’s patient has far better tools to become informed about the prescription drugs available to them. The proliferation of information publically available on the internet has left the FDA racing to issue guidance for the monitoring of interactive media and flooding federal websites with new data sets every month. This same information is available to health care providers. Patients and physicians alike now have access to everything from peer reviewed journal articles to patient blogs. The industry is seeing the information gap close, creating a new patient-consumer who is able to make complex decisions that balance health and economic considerations. If a $50 injection can be used off-label to treat a patient’s condition with comparable safety and effectiveness to a $500 injection used on-label, wouldn’t price information be of great value in making the decision about which drug to use? More and more, patients have access to that type of information.
Let’s talk about Non-Biologic Complex Drugs (NBCD). If you look at the FDA’s recent actions relative to raising the issue of quality and performance of generic products and working with outside partners to seriously investigate the problem, you’d think that NBCDs are an obvious top of mind agenda item for the agency to consider and act on via Guidance. But, as with many difficult regulatory questions, predictability comes at the expense of ambiguity – and regulators have a penchant for embracing ambiguity.
When it comes to NBCDs (as with so many other issues), predictability is power in pursuit of the public health.
Friend and colleague Scott Gottlieb pulls no punches in his Forbes column on the FDA’s approach (or lack thereof) to NBCDs.
(For more on the issue see “FDA’s Conditional Response to NBCDs”)
Commentary: FDA's Looming Decision On A Generic To Teva's Copaxone Reveals Drug Approval Woes
Scott Gottlieb
A year ago, the Food and Drug Administration quietly posted a public notice that it wanted to hire an independent lab to test a generic drug that it had already approved. FDA wanted to make sure the drug was safe and effective.
The issue concerned a copy formulation of a complex, intravenous medicine used to replenish kidney-dialysis patients’ stores of iron. FDA had approved this “generic” version of the drug in March 2011 because it believed that laboratory data showed that the replica version of the drug was the exact same as the original branded medicine it was copied from. In announcing the request for independent testing of the generic version, FDA was indirectly saying it might have been wrong.
FDA was going back to get more evidence – including data looking at how the drug was behaving in patients – to make sure that its original decision was sound. Additional evidence was needed because this type of drug represents a new chapter in FDA drug approvals. By law, generic drugs are supposed to contain identical copies of the active ingredient of the original branded medicine that they are copied from. With almost all generic drugs, making identical copies has been relatively easy because the original medicine was a small molecule, which has a simple molecular structure. In contrast, complex drugs involve large molecules and are difficult to copy. In fact, their physical and chemical properties may not be fully understood. Even so, FDA has begun to approve generic copies of complex drugs.
Since approving the generic IV iron medicine in March 2011, FDA has approved several other generic complex drugs, including a generic version of a drug that fights several types of cancer, called Doxil. None have been smooth affairs. At the time it approved that cancer drug Doxil, for example, FDA said it had developed a “novel bioequivalence method” to judge the copy drug same as its branded alternative. Like the case with IV Iron, FDA sought a “post-market” study in 2013 and another one in 2014 to make sure its original approval of Doxil was scientifically sound.
Now, on the anticipated eve of one of the most significant generic drug approval decisions in recent years—involving another complex drug—the lesson from the generic IV iron episode bears reminding. FDA is widely known to be considering the approval of a generic version of Teva Pharmaceutical’s (NYSE:TEVA) blockbuster drug for multiple sclerosis, Copaxone. The patents covering Copaxone for its 20mg/ml strength expired on May 24th. After patent expiration, FDA could approve generic copies of the drug at any time. But some of the same challenges that caused the agency to struggle with and sometimes stumble over its similar previous decisions still linger, and will color FDA’s decision concerning Copaxone.
When it comes to evaluating copies of these complex drugs, the fact is FDA doesn’t have very good tools and policies. These drugs slip between FDA’s other generic drug constructs. They are less complex than biological drugs, which have their own separate law governing how the agency should review and approve copy versions. (Unlike with the generic drug law, the approval of copy versions of biologicals generally must be supported by evidence from human studies.) But non-biological complex drugs are far trickier than generic versions of the normal, small molecule pill drugs that FDA is accustomed to evaluating. It’s that framework for these small molecule drugs that FDA has been trying to apply to these complex drugs.
These challenges illustrate a need to reconsider how FDA approves copy versions of complex drugs. Perhaps different approval standards should be used. Current law already contains an appropriate alternative to the generic drug law in the pathway used for the review and approval of copies of biological drugs, which gives FDA more latitude when it comes to the data it can use as a the basis for these approvals. Some of these principles could be applied to a new category that addresses the complex drugs. Or Congress could re-write certain aspects of the generic drug law, tailoring generic drug principles to the unique challenges of copying complex drugs.
FDA also needs to change its practices when it comes to these complex drugs, to more clearly establish reliable principles for how generic copies of these medicines can be safely brought to market once brand-name patents have expired. It needs to develop these scientific principles in a more transparent and inclusive process that leverages the expertise that FDA doesn’t readily posses to discern these laws of drug science. More on these policy challenges, and their potential resolutions later.
The complex drugs fall in a regulatory gap. FDA has tried to retrofit the “Hatch Waxman” generic drug law and policies that govern approval of small molecule drugs to these complex drugs, with sometimes troubling results. Regardless of the decision FDA makes with Copaxone, it remains clear that Congress and FDA alike need to re-examine the regulatory process when it comes to these intricate drugs.
The problem is that FDA has refused to define these complex drugs as distinct from normal, small molecule medicines. That has forced the agency to rely on less information in approving these complex copies than it probably would like. The agency’s desire to try and squeeze these complex drugs through its existing generic law approval pathway may have as much to do with political expediency as with good science. FDA is probably well aware that getting Congress to define a distinct category for these medicines, and give FDA proper tools, could be a heavy political lift. So FDA is doing what it often does: trying to massage its existing authorities and regulatory practices to fit novel challenges. But at what cost?
These non-biological complex formulations are different than small molecule drugs. As a result, they don’t fit the standard paradigm on which copy (generic) versions of branded drugs are typically reviewed and approved by FDA.
To approve a generic drug, the generic drug law and subsequent regulations discourage FDA from asking for data other than bioequivalence data. As a result, these generic drug approvals typically rely on “pharmacokinetics” data that shows that the copy drug gets into the blood in the same predictable fashion as its brand-name alternative. But for complex intravenous drugs, the behavior of the medicine often depends on aspects of the mixture that are hard to copy and even harder for FDA to fully characterize (i.e., understand the physical and chemical properties). Like the IV iron formulations, Copaxone is a complex drug – perhaps more complex than any drug of this type, where FDA has been asked to review copies. When it comes to these drugs, looking at bioequivalence data alone can be insufficient to tell how the drug will behave once it’s administered to the patient.
So sometimes the agency cheats a little. At times it has looked at human testing data after the fact, to make sure it didn’t err (as was the case with the generic IV iron medicines). Other times, FDA tries to expand the scope of what it can include in a generic application. This was the case when it came to the approval of generic versions of the blood-clot prevention drug, Lovenox. In that example, FDA looked at human data to make sure the two drugs didn’t cause different reactions from the body’s immune system. (FDA was accused of exceeding its authority under the generic drug law and was sued for this, but ultimately prevailed in court because the courts give great deference to FDA. Interestingly, Europe regulates generic Lovenox as a biological product, which means that evidence from human studies is required)
Copaxone is an especially hard case, because the drug’s benefits are thought to turn on the complexity of the mixture, which isn’t well understood.
The drug exits as a complex mix of long and short chains of carbohydrates. It is believed that the precise proportion of these long and short chains in the solution is tied to the drug’s therapeutic attributes. But making sure that a copy batch of the drug can reproduce the same quantity of long and short chain carbohydrates, in the same proportion, isn’t straightforward. And the generic drug law effectively bars FDA from looking at evidence from human studies to see if the copy is working as well as the brand-name alternative. For the most part, all FDA can do is examine data comparing the two solutions, and how they get into the blood (bioequivalence data). But FDA can’t look at how the generic version affects outcomes in patients.
So in the case of Copaxone, for example, FDA is widely believed to be considering gene expression data that shows how the drug turns on and off the function of certain genes. The genes FDA is looking at are thought to be involved in regulating how the drug modulates the immune system in multiple sclerosis. If FDA is relying on this sort of gene expression, it would be largely because FDA needs to find some potential surrogate marker in lieu of full comparative clinical endpoint studies, which FDA can’t ask for under the generic drug approval process. But here again, FDA would be creating brand new scientific criteria by establishing that the gene expression data can stand in for clinical outcomes data. These aren’t just review criteria that FDA is establishing in the context of its struggle with this particular application, and its desire to find a way to prove “sameness” based on laboratory testing data (so that it can approve the generic Capaxone). By relying on the gene expression data, FDA is establishing what should be immutable laws of drug science. Using the twists and turns of a meandering and secretive generic drug review is not the right place to be establishing these sorts of generalizable scientific principles.
To these ends, the challenge isn’t just the generic drug law, which doesn’t allow FDA to look at much more than bioequivalence data. The setback is what FDA has done in response to these limitations, to try and retrofit its existing policies on complex drugs where the generic drug principles are sometimes poorly suited. And FDA has entered this new chapter in generic drug approvals largely under the radar. Congress and the public generally are not aware of the new direction FDA is taking.
Instead of acknowledging that it needs a broader scope of data to ensure “sameness” (the statutory standard for a generic drug approval) between the original and the copy drug, FDA has typically divined new science in these circumstances – coming up with novel principles of drug science to determine how two drugs can be declared the same by comparing laboratory data that FDA often establishes on its own novel principles. Such is the case with the gene expression data that FDA is examining in the case of Copaxone. FDA will typically announce these new principles after the fact, often at the time of approval of the generic drug.
Problem is FDA doesn’t do this sort of science well. Establishing new principles on which sameness can be determined between complex formulations of drugs is something that requires expertise in these fields. FDA is in the business of evaluating data against known standards, not establishing those standards de novo. The enterprise of establishing standards upon which two highly complex drugs can be judged the same requires a great deal of expertise in discrete areas of science. This sort of expertise doesn’t exist in one place, and certainly isn’t the province of FDA. That’s not a knock on FDA, or its scientists. This sort of work just isn’t the business that Congress has tasked the agency with doing. FDA is not staffed or resourced to take on the task of developing novel principles of biology and discovering the standards for measuring how drugs affect biological systems.
As a result, FDA has often established principles that are at times embarrassingly incomplete, and sometimes spectacularly wrong. The re-adjudication of the generic IV iron approvals is one example. The problems FDA had in 2008 assuring safety and effectiveness of generic, copy versions of intravenous heparin is another example. FDA had to recently walk back guidance it put out on how to copy a popular eye drop that was another complex formulation. In each case FDA had established some principles upon which the agency thought it could reliably determine that two complex drugs were the same. In each case, FDA was wrong.
When it comes to certain complex drug formulations, Congress may need to update the law to give FDA broader discretion to use a larger complement of information to make sure that a copy version of a drug is the same as its branded counterpart (while still enabling the copy to be approved as a generic, fully substitutable medicine). If FDA had such latitude, it could actually speed generic entry of these complex drugs. Right now, each approval has been a long and tortuous process that often extends well past the expiry of legitimate patents. Congress, for example, crafted specific legislation when it came to copies of biological drugs. It recognized that the generic drug law did not adequately address how to develop and approve copy versions of these highly complex drugs. Right now, the non-biological complex intravenous drugs fall within a gap between the existing small molecule (pill form) medicines and the highly complex biological medicines. Neither approval pathway seems to address copy versions of non-biological complex medicines well.
But there’s another problem. This one is of FDA’s own making. In cases where FDA believes that the existing generic drug framework already gives it ample discretion, FDA needs to adopt a more transparent and inclusive process for developing the scientific principles upon which it makes these judgments. This sort of process ends up establishing final principles of drug science. Rather than these principles being divined through regulatory fiat, they need to be established in an open scientific process that readily draws on all of the available expertise in adjudicating these principles. FDA workshops and advisory panels could provide a forum for these discussions, should FDA choose to use them.
Moreover, FDA needs to generalize these principles in guidance, preferably well in advance of patent expirations that create the opportunity for generic entry. These standards, once established, often end up affecting many different kinds of generic drug approvals. By establishing them in an open process, FDA would make this important knowledge generally available, and would lower the barrier to market entry by generic firms of different levels of technical sophistication. It should be emphasized that FDA’s current lack of transparency makes it hard for many generic-drug companies to get on the playing field. The big companies, that have more access to FDA’s thinking, end up being advantaged over smaller generic players that don’t have this proximity. Transparency could promote generic competition.
In the case of the IV iron drugs, even after approving generic copies of these medicines, FDA went back in 2013 and commissioned research to develop a methodology for how it could determine sameness between a brand name and generic formulation of IV iron. It begs the question, what criteria were FDA using all along when it approved generic copies of these drugs? The scientist who received that award issued a press release referring to her work as “uncharted territory”.
The consideration of a generic version of Copaxone is being closely watched as, among other things, another indication of how permissive FDA has become in approving these generic complex formulations. In the past, the answer seemed to be as permissive as FDA needed to be in contorting rules of law and science to advance these approvals. It shouldn’t be that way. Congress should be tapped to give FDA the latitude to look at the science necessary to make comfortable and reliable determinations. The broader scientific community should be leveraged, through open dialogue, to give FDA the princiA new European Commission working paper positions the pharmaceutical industry at the heart of the region’s economic growth prospects.
Pharmaceutical Industry: A Strategic Sector for the European Economy (available here) marks a significant turning point towards an integrated life sciences strategy for Europe. The working paper takes stock of the sector’s current situation, focusing on developments made over the last years as the first step in preparation for a new strategic agenda.
The paper highlights several points for strategic focus including:
- The presence of a viable pharmaceutical industry contributes to the health and the quality of life of citizens by providing remedies to an increasing number of patients, through a more timely, widespread and equal access to pharmaceuticals.
- Intellectual property rights related to pharmaceuticals have gained prominence in debates about intellectual property rights policy. They have been at the forefront in discussions about the impact of intellectual property rights in terms of the access to medicines, particularly in developing countries. In the light of these divergent views, European companies are often faced with significantly lower levels of intellectual property protection in third countries, particularly in emerging economies. The challenges range from a lack of or non-enforcement of patents to the disclosure or reliance on data submitted by the original manufacturer for obtaining a marketing authorization by regulatory authorities, thus depriving companies of the economic benefits of their investments.
- Assessing pharmaceutical expenditure also requires taking into account the effects on other health-related costs (like hospitalization, sick leave, pensions, etc.) as well as the overall implications for industrial competitiveness and external trade.
The paper suggests a comprehensive approach to streamlining the policy formulation processes impacting the pharmaceutical industry at European and Member States level. Against this backdrop, the European Commission will organize an event bringing together relevant EU and national public and private stakeholders: decision-makers from public bodies in charge of industrial competitiveness, health, pricing and reimbursement, research and innovation at Member States level, and their Commission counterparts, patients, healthcare professionals, trade unions and industry representatives.
The strengthening of the competitiveness of the European pharmaceutical industry requires actual implementation of innovation policies at EU and Member States level in order to create incentives and rewards for a sustainable, competitive pharmaceutical sector that addresses public heath needs.
On the intellectual property rights front, more than half of EU industries are considered IPR-intensive, providing for 35% of European jobs and 39% of total economic activity. It is crucial to ensure a strong and effective framework for IP protection and enforcement if we are to preserve the ability of EU industries to adequately grow and export. This also implies raising awareness as to the critical need for IP.
In related news, the new EU Action Plan of DG MARKT addresses infringements of intellectual property rights in the EU, strengthens the enforcement policy framework against commercial scale IP infringements, by defining a set of 10 innovative actions and tools. This action plan notably embodies the "follow the money” approach, which deprives infringers of their revenues.
The revised Strategy of DG TRADE for the protection and enforcement of IPRs in third countries rightly accounts for the current challenges which right-holders are faced with when trying to protect or enforce their intellectual property rights abroad. Addressing specifically the challenges of access to medicines worldwide, this new strategy recalls there are "many factors affecting access but mostly unrelated to IPRs". The Commission highlights the need to come up with a broad response to this complex and multifaceted problem, to ensure affordable access to medicines without undermining the incentives needed for continued pharmaceutical research.
The Commission documents are must-reads for all health and finance ministries from Pretoria to Beijing, to Delhi and elsewhere as they debate and consider the future roles of both IPR and strategic collegiality in the realm of pharmaceuticals and the public health.
(At least on paper.)
As reported in BioCentury, FDA has released a draft four-year plan for 2014-2018 that reiterates its emphasis on advancing regulatory science. The agency said it plans to increase the use and capacity of regulatory science -- which it defines as the science of developing tools, standards and approaches to assess the safety, efficacy, quality, toxicity, public health impact or performance of a food or medical product -- to inform standards development, analysis and decision-making and to effectively evaluate products.
In the agency's strategic priorities for 2011-2015, the advancement of regulatory science was listed as the top priority for the agency as a whole. FDA has since published a strategic plan for regulatory science, which details eight priority areas and calls on the agency to collaborate with stakeholders to develop and refine clinical trial designs.
Other priorities include addressing globalization; advancing safety and quality by reducing risks in the manufacturing, production and distribution processes; strengthening detection and surveillance of problems; and improving response to identified and emerging problems. The agency said it intends to increase the exchange of information with foreign sources by assembling global coalitions of regulators. Earlier this year, the agency launched an initiative to exchange information with EMA and the European Commission on foreign inspections, building on a three-year pilot launched in 2012. Comments are due July 31.
How important is the issue of opioids? Well, important enough that it was the very first panel offered at the 2014 BIO Convention’s regulatory affairs track. And it didn’t disappoint.
Moderated by yours truly, I was joined by three experts (Douglas Throckmorton, MD, Deputy Director of Regulatory Programs, FDA’s Center for Drug Evaluation and Research, Richard C. Dart, MD, PhD, Director of the Rocky Mountain Poison and Drug Center, and J. David Haddox, DDS, MD, Vice President of Health Policy for Purdue Pharma, L.P.) and a room full of engaged and inquisitive attendees. The session began with a question – Who lost opioids?
I reminded the audience of the old public relations maxim that, “Everything you read in the newspaper is true – except for those things you know about personally.” And today that means the preeminence of social media. Google “opioid abuse deterrence” and you’ll find a lot of hits from lawyers and elected officials in the mainstream media -- but you have to know where to look (or who to ask) to access expert thinking from the FDA.
There’s certainly no dearth of verbiage and suggested solutions from the law enforcement community. Alas, those fixes rely on the general philosophy that the only good opioid is a recalled opioid. And that results in strategies that require strict prescribing limitations, and severely limited access. Punishing the legitimate pain patient, all the panelists agreed, is the wrong way to go.
Then there’s the legislative solution – but what this really means is allowing politics to drive the agenda. The posturing and hyperbole that has surrounded the issue of opioids pain medicines hasn’t resulted in a single workable solution. And the premature promptitude of many attorneys general and chief executives such as Massachusetts Governor Deval Patrick has led to numerous headlines but, in the end, nothing but fruitless lawsuits.
As Mark Twain quipped, “For every complex problem there is usually a simple answer – and it is usually wrong.” What those seeking to solve the problem with one-shot solutions have ignored is that pain in America is a medical problem of enormous proportion.
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 the pain disables them. Pain costs the US economy about $600 billion dollars a year in lost productivity and healthcare cost. And lawsuits, recalls, and police actions won’t change those dire statistics.
But just as opioids aren’t the problem, neither are they a panacea. Yet payers often implement barriers to the use of branded, on-label non-opioid pain medicines, relegating these treatments to second line options. 52% of patients diagnosed with osteoarthritis receive an opioid pain medicine as first line treatment, as do 43% of patients diagnosed with fibromyalgia, and 42% of patients with diabetic peripheral neuropathy.
Aren’t abuse deterrent opioids the magic bullet we’ve all been looking for? Not really. First of all, what does “abuse deterrence” even mean? As FDA Commissioner Peggy Hamburg testified to Congress, “It doesn’t do any good to label something as abuse deterrent if it isn’t actually abuse deterrent, and right now, unfortunately, the technology is poor.” Abuse deterrence is a goal. And at present, it’s an elusive one.
Abuse deterrence also raises some very important and difficult regulatory questions for the FDA. What type of 21st regulatory science will be required to review abuse deterrent applications? How will the agency approach the approval of non-abuse deterrent generics? What about more sophisticated pharmacovigilance programs? And, last but not least, how can the FDA better protect the public health while simultaneously preserving innovative development programs?
Dr. Throckmorton’s presentation noted that both FDA and other government epidemiologists are working to improve the surveillance databases and tools used to assess impact of abuse deterrent formulations in US market. He specifically mentioned the “DAWN” (Drug Abuse Warning Network) database replacement, measuring appropriate access to opioids by pain patients. The development and broad adoption of successful abuse-deterrent formulation remains an important priority for FDA. But we’re in the early days of the science, with much important work to be done.
But what else can be done?
As former Canadian Prime Minister 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 – particularly for opioids? As CDER Deputy Director (and the FDA’s point-man on opioids) Dr. Douglas Throckmorton said, “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.”
While scene-stealing members of Congress, some governors, and a gaggle of state attorneys general are trying to run roughshod over science-based regulation to great attention from the media, the FDA has been quietly doing the right thing without anybody noticing. In the immortal words of Don Draper, “If you don't like what is being said, then change the conversation.
The FDA must play a lead role in facilitating physician education, not only through labeling language but physician education. The FDA has, of late, repeatedly discussed enhancing continuing medical education (CME) and working to develop (with a broad constituency) validated tools for physicians to use in determining which patients may be more prone to slide into abuse so they can choose their therapeutic recommendations more precisely.
In the words of FDA Commissioner Hamburg, “It all comes back to provider education.” Amen.
Provider education – the Hamburg Manifesto.
That’s not regulatory mission creep; it’s the appropriate application of the agency’s Safe Use of Drugs initiative. The way you make a drug “safer” is to ensure that it is used by the right patient in the proper manner.
Abuse deterrence is a worthy goal and will evolve when all the players work together in a more regular and synchronistic fashion. Fortunately, all panelists agreed this was the reality.
As the Japanese proverb goes, “Don’t fix the blame, fix the problem.”
The Massachusetts Senate has passed legislation to allow pharmacists to substitute a biosimilar for a biological medicine when the United States Food and Drug Administration has determined that the two biological products are interchangeable and the prescriber has not instructed otherwise.
Following a substitution, the bill requires pharmacists to notify the prescribing practitioner and the patient. The bill will now go to the Governor for his signature.
Sounds good, right? Physician notification. But the bill was obviously drafted before the FDA expanded the types of biosimilars it will consider. Once upon a time there were two categories: biosimilar and interchangeable. But today there are four: not similar, similar, highly similar or highly similar with a fingerprint-like similarity -- depending on the type, nature and extent of any structural and functional differences revealed.
The reality is that “interchangable” is a thing of the past – even before it was a thing of the present.
In keeping with the spirit of the Massachusetts legislation (as well as that in many other states), the nomenclature should be reconsidered to reflect the realities of the evolving regulatory science.
First-Ever Patient-Initiated “Guidance for Industry” for Duchenne Muscular Dystrophy Submitted to FDA
Parent Project Muscular Dystrophy-led guidance seeks to address unmet clinical needs of individuals with Duchenne muscular dystrophy and accelerate development of safe and effective therapies
Washington, DC–June 25, 2014 -- Parent Project Muscular Dystrophy (PPMD) and a broad coalition of stakeholders today submitted the first-ever patient advocacy-initiated draft guidance for a rare disease to the U.S. Food and Drug Administration (FDA) to help accelerate development and review of potential therapies for Duchenne muscular dystrophy (Duchenne).
“This landmark guidance represents a major milestone for the Duchenne community and may open the way for other rare disease groups to incorporate the patient perspective in a well-documented and quantifiable way, moving beyond any one family’s experience,” said PPMD President Pat Furlong. “By working closely with the FDA to provide industry and other clinical trial sponsors with clearer guidance from the patient perspective, we will increase the likelihood that clinical trials will be designed to better match the unique needs of Duchenne patients. It is our profound hope that this, in turn, will lead to the approval of much needed treatments for all people living with Duchenne muscular dystrophy.”
Duchene, the most common lethal genetic disorder diagnosed in childhood, is a progressive and degenerative condition with no cure or disease-modifying treatments available in the United States.
Clinical trials for rare diseases like Duchenne are difficult to design and implement because of challenges such as small study populations, incomplete and evolving understanding of rare diseases, and effective ways to measure clinical impact of therapies being studied. Last year, FDA collaborated with PPMD and its scientific advisors to convene a policy forum that informed the process for developing the Duchenne community’s suggested guidance.
“The U.S. Food and Drug Administration is appreciative of the input of Duchenne patients and patient advocates. Their input will enhance the essential data-driven process and evaluation of new therapies,” said Janet Woodcock, M.D., Director of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.
About The Suggested Guidance
More than 80 representatives of the Duchenne community - including parents and patients, medical experts, academics, and biopharmaceutical industry representatives -- participated in seven working groups that met over the past six months to draft the guidance.
The cornerstone of the guidance encourages the FDA and trial sponsors to engage patients and their families at all stages of trial development and to take into account what they consider acceptable risk in clinical trials. A recent PPMD study published in the journal Clinical Therapeutics* shows that parents of children with Duchenne will accept substantial risk when balanced with noncurative slowing or stopping of the progression of muscle weakness, even with no improvement in life expectancy. The results came from the first-ever scientific survey of benefit/risk perspectives that PPMD conducted last year involving 120 Duchenne parents.
“As the FDA evaluates new drug applications for Duchenne therapies, it is imperative to take into consideration the value that parent decision makers place on even moderate benefits to function and mobility, and their tolerance for considerable risk and uncertainty,” said Furlong. “Parents and caregivers of Duchenne children know firsthand that every day without treatment is another day closer to their child losing essential activities of daily living such as walking, feeding oneself, and eventually, breathing. When your child is living with Duchenne, you find yourself willing to take significant risk for even the hope of modest benefit. Parents can make these decisions thoughtfully and the FDA must recognize that. They cannot protect us from what we think is important in the drugs we need now.”
Each section of the guidance includes extensive published or in-press peer-reviewed articles and focuses on six areas aimed at overcoming the challenges in trial design and implementation:
* Benefit/Risk Assessment – providing a community-centered approach for the benefit-risk framework fundamental to the regulatory process and reflecting the community’s tolerance of potential risks or uncertainty of benefit associated with new treatment options.
* Diagnosis – referring sponsors to guidance produced by the American Academy of Pediatrics (AAP) on a diagnostic algorithm, as well as, providing context on diagnostic delay and importance of genetic analysis using modern technologies, including access to genetic testing.
* Natural History – accurately characterizing the clinical course of Duchenne to reflect the timing of the loss of certain abilities based on current medical management practices, including how Duchenne affects cardiac and pulmonary function.
* Clinical Trial Designs, Outcome Measures and Considerations – ensuring that trials – to the degree possible – are inclusive of Duchenne patients of all ages and disease stages.
* Muscle Biopsy-Based Biomarkers – addressing key considerations when performing muscle biopsies, including the ethical imperative to perform them only when needed and precautions to assure usable specimens; sponsors are also referred to an international effort to standardize methodologies and emerging technologies.
* Non-Muscle Biopsy-Based Biomarkers – exploring the ability to bring non-invasive imaging techniques to replace biopsy (e.g., MRI/MRS skeletal muscle imaging) and eventually reach the goal of being a surrogate endpoint for treatment trials.
PPMD-Led Efforts
The suggested FDA guidance represents the culmination of PPMD’s 20 year history of improving care and developing urgently needed therapies for Duchenne. PPMD led the effort to pass the MD-CARE Act, which created the Senator Paul Wellstone Muscular Dystrophy Cooperative Research Centers. The draft guidance builds on PPMD’s effort to shape federal policy that reflects the needs of families living with Duchenne, including the release of “Putting Patients First” which calls on the FDA to act more flexibly when reviewing applications for Duchenne therapies. PPMD also ensured that the FDA Safety & Innovation Act of 2012 (FDASIA) responded to the needs of the community; recently published a groundbreaking benefit/risk study which documented the willingness of families to live with risk; and held a national PPMD-FDA Duchenne Policy Forum where the community made its needs and preferences in drug development known to the Agency.
*[EDITOR’S NOTE – Peay H.L. et al: A community-engaged approach to quantifying caregiver preferences for the benefits and risks of emerging therapies for Duchenne muscular dystrophy; Clinical Therapeutics, Vol. 36, No. 5, 2014; available for access: http://www.clinicaltherapeutics.com/article/S0149-2918(14)00209-4/abstract.]
The New York Times has written quite a lot lately on the cost of drugs – without a word on either the value of new medicines or the cost of investing in innovation. On the up side, the Gray Lady has finally discovered the cost of poor medicines quality.
For years, Dr. Harry Lever, a cardiologist at the Cleveland Clinic, has been warning nearly anyone who would listen of his growing suspicions about generic versions of a widely used heart drug, Toprol XL.
Patient after patient, he said, would visit his office complaining of chest pains or other symptoms after switching from the brand-name version, made by AstraZeneca, to a generic product, often one made in India. When he switched them back to the brand — or to another generic — the symptoms disappeared, he said. Dr. Lever wrote a letter outlining his concerns to the Food and Drug Administration in 2012, and this year, he traveled to Washington to try to get the attention of Congress.
Dr. Lever could not prove that the generic drugs were to blame. “You see enough people and you get a feel, but it’s anecdotes,” he said in an interview Monday. “It’s not science.”
This is in keeping with a March Reuter’s story on the same topic:
Some U.S. doctors are becoming concerned about the quality of generic drugs supplied by Indian manufacturers following a flurry of recalls and import bans by the Food and Drug Administration.”
"I'm just beginning to realize the gravity of the problem," said Dr. Steven Nissen, head of cardiology at the Cleveland Clinic. "It's terrible and it is starting to get a lot of traction among physicians."
Hopefully the Times story will provide further traction because, as Dr. Lever said (in the Reuter’s story),
We are losing control over what people are swallowing," said Dr. Harry Lever, a cardiologist at the Cleveland Clinic who is trying raise awareness of the matter among U.S. lawmakers. "Now, when a patient comes in who is not doing well, the first thing I do is look at their drugs and find out who makes it."
It’s too simplistic to call these “quality” problems. There’s a range from sub-standard API and manufacturing issues, to excipient changes and, most importantly, bioequivalence and bioavailability standards.
Bioequivalence does not always equal therapeutic equivalence – and that’s as true for Toprol XL as it is for Wellbutrin. According to the Times story, Two large Indian manufacturers, Wockhardt and Dr. Reddy’s Laboratories, have announced recalls over the last two months totaling more than 100,000 bottles of Toprol XL because their products were not dissolving properly — therefore probably not working as they should. The drug is a beta blocker that treats high blood pressure and heart ailments. Not good.
FDA’s recent draft guidances on bioequivalence for both generic and innovator products, as well as the move towards independent labeling for generic products are additional steps the agency has recently taken to address the issue of drug quality beyond safety and efficacy. And the implications for biosimilars is obvious
(Something else to consider is for the FDA to report BE and BA and PK data in generic labels.)
Small is the new Big means we must think differently about pharmacovigilance. While we must continue to capture adverse event data, we must also strive to capture Substandard Pharmaceutical Events (SPEs). SPEs occur when a product does not perform as expected—perhaps because of API or excipient issues. SPEs can arise because of an issue related to therapeutic interchangeability. When it comes to 21st-century pharmacovigilance, we have to both broaden and narrow our views about bioequivalence to the patient level.
Where's the Times editorial on that?
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.
