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Despite what you might think, the various actions and directives emanating from White Oak tell a very liner story with very steady red thread – and that thread is the difference between communications and marketing.
To many in pharmaceutical company marketing and regulatory review departments it may seem a distinction without a difference. But that’s a fundamental misunderstanding of the FDA’s mindset when it comes to social media.
As Casey Stengel used to say, “Let’s look at the record.”
In April of 2009, the FDA send out 14 warning letters on sponsored Google links – and many pharmaceutical regulatory review professionals said, “See, told ya – you can’t use social media,” and breathed a secret sigh of relief – the first sign of an ever-growing regulatory social media Stockholm Syndrome.
But they were wrong; because when you read the letters it becomes quickly evident that the FDA’s then Division of Drug Marketing, Advertising, and Communication properly equated “sponsored links” not with social media – but with paid advertising. In the context of those letters, “sponsored” equals “paid.” And there are rules for that.
Even before the famous 14 Google letters, in September 2008, the FDA sent out a warning letter regarding a YouTube video in which a paid celebrity spokesperson said that a drug had “cured” his disease (a decidedly off-label claim, shades of Dorothy Hamill and Vioxx). And many internal reviewers industry-wide said, “See, you can’t use YouTube.” Not so. Read the letter. If the content is non-compliant, then it is non-compliant regardless of platform. It’s the content that counts.
In March 2013, there was much angst over the FDA’s Warning Letter to AMARC Enterprises because of their Poly Mva FaceBook page. Aha! said our friends in legal and regulatory review said – you can’t use FaceBook!
The gist of that letter is that the company is marketing its veterinary dietary supplement as a human oncology drug. OPDP spends a lot of space on violative claims made on the company’s website and then – at the very bottom of the letter – addresses the issue of FaceBook. The OPDP writes that, We also note that your Facebook account includes a post which was “liked” by “Poly Mva”:
“Poly MVA has done wonders for me. I take it intravenously 2x a week and it has helped me tremendously. It enabled me to keep cancer at bay without the use of chemo and radiation…Thank you AMARC”
That’s a violative statement on any media platform. It just happened to take place on FaceBook. And the letter was rather prescient when you consider the FDA’s most recent social media draft guidance of June 2014, Correcting Independent Third-Party Misinformation About Prescription Drugs and Medical Devices:
If a firm chooses to respond to misinformation about its products using non-truthful or misleading information or in a manner other than that recommended in this draft guidance, however, FDA may object if the information provided by the firm does not comply with applicable regulatory requirements related to labeling or advertising, if any.
“Liking” a violative third-party statement on your own FaceBook is violative behavior. Not rocket science and a clear and clarion call to the distinction between communications and marketing.
Now let’s go back in time to the agency’s December 2011 draft guidance, Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices.
This draft guidance doesn’t address many of social media’s (referred to in the document as “emerging electronic media”) regulatory red flags such as adverse events, the question of property owner vs. property user, and a more precise discussion of what “sponsored” means.
But the giant regulatory bugaboo, not only of social media but of regulated speech writ large, is off-label communications. So those who complained this document isn’t “comprehensive enough” don’t understand what it has to offer. Most importantly, it continues the red thread of marketing vs. communications, expanding in a crucial way to off-label marketing vs. off-label communications.
Consider the following verbiage from the draft guidance:
FDA has long taken the position that firms can respond to unsolicited requests for information about FDA-regulated medical products by providing truthful, balanced, non-misleading, and non-promotional scientific or medical information that is responsive to the specific request, even if responding to the request requires a firm to provide information on unapproved or uncleared indications or conditions of use.
The agency recognizes companies are already responding to unsolicited requests for off-label information. That means the current procedures companies have in place to address these requests are (when properly followed) FDA compliant.
That’s not, however, a get-out-of-jail-free card by any means. Just as with traditional communications, there’s a great deal of regulatory ambiguity and use of the FDA’s favorite tense -- the conditional tense:
Statements that promote a drug or medical device for uses other than those approved or cleared by FDA may be used as evidence of a new intended use.
In other words, the role of legal and medical in the review of social media communications (relative to off-label issues and beyond) is still crucial. This draft guidance doesn’t lighten the regulatory burden – it just makes it more feasible.
What it also says (IMHO) is that responding to unsolicited off-label communications is, indeed, in the best interest of the public health:
FDA recognizes that it can be in the best interest of public health for a firm to respond to unsolicited requests for information about off-label uses of the firm’s products that are addressed to a public forum, as other participants in the forum who offer responses may not provide or have access to information about the firm’s products.
The agency has, importantly, made a clear distinction between “solicited” and “unsolicited” off-label questions:
Unsolicited requests are those initiated by persons or entities that are completely independent of the relevant firm. (This may include many health care professionals, health care organizations, members of the academic community, and formulary committees, as well as consumers such as patients and caregivers). Requests that are prompted in any way by a manufacturer or its representatives are not unsolicited requests.
The draft guidance makes it clear that misinformation is an important issue:
The Internet has also spawned a variety of social media tools that host online content primarily created and published by users other than the intellectual property owner or product manufacturer. In some cases, this online content may not be accurate.
Which brings us to the June 2014, Correcting Independent Third-Party Misinformation About Prescription Drugs and Medical Devices.
For those of you not currently on NoFocus therapy, you will remember the 2009 Part 15 hearing on social media – the “SuperBowl of FDA Part 15 hearings.” One of the key questions the agency wanted to discuss was how to correct erroneous product information. All they got were blank stares and request for FDA guidance. Five years later – voila!
The agency writes:
This draft guidance is intended to describe FDA’s current thinking about how manufacturers, packers, and distributors (firms) of prescription human and animal drugs (drugs) and medical devices for human use (devices) should respond, if they choose to respond, to misinformation related to a firm’s own FDA-approved or -cleared products when that information is created or disseminated by independent third parties on the Internet or through social media or other technological venues (Internet/social media), regardless of whether that misinformation appears on a firm’s own forum or an independent third-party forum or website.
Key take-away is that the decision to correct errors is purely voluntary. (But, then again, technically so are all product recalls.) Where that becomes more complicated is how companies may choose to cherry-pick where they interceded for corrective purposes. This is not an issue addressed by the FDA in this draft guidance. One thing this all means is more work for legal and regulatory review.
This draft guidance is all about user-generated content. The agency writes:
The Internet and Internet-based technologies have made it easier for third parties who are independent of firms to disseminate information about drugs and devices. Information created by third parties (which for purposes of this guidance is user-generated content (UGC)) might appear on an interactive portion of a firm controlled website or other interactive Internet/social media platform, or information might appear on a website or other Internet/social media platform that is independent of, or not under the control or influence of, a firm.
Many Internet/social media platforms allow for real-time and continuous communications and interactions (e.g., blogs, microblogs, social networks, online communities, and live podcasts) while other platforms do not provide a means for interactive content to be posted. Whether a forum is interactive may affect the means by which a firm is able to respond to information.
And, the agency stipulates, “UGC might not always be accurate and may be dangerous or harmful to the public health.” Well, yes. What’s a manufacturer to do?
Five years later, some helpful advice from the good people at White Oak.
Specifically:
If a firm voluntarily corrects misinformation in a truthful and non-misleading manner and as described in this draft guidance, FDA does not intend to object if the corrective information voluntarily provided by the firm does not satisfy otherwise applicable regulatory requirements regarding labeling or advertising, if any.
From a regulatory perspective, that’s a lot of wiggle room and should provide significant food for thought in erring on the side of more rather than fewer voluntary corrective actions.
But (per 12/11) guidance:
If a firm chooses to respond to public unsolicited requests for off-label information, the firm should respond only when the request pertains specifically to its own named product (and is not solely about a competitor's product).
Forewarned is Forearmed. Don’t get to cute. Follow the red thread.
The June 2014 draft guidance isn’t about sponsored communications. The agency writes:
This draft guidance does not apply when a firm is responsible for the product communication that contains misinformation. A firm is responsible for communications that are owned, controlled, created, or influenced, or affirmatively adopted or endorsed, by, or on behalf of, the firm.
A firm is thus responsible for communications on the Internet and Internet-based platforms, such as social media, made by its employees or any agents acting on behalf of the firm to promote the firm’s product, and these communications must comply with any applicable regulatory requirements.
Specifically:
… this draft guidance applies when a firm is not responsible for a product-related communication that appears on the firm’s own forum, an independent third- party website, or through social media, and the firm chooses to correct misinformation about its own product contained in that communication. In such cases, we recommend that the firm do so as described in this draft guidance.
Here are the agency’s eight ground-rules for “appropriate corrective information;”
* Be relevant and responsive to the misinformation;
* Be limited and tailored to the misinformation;
* Be non-promotional in nature, tone, and presentation;
* Be accurate;
* Be consistent with the FDA-required labeling for the product;
* Be supported by sufficient evidence, including substantial evidence, when appropriate, for prescription drugs;
* Either be posted in conjunction with the misinformation in the same area or forum (if posted directly to the forum by the firm), or should reference the misinformation and be intended to be posted in conjunction with the misinformation (if provided to the forum operator or author);
* Disclose that the person providing the corrective information is affiliated with the firm that manufactures, packs, or distributes the product.
Truthful. Accurate. Transparent. Three good rules of thumb. But what about “timeliness?” No advice from the agency on this one – but something crucial for manufacturers to consider since the goal here is to protect the public health.
Again, the agency offers important nuance on how to correct. For example, don’t just correct one mistake when multiples ones appear. The draft guidance also offers absolutely critical commentary relative to the depth and breadth of responsibility when correcting one piece non-sponsored UGC, “The firm is not expected to correct misinformation that appears on other webpages of the website.”
Those sweet sixteen words address a world regulatory angst.
Further:
Once a firm undertakes the correction of misinformation, FDA does not expect the firm to continue to monitor the website or communication that previously included UGC containing misinformation.
This does, however, point to the need for individual companies to develop their own policies in this regard. More work for legal/regulatory review teams!
And, for those of you who are thinking a little too hard, consider this important caveat:
… if a firm chooses to correct only misinformation that portrays its product in a negative light in a third-party communication but does not address misinformation that overstates the benefits of its product in that same clearly defined portion of the communication, the firm’s actions do not meet the recommendations in this draft guidance.
Voluntary corrective action isn’t just about “bad” information. Another nod to the distinction between marketing and communications.
And, importantly:
FDA recognizes that a firm cannot control whether an independent third party refuses to correct the misinformation, or corrects only a portion of the misinformation even though the firm provided complete corrective information, or declines to include the respective required labeling, or declines to remove misinformation, or does not correct all the misinformation in one clearly defined part (if the firm sought to correct more than one piece of misinformation). Accordingly, FDA will not hold a firm accountable for an independent third party’s subsequent actions or lack thereof.
The perfect shall not impede the public good.
And, lastly:
FDA does not expect firms to submit corrections to the Agency when correcting misinformation pursuant to this draft guidance; however, FDA recommends that firms keep records to assist in responding to questions that may come from the Agency. The records should include, for example, the content of the misinformation, where it appeared, the date it appeared or was located, the corrective information that was provided, and the date the corrective information was provided.
A few words (no pun intended) on the other June draft guidance for Industry Internet/Social Media Platforms with Character Space Limitations — Presenting Risk and Benefit Information for Prescription Drugs and Medical Devices.
The agency writes:
Risk information should be comparable in content and prominence to benefit claims within the product promotion (i.e., a balanced presentation). Achieving a balanced presentation requires firms to carefully consider the desired benefit claims and risk profiles for their products when choosing a promotional platform.
That’s good advice – choose the platform that best suits any given communications need. But, it’s not really any communications need – it’s any promotional program. That’s important because promotional speech is regulated speech. And that’s not just regulatory rhetoric. And this begs a crucial question not covered in the draft guidance – What it the intent of the communications?
Don’t wait for the FDA to offer guidance on that. They will not and should not. That’s a question only the communicator can answer. And it needs to be done honestly and early in the communications development process. Is it a marketing strategy or a service to the public health?
The agency writes:
FDA acknowledges that Internet/social media platforms associated with character space limitations may pose challenges for firms in providing a balanced presentation of both risks and benefits of medical products, as discussed above … The firm should also provide a mechanism to allow direct access to a more complete discussion of the risks associated with its product.
It’s not Brief Summary, it’s Tweet Summary.
The agency’s most important advice appears on Page 12 of the draft guidance:
In communicating risk information on Internet/social media platforms with character space limitations, firms should consider the following points:
1. Risk information should be presented together with benefit information within each individual character-space-limited communication (e.g., each individual message or tweet).
2. The content of risk information presented within each individual character - space-limited communication should, at a minimum, include the most serious risks associated with the product.
3. A mechanism, such as a hyperlink, should also be provided within each individual character-space-limited communication to allow direct access to a more complete discussion of risk information about the product … the Agency recommends that a direct hyperlink to a landing page that is devoted exclusively to comprehensive risk information about the product be initially included within the original character-space-limited communication.
Not rocket science, but urgently important to remember when considering both the design and appropriateness of a limited-character platform. Also, the use of hyperlinks is crucial. (Note – the agency makes it clear that a link’s name should also be considered. Specifically, it shouldn’t be a claim (i.e., www.bestcancercuredrug.com).
Marshal McLuhan wrote that, “At electronic speed, all forms are pushed to the limits of their potential.” Now replace “electronic” with “digital” and you have a good headline for both the obstacles and the opportunities of social media for regulated industry. The challenge, as James Fowler of the University of California, San Diego puts it, is for Pharma to “recognize its network potential.”
And that’s potential not just for marketing, but for public health communications. It is the convergence of social media and social marketing.
Ian Read (Chairman and CEO of Pfizer and the current Chairman of PhRMA) recently published a piece on LinkedIn under the title, Why Society Needs a Vibrant Pharmaceutical Industry: Improving Patients' Lives.
Read writes:
As an industry we are working diligently to improve our standing in society. We understand that we have a great responsibility. We are at the center of society’s desire and expectation for delivering potential cures and new lifesaving treatments. We will continue to fulfill that vital purpose.
Fine sentiments and well-crafted words – but working hard alone isn’t enough to earn trust. Pharma must work hard to do the right thing.
The genesis of Mr. Read’s philosophy began (at least publically) this past April at PhRMA’s 14th annual meeting in Washington DC.
During his inaugural remarks as incoming PhRMA board chair Read shared his concern about the industry’s failure in getting the message out about “the value we generate.” His key message, “We need to fix the misperception gap.”
Specifically he talked about the industry’s need to broaden the conversation from the economic performance of biopharmaceutical companies to the value that accrues to society and called for a “dialogue with society.” Bravo.
Pharma must embrace a new paradigm. Rather than focusing on traditional ROI (Return on Investment), they must now also consider Return on Integrity.
Integrity comes in many forms. Honesty. Virtue. Morality. But it also means (in more common parlance) “doing the right thing.” It means not waiting to be told to do it or waiting to see what others do first. Integrity means being principled and, as my father used to say, “A principle doesn’t count until it hurts.”
For there to be Return on Integrity, integrity must first be demonstrated – publically demonstrated with names attached. This is especially true in the age of social media where the public is watching and commenting. And nature abhors a vacuum.
The FDA’s “Correcting Independent Third-Party Misinformation” presents an opportunity.
If a firm voluntarily corrects misinformation in a truthful and non-misleading manner and as described in this draft guidance, FDA does not intend to object if the corrective information voluntarily provided by the firm does not satisfy otherwise applicable regulatory requirements regarding labeling or advertising, if any.
This provides industry with a tailor-made opportunity to demonstrate integrity at little or no risk – by correcting the mistakes of others about their products in a transparent and appropriate manner.
Who will step up to the plate? Who will be first? Who will earn the return on integrity? Good guidance has been provided. Now it’s time for industry to do the right thing.
And internalizing the difference between digital marketing and social media communications is a good place to start. It’s time for pharma to cross the social media Maginot Line.
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 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
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?
According to Poor Quality Drugs and Global Trade: A Pilot Study (a new paper from the National Bureau of Economic Research), Indian pharmaceutical companies are selling lower quality drugs at higher prices in Africa while at home on the Subcontinent, they’re selling the same drugs, manufactured to a higher quality standard at lower prices.
According to the paper’s abstract:
Experts claim that some Indian drug manufacturers cut corners and make substandard drugs for markets with non-existent, under-developed or emerging regulatory oversight, notably Africa. This paper assesses the quality of 1470 antibiotic and tuberculosis drug samples that claim to be made in India and were sold in Africa, India, and five mid-income non-African countries. We find that 10.9% of those products fail a basic assessment of active pharmaceutical ingredients (API), and the majority of the failures are substandard (7%) as they contain some correct API but the amount of API is under-dosed. The distribution of these substandard products is not random: they are more likely to be found as unregistered products in Africa than in India or non-African countries. Since this finding is robust for manufacturer-drug fixed effects, one likely explanation is that Indian pharmaceutical firms and/or their export intermediaries do indeed differentiate drug quality according to the destination of consumption.
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? 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.
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.
As my friend and former FDA colleague Dr. Scott Gottlieb has pointed out, 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.
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 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.
Gottlieb believes (and I concur), that 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.
As Gottlieb points out, 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.
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.
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.
The foundational problem here is that the 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.
Per Gottlieb, 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.
Not subtle – but 100% on target.
FDA needs to adopt a more transparent and inclusive process for developing the scientific principles upon which it makes judgments on NBCDs and draft guidance that generalizes these principles, preferably well in advance of patent expirations that create the opportunity for generic entry. 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. Transparency, per Gottlieb, could promote generic competition.
Amen.
The fact-finding phase is over. At the September 10th 21st Century Cures Initiative roundtable, E&C Chairman Fred Upton (R/MI), said that committee staff will now begin developing draft legislation. “We intend to release a Cures legislative discussion draft in early January 2015 and will look to swiftly move the legislation early in the next Congress.”
But, per Ranking Committee Member Henry Waxman (D/CA), “If we come in with a blunt instrument, suddenly recreating the FDA authorities or mandating things for FDA or … the Department of Health and Human Services to do things they are not equipped to do – and that we of course don’t fund them to do – I think we have to be cautious about some the legislation that may be proposed.”
Waxman’s fear of unintended consequences may seem unusual for someone who often advocates for an active government role in addressing societal problems, but he noted that one of the major reforms at FDA in recent decades, the creation of accelerated approval, was spurred on by AIDS activists, and not by legislation. “The people that brought home the reform at FDA, that got some of these therapies out quickly, were the ACT UP group and the gay community,” he said. “They studied the law of FDA and argued, ‘You don’t need to take so long, you don’t have to weight to the end result to show that the therapy is safe and effective, you can have markers to get these products out more quickly.’”
Stand by for action.
This is being dumb by design or default. Either way it's dumb.
What is a me-too drug? Does Schnipper regard all medicines that treat HER-2 positive tumors as alike? What about the variations in epigenetics that a range of drugs control for? Should an oral version of an older drug be considered me-too?
And again Schnipper talks about 'marginal gains.' He has previously said 3 months of life is marginal. And he has yet to explain how spending on new medicines to extend life is more of a waste of money than, say, spending money on pre-natal care which has also produced marginal results. Or more broadly, why spending money on new medicines where there is no other treatment available somehow wrecks our economy. Really? When if we DOUBLED what we spent on cancer medicines it would be all of 1 percent of total health care spending??
Schnipper's obsession with ending life by force or fiat is what explains his drive and shapes his desire to ration drugs. And so far, he and ASCO have avoided debating or discussing the cancer rationing app.
That's playiing dumb. By design.
For those of you interested in the other side of this issue, here's my article on the ASCO cancer rationing app.
http://bit.ly/1seDNhl
From today’s edition of the Washington Examiner …
Cheaper drugs can also mean less choice without savings for patients
Peter J. Pitts
The economics of American healthcare are dictated by the Golden Rule: "He who has the gold makes the rules.” And those rules reward corporate greed at the expense of physician empowerment and patient care.
The gold in this case is the money leveraged by pharmacy benefit managers (PBMs) to reimburse patients for their medicines. And it’s a golden hammer used to negotiate lower prices from pharmaceutical companies. But where do those savings go, and what is the impact on a physician's ability to practice medicine and — most importantly, therapeutic outcomes for patients?
PBMs are large organizations responsible for not only processing and paying prescription drug claims, but developing and maintaining an insurance company’s formulary (the list of prescription drugs covered by a particular drug benefit plan), contracting with pharmacies, and negotiating discounts and rebates with drug manufacturers. Today, whether or not they know it, more than 210 million Americans nationwide receive drug benefits administered by PBMs.
But the savings garnered through bare-knuckle negotiations are not being passed down to patients. Lower drugs costs negotiated by payers are being used to fatten the corporate coffers of those same organizations. Consider the 2010 comment of George Paz, chairman and chief executive of Express Scripts (one of our nation’s largest PBMs), “The cheapest drugs is (sic) where we make our profits.” And just who is “cheaper” better for? "Our whole model is switching people to lower-cost drugs. The more money my shareholders make, the more money I make."
Paz ranked sixth on the 2012 Forbes CEO compensation list, with $51.5 million in total compensation the preceding year, and $100.2 million over a five-year period.
More money for George and Co., but less choice and no savings for patients. This has been the case with brand vs. generic medicines for years. But at least these often resulted in lower out-of-pocket co-pay expenses for patients. Today, the same fatten-George’s Wallet schemes are being used for drugs for evermore serious and life-threatening conditions. Consider Multiple Sclerosis, an autoimmune disease that affects the brain and spinal cord of over 400,000 Americans.
Express Scripts has decided to only reimburse for some MS treatments — and the differentiator isn’t paying for “better” ones. The ones they chose are generally newer medicines with the highest market share. Why? Consider the math. The higher the volume, the bigger the cudgel, the larger the cumulative discount.
But what about those patients whose disease is being well managed on older therapies with smaller market share? Sorry, no dice. Physicians are being told (told!) by Big Payer to monkey with successful therapies because they don't add enough to the bottom line. This is particularly galling in the case of MS, where the ability to successfully manage any given patient’s disease with any given medicine cannot be predicted. There is no way to determine ahead of time which drug works best for any given patient. And one drug (say an older treatment with a single-digit market share) is not necessarily interchangeable with a newer drug (which has double-digit penetration).
Another frightening fact is that upwards of 20 percent of MS patients, when forced to switch from successful treatments to payment-dictated ones simply stop taking their medicines or opt for “drug holidays” because of new and unpleasant side effects.
If patients are in an uproar, physicians are furious — and frightened. If a doctor is forced to change a patient’s therapy because of Big Payer pressure, what happens when something goes wrong and a malpractice suit gets filed? Is there any validity to “the payer made me do it” defense? Nobody wants to be the test case.
PBM’s will say they’re negotiating on behalf of the employer health plans they serve, that their tactics reduce employer costs. Not true. Higher co-pays for off-formulary medicines lead to dramatically higher rates of non-adherence. Data from one large employer with over 60,000 insured workers shows that in the first few months since the implementation of PBM drug exclusions, nearly 50 percent of “rejected” prescriptions remain unfilled. Non-adherence is the major cause of poor health outcomes. That’s a pyrrhic trade-off.
This is healthcare reform? Indeed it is, since the basic tenet of Obamacare is to reduce costs rather than expedite appropriate care. In fact, the drug formularies of most state exchanges are equally if not more draconian than those designed by Express Scripts. Unfortunately, no two patients have the same biochemistry and no two medicines are exactly equivalent. But if your primary goal is to minimize short-term costs so that you can maximize your quarterly profit (in the case of Express Scripts) or keep premiums low but co-pays high (the goal for state healthcare exchanges), that's an inconvenient truth.
The repercussions of choosing short-term thinking over long-term results, of cost-based choices over patient-based care, of “any-medicine-will do,” over the right medicine for the right patient at the right time are pernicious to both the public purse as well as the public health.
Welcome to “the Purple Book” – FDA’s “Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations.”
On the nomenclature front, one immediate take-away is that the FDA makes clearly states:
“The lists cross-reference the names of biological products licensed under section 351(a) of the Public Health Service Act (PHS Act) with the names of biosimilar or interchangeable biological products licensed under section 351(k) of the PHS Act by the FDA (see below for an explanation of the sections 351(a) and 351(k) of the PHS Act).”
Per the FDA:
The “Purple Book” lists biological products, including any biosimilar and interchangeable biological products licensed by FDA under the Public Health Service Act (the PHS Act). The lists include the date a biological product was licensed under 351(a) of the PHS Act and whether FDA evaluated the biological product for reference product exclusivity under section 351(k)(7) of the PHS Act. The Purple Book will also enable a user to see whether a biological product licensed under section 351(k) of the PHS Act has been determined by FDA to be biosimilar to or interchangeable with a reference biological product (an already-licensed FDA biological product). Biosimilar and interchangeable biological products licensed under section 351(k) of the PHS Act will be listed under the reference product to which biosimilarity or interchangeability was demonstrated.
Separate lists for those biological products regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) will be updated periodically.
For those of you following the debate on Non-Biologic Complex Drugs (NBCDs) – such as Copaxone – the fact that the agency is drawing a distinction between CBER and CDER is significant. It is distinction with a difference.
IMHO, products such as copaxone should demand "to be purple rather than orange." Clearly, copaxone has much more in common with biologics -- and since the agency is now making a distinction between large molecules approved by CDER and CBER -- it seems logical to "keep like things together." NBCDs aren't small molecules and don't belong in the Orange Book.
Purple, after all, is the color of good judgment.
Background Information: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations
What are these lists?
These lists are designed to help enable a user to see whether a particular biological product has been determined by the Food and Drug Administration (FDA) to be biosimilar to or interchangeable with a reference biological product. The lists cross-reference the names of biological products licensed under section 351(a) of the Public Health Service Act (PHS Act) with the names of biosimilar or interchangeable biological products licensed under section 351(k) of the PHS Act by the FDA (see below for an explanation of the sections 351(a) and 351(k) of the PHS Act). There will be separate lists for those biological products regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).
For products licensed under section 351(a) of the PHS Act, the lists identify the date the biological product was licensed and whether FDA evaluated the biological product for reference product exclusivity under section 351(k)(7) of the PHS Act (see below for an explanation of reference product exclusivity). If FDA has determined that a biological product is protected by a period of reference product exclusivity, the list will identify the date of first licensure and the date that reference product exclusivity (including any attached pediatric exclusivity) will expire. The list will not identify periods of orphan exclusivity and their expiration dates for biological products as those dates are available at the searchable database for Orphan Designated and/or Approved Products.
Biosimilar and interchangeable biological products licensed under section 351(k) of the PHS Act will be listed under the reference product to which biosimilarity or interchangeability was demonstrated.
What is a reference product, biosimilar, and interchangeable product?
Under section 351(i)(4), a “reference product” is the single biological product licensed by FDA under section 351(a) of the PHS Act against which a proposed biological product is evaluated in an application submitted under section 351(k).
Under section 351(i)(2), “biosimilar” or “biosimilarity” means that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency of the product.
Under 351(k)(4), an “interchangeable” biological product is a product that has been shown to be biosimilar to the reference product, and can be expected to produce the same clinical result as the reference product in any given patient. In addition, to be determined to be an interchangeable biological product, it must be shown that for a biological product that is administered more than once to an individual the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.
What is reference product exclusivity?
Section 351(k)(7) of the PHS Act describes reference product exclusivity as the period of time from the date of first licensure of a reference product, the single biological product licensed under section 351(a) of the PHS Act against which a biological product is evaluated in a 351(k) application, during which a 351(k) sponsor is not permitted to submit and FDA is not permitted to license a 351(k) application that references the reference product. Specifically, if the reference product has reference product exclusivity under this section, approval of a 351(k) application may not be made effective until the date that is 12 years after the date of first licensure of the reference product, and a 351(k) application may not be submitted for review to FDA until the date that is 4 years after the date of first licensure. See 351(k)(7). For additional information on how FDA determines the date of first licensure and reference product exclusivity, please see the draft guidance for industry, “Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (PDF - 99KB).”
What does the reference product exclusivity expiry date indicate?
The reference product exclusivity expiry date indicates (1) the date that is 12 years from the date of first licensure as described in 351(k)(7); plus (2) any pediatric exclusivity granted pursuant to section 505(A) of the FD&C Act, if applicable. The reference product exclusivity expiry date is the date on which a 351(k) application referencing the reference product may be licensed, assuming it is not blocked by orphan exclusivity and otherwise meets the requirements for licensure under 351(k). To determine whether there is unexpired orphan exclusivity for an indication for which the reference product is licensed, please refer to the searchable database for Orphan Designated and/or Approved Products.
For additional information on determining the date of first licensure for purposes of determining reference product exclusivity, please see the draft guidance for industry, “Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (PDF - 99KB).”
Why is a determination of the date of first licensure not made for every 351(a) biological product licensed and currently marketed?
Although FDA has not made a determination of the date of first licensure for all 351(a) biological products included on the lists, it does not mean that the biological products on the list are not, or were not, eligible for exclusivity. A determination of the date of first licensure and of when any remaining reference product exclusivity will expire for a biological product submitted under section 351(a) of the PHS Act will generally be made for reasons of regulatory necessity and/or at the request of the 351(a) application license holder.
How often will these lists be updated?
As resources permit, these lists will be updated periodically when FDA licenses a biological product under section 351(a) or section 351(k) of the PHS Act and/or makes a determination regarding date of first licensure for a biological product licensed under section 351(a) of the PHS Act.
What should a healthcare practitioner keep in mind while using these lists?
Professional care and judgment should be exercised in using these lists. Evaluations of biosimilarity and interchangeability for biological products are based on scientific and medical evaluations by FDA under section 351(k) of the PHS Act. FDA’s determination that a product is biosimilar to a reference product or interchangeable with a reference product means that FDA has determined that the biological product meets the requirements for such products (see definitions above).
Why Purple?
The “Purple Book” is an easy-to-remember nickname for the “Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations.” Using a color for the nickname of the list draws upon FDA’s long-held practice of using “The Orange Book” to refer to “Approved Drug Products with Therapeutic Equivalence Evaluations,” the Agency’s reference listing of all drugs approved under the Federal Food, Drug and Cosmetic Act. Over the years, health care professionals and other stakeholders have come to use the term “Orange Book” in place of this longer, official title. FDA wanted a similarly user-friendly term for a reference listing biologics, biosimilars, and interchangeable products. During a meeting, a staff member said, “how about purple?” Ever since, we’ve called it the “Purple Book.”
In a Huffington Post article, Patrick Krill, director of the Legal Professionals Program in the Hazelden Betty Ford Foundation, in an Huffington Post voices support for the recent lawsuits by California and Chicago against the manufacturers of opioid painkillers, pointing out that the some pharmaceutical companies “used deliberately misleading marketing techniques to cause an explosion in prescriptions for, and sales of, some of the most addictive chemical compounds man has ever engineered.”
At the same time, per law360.com, numerous pharmaceutical companies asked an Illinois federal judge on Friday to throw out the city of Chicago's suit claiming that their allegedly irresponsible marketing of addictive opioid painkillers has caused a costly public health crisis, arguing that the claims are too generalized to move forward.
In multiple motions to dismiss, Purdue, Janssen Pharmaceuticals Inc., Teva Pharmaceutical Industries Ltd., Endo Health Solutions Inc. and Actavis PLC make similar arguments asking U.S. District Judge Elaine E. Bucklo to toss the case. According to the drug companies, the complaint fails to adequately state a claim against individual defendants, some of which the companies say are barely mentioned in the complaint at all.
“The city simply lumps all defendants together as a group, ignoring relevant differences between the drugs they are alleged to have manufactured, the U.S. Food & Drug Administration-approved indications and the warnings the drugs carried, and the dates the drugs were marketed, and providing no specifics about any defendant’s alleged role in the alleged scheme,” the drug companies’ motion states. “The complaint could serve as a textbook example of improper group pleading.”
In addition to arguing the case should be tossed because of a failure to state a claim, the drug companies urged Judge Bucklo to dismiss Chicago’s complaint based on the doctrine of primary jurisdiction, arguing the city’s claims raise complex issues uniquely suited for the FDA and that those issues are currently being considered by the agency.
“In asking this court to decide scientific and policy matters that fall squarely within the province of, and are currently being addressed by, the FDA, the city has jumped the gun by suing before the FDA has resolved those issues,” the defendants’ motion states. “As multiple courts have done, this court should dismiss or stay this action to allow the FDA to first address these matters within the framework it has defined and is currently implementing.”
The case is City of Chicago v. Purdue Pharma LP, et al., case number 1:14-cv-04361, in the U.S. District Court for the Northern District of Illinois, Eastern Division.
Healthcare innovation saves lives, saves money, promotes economic growth, and provides hope for hundreds of millions of people (both patients and care-givers) in the United States and around the world. But innovation isn’t easy.
In 1950, Americans spent about 5 percent of their income on health care. Today the share is about 16 percent. According to Harvard University economist N. Gregory Mankiw, “many pundits take the increasing cost as evidence that the system is too expensive. But increasing expenditures could just as well be a symptom of success.”
And he hits a homerun with a clear, concise, and common sense explanation. “The reason Americans spend more than their grandparents did is not waste, fraud and abuse, but advances in medical technology and growth in incomes. Medical science has consistently found new ways to extend and improve lives. Wonderful as they are, they do not come cheap.”
The issue of access to innovation is crucial – and the topic of a new paper from the Center for Medicine in the Public Interest, “Access to Medical Innovation: Obstacles and Opportunities.”
Consider the recent FDA approval of Merck’s Keytruda, the first of an eagerly awaited new class of cancer drugs that unleashes the body’s immune system to fight tumors.
As Andrew Pollack writes in the New York Times, “Cancer researchers have been almost giddy in the last couple of years about the potential of drugs like Keytruda, which seem to solve a century-old mystery of how cancerous cells manage to evade the body’s immune system.”
There are many roadblocks beyond those of discovery and development. The complicated and conflicting dynamics of politics, perspectives on healthcare economics, of friction between payers, providers, manufacturers, and regulators, the battle for better patient education, and the need for a more forceful and factual debate over the value of innovation all create the need for a more balanced and robust debate.
Shortly before his death, I had the privilege of a private meeting with Nobel laureate Joshua Lederberg. We talked about the state of applied science, the prioritization of development science, biomarkers, and a host of other future-oriented issues. At the end of the meeting he put everything into perspective in a single sentence. He leaned over the table and said, “The real question should be, is innovation feasible?”
Let’s hope so. Innovation equals hope.
CMPI in participating in a national awareness campaign to accelerate the fight against cancer.
Mylifeisworthit.org, our patient-centered project to promote access to innovative medicine was featured today in a USA Today supplement. It can be found at http://futureofcancercare.com
Each year a quarter of million people, many of them children, die from cancer or cancer related complications because of delay and indifference.
Many have as little as a 6 percent chance of living five years and none have more than a 50 percent chance of living that long.
Meanwhile, it takes two years just to put together a clinical trial to study potential treatments for cancer and another 8 years to complete one. In the time it takes to organize a clinical trial over 200000 people with cancer will die. By the time a clinical trial is finished, 2.5 million people, including 200,000 children with cancer will die.
Defenders of the status quo claim we need to go slow to ensure patient safety. But it is evident that millions of people are being protected to death.
In fact, the situation facing people living with many tumor types is just like the challenge people living with HIV faced nearly 40 years ago. Then, as now, people without effective therapies are dying in less time than it takes to test new medicines.
At the height of the movement to speed up access to HIV drugs, people living with HIV forced the Food and Drug Administration to dramatically slash the time required to study potential HIV medicines. These changes were made to allow patient’s maximum hope for cure and the opportunity for some control over our destiny.
Today, researchers and doctors know more about the underlying mechanisms of cancer than they did about HIV. It is now possible to deliver precise therapy to people on the basis of that individual's tumor. There are no 2 different cancers that are the same anywhere. Just like there are no 2 individuals who have the same DNA, that's the same for a tumor.
And while HIV patients used notebooks and faxes to share data, today’s patients have the digital ability to learn, join, share and take part in advocacy and research faster than ever before.
Cancer is the current system of clinical trials. These require any new drug/treatment to successfully complete three phases of trials aimed primarily at assuring the safety of new drugs. The phase 1 trial is frequently completed in a few months, involves only a few patients and a few hundred thousand dollar investment. The phase 2 and 3 trials for any given new treatments however take up to ten years or more and tens of millions of dollars, all to obtain additional safety data on a few hundreds to a thousand or so patients.
Yet, most cancer trials are conducted as if these technological advances did not exist. People are herded into studies that replace a deep understanding of how to match medicines to tumors with randomized trials (including placebos) that assume everyone responds the same way and for the same amount of time. It’s as if we ignored someone’s shoe size and instead told everyone to try on the same to try a size 6 to see if a shoe fits.
There are treatments now in phase 3 trial with years to go before any possibility of approval, but where the early phase I results of ten years ago are still big improvements over the treatments approved by the FDA many years ago known for these cancers. Only those lucky few are can qualify for the phase 2 and phase 3 trials will get this treatment until the treatment receives FDA approval years from now. What is gained by denying such a treatment to patients right now? Today. What justifies the withholding of a possibly life extending treatment to anyone who needs it and is willing to accept any the possibility that it might not help?
Such an approach and such delay is neither scientifically or morally supportable particularly to people living with a tumor types without effective therapies. Indeed, what we seek has been for HIV drugs and can be done under FDA’s existing regulatory authority.
Nearly 500,000 people each year are told they have a form of cancer that will kill them in two years or less because there is no effective treatment. Each year, half of all people who die of cancer. Yet it takes ten years to bring a new cancer therapy to patients. We can save lives faster and give people living with cancer hope that can last a lifetime.
Here's some actions we can take to reduce the time drastically.
• Empower the Food and Drug Administration to approve new drugs after phase 1 for patients whose tumors respond to a specific treatment in those early studies. Such treatments should be granted conditional approval with the requirement that they are then monitored very carefully in real world settings. NCI funding should be increased to support this approach.
• Increase funding for cancer prevention programs, including early detection and identification of genetic mutations that increase cancer risk.
• Accelerate access to and reduce the cost of experimental treatments to patients, especially children, who have run out of treatment options and can’t wait for or excluded from clinical trials. Patients should be able to use any experimental treatment provided that all data (except the patient’s identity) is made freely available to other patients, researchers and the FDA. Companies that make products available under this program could receive accelerated approval for that drug or another drug under FDA review.
• Eliminate health insurance cost-sharing schemes that create barriers to cancer patients’ ability to access potentially life-saving medicines by passing legislation that provides equal access and insurance coverage for ALL anti-cancer regimens and eliminates fail first policies forcing patients to switch from one drug to another.
If you believe it's important to accelerate access to innovative therapies, join us at http://www.mylifeisworthit.org
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.
