Latest Drugwonks' Blog
Why ‘pricey’ drugs save money — and lives
Expensive new drugs often get fingered as the culprit to rising US health-care costs. The truth is closer to the reverse.
First off, it’s hard to see how pharmaceuticals can be a major driver of costs when they’re just over 11 percent of the total US health-care budget.
But more important is that even extremely pricey drugs still save money if used right.
Consider Sovaldi, which has a 90 percent cure rate for Hepatitis C, a disease affecting over 3 million Americans. A three-month treatment cycle of the new drug costs upward of $84,000. On the market for just a few months, Sovaldi has already clocked in a record-shattering $2.3 billion in sales.
Some are calling foul, accusing the drug’s developer — Gilead Sciences Inc. — of exploitative pricing. “The company in this case is asking for a blank check,” says Karen Ignagni, president of America’s Health Insurance Plans. “It will blow up family budgets, state Medicaid budgets, employer costs and wreak havoc on the federal debt.”
That’s 100 percent wrong — the exact opposite of reality. New, better medications are actually the best and swiftest way for this country to cut down on our health-care expenses. By more effectively combating disease and improving patients’ lives, drugs reduce long-term medical costs and bolster the overall economy.
Consider one pre-Sovaldi “best practice” treatment for Hepatitis C, the drug Pegasys. This requires one injection a week for 48 weeks — and very few patients see the treatment through to completion, so much of that treatment, both physician time and drug cost, is wasted. Nor is it that much cheaper: At about $7,000/month, the full course of treatment is over $70,000 — barely less than cost of the three months needed for Sovaldi to work a cure.
And the price of not using Sovaldi is very high. One in three patients with the Hepatitis C virus eventually develops liver cirrhosis, and managing these patients is costly. A “routine” liver transplant (where the liver is from a cadaver) costs close to $300,000; a “living donor” transplant is even more expensive.
Thanks to Sovaldi, a pill that cures the disease when taken once a day over 12 weeks will eradicate the need, the risks and the costs of liver transplantation. Such radical innovation deserves to be both lauded and rewarded.
And Sovaldi’s costs will come down. The initial price of such breakthrough medications reflects the huge R&D costs required to bring the drug to market, not avarice.
As Food and Drug Administration official Dr. Janet Woodcock noted of the Sovaldi controversy: “We may have to put a big down payment down now to get something really good.”
It’s remarkable that some large insurers have the chutzpah to complain that curing 3 million Americans of hepatitis C will bankrupt health-care systems. Data recently published by the PwC Health Research Institute suggests the reverse. The study shows that the use of Sovaldi will actually drive down overall spending within a decade. According to the authors, “The challenge may lie in targeting the patient most in need of the more expensive course of therapy.”
In short, drugs aren’t the cause of rising health-care costs — they’re the solution. Demonizing new treatments distracts from the real problem in the US biopharmaceutical industry: top-down cost-centric policies that focus on the near-term, short-changing long-term patient outcomes, and so endanger “sustainable innovation” by denying fair reimbursement for high-risk investment in R&D. (Research and development costs big even if a drug never makes it to market — and most don’t.)
New treatments are a bargain. Disease is always much more costly.
Unfortunately, under ObamaCare health plans are sticking more people with a bigger share of drug costs — a strategy designed to discourage use by the people in greatest need and direct outrage away from insurers to drug companies.
Breakthrough drugs could generate huge new savings in the US economy — but only if federal regulators don’t smother them in the womb with expensive and unnecessary legal hurdles. Left unencumbered, domestic medical innovation will generate the new treatments to improve lives, stave off disease and cut down on long-term health-care costs.
If we don’t reward risk-taking on behalf of human health, both will shrink.
Peter J. Pitts, a former FDA associate commissioner, is president of the Center for Medicine in the Public Interest.Whether it’s allergy medications, treatments for erectile dysfunction or high cholesterol, the issue of Rx-to-OTC switching is complicated, important – and timely. The FDA’s September 2011 draft guidance provides a valuable resource for those thinking about proceeding with OTC switches based on self-selection studies. It's fair to say that support of Rx-to-OTC switches reflects FDA's interest in drilling down for greater insight into consumers' thought processes.
Can a patient self-diagnose and self-dose? Do symptoms hide another, potentially more serious, underlying condition? And what of safety concerns? In considering an Rx-to-OTC switch, the FDA looks to see whether patients can use the product safely without the oversight of a physician or pharmacist. This includes ensuring that the right patients use the drug in the appropriate way ("safe use"). The agency is not evaluating the risk-benefit of the product, since that was done earlier when it was approved as a prescription drug.
The journal SelfCare has published "an essential blueprint for designing and implementing any Rx-to-OTC drug development program," says lead author Bill Soller, professor and executive director of the Center for Consumer Self Care at the University of California, San Francisco, School of Pharmacy. Well, maybe not essential -- but certainly intriguing.
Soller and his colleagues list questions - "OTC Considerations" - based on switch principles FDA set in 1990 and 1998 and questions to post-2002 advisory committees that evaluated first-in-class switches.
The analysis recommends 11 primary questions about the Rx fundamentals of a drug, its "OTCness" and overall risk vs. benefit.
1- Has the Rx product been on the market for a sufficient time and extent to enable full characterization of the drug's safety profile?
2- Can the condition be adequately self-diagnosed or is there a need for physician diagnosis?
3- Is the minimally effective dose known?
4- Are there efficacy studies needed to support the intended OTC use of the switch candidate?
5- What are the patterns of diagnosing, prescribing and patient use in the Rx setting related to OTC intended use?
6- Are the studies supporting OTCness generalizable to the intended OTC target population?
7-Do consumers understand key communication objectives of the label, relating to directions for use, contraindications, in-use warnings and precautions?
8- Do consumers show they would be likely to be able to assess and take action on the treatment effect (e.g., take appropriate action if the drug is not working, serious side effects emerge, or self-monitoring is needed)?
9- Do consumers demonstrate successful self-selection and de-selection of the product under conditions (or simulated conditions) of actual use?
10- Does the pattern of actual use support that the label can be successfully used in practice?
11- Do the benefits of OTC availability outweigh the risks?
The authors say FDA "uses its discretion to select areas of concentration for advisory committee discussions on switch." Factors influencing the agency's questions for advisory committees include the novelty and uniqueness of a proposed OTC indication or Rx active ingredient; intrinsic and extrinsic toxicity of a switch candidate; and robustness of published and NDA-derived data and worldwide post-marketing surveillance evaluations.
But there are other important factors at play that, while not entirely within the scope of FDA’s regulatory authority, need to be considered within the context of the broader Rx-to-OTC switch conversation. These factors fall under the general headline of “the consumer healthcare continuum.”
Today’s healthcare consumer has access to much more information than ever before. (Some of it is even accurate.) More importantly, they seek choice and empowerment. At the same time healthcare providers are under multiple pressures to further decrease the amount of time spent with their patients. Moving certain products from Rx to OTC would certainly decrease (in a safe and appropriate manner) a provider's patient load, while at the same time obviating the need for a patient (otherwise known as a “consumer”) to spend both the time and money (office co-pay as well as time off from work) required for an office visit -- allowing physicians to focus their limited time on high-risk patients or those with more complex conditions.
And what about the evolving role of pharmacists and the important question (among others) of pharmacy scope of practice (blood tests, etc.). The removal of the Rx designation doesn’t require the removal of a learned intermediary.
There is also good research showing that patients on OTC medications demonstrate higher rates of utilization. A 2013 study indicates that offering OTC forms of a prescription medication increased utilization per drug class by 30 percent, potentially closing treatment gaps. And, in contrast with many Rx treatments for chronic disease (such as high cholesterol), adherence rates are higher for OTC medications.
Patient, treat thyself. That’s one way of looking at it. Knowledge is power. But is a little knowledge a dangerous thing?
The consumer healthcare continuum continues.
Desperate too-clever-by-half efforts to derail biosimilar pharmacovigilance are contrary to the public health and require rebuttal.
Some generics manufacturers, payers, and national chain drug stores have interwoven half-truths, out of context comments and just plain misinformation to build a fatuous argument dressed up as support for patient safety. But the actual patient and safety communities are firmly on the polar opposite side – in favor of safety, choice, and transparency.
The insurance-industry driven effort claims that distinguishable names for biologics “could lead to patient and prescriber confusion, increasing the possibility of medication errors.” Unpacking that a bit, biologics are complex therapies that are made from living cells and prescribed for patients with difficult-to-target, debilitating and life-threatening health conditions such as cancer, diabetes, MS, lupus, Crohn’s disease and rheumatoid arthritis. There are no generics for them but it is expected that the closest thing – biosimilars – will soon enter the US marketplace. What the insurers are essentially saying is that, a biosimilar that relates to a biologic should have exactly the same name as that biologic.
In the case of biologics and biosimilars, even minute differences between products can cause individual patients to respond differently even though each product is considered safe and effective. Of greatest concern is immunogenicity, which carries a significant risk for all biologics. Because of the size and complexity of the biologic molecule, patients can experience unwanted immune reactions; these reactions can occur months after a patient begins taking the medicine and it is often difficult to know if it is due to the reaction to the medicine or simply the progression of the patient’s condition.
With all of these considerations, it stands to reason that the name of biologics and biosimilars should be similar, not the same. But rather than taking my word for it, consider these important viewpoints:
“Distinguishable names…will enable the gathering of sufficient data to ultimately allow providers to fully understand how all biologics – including biosimilars – are performing for minorities. This will lessen the inevitable confusion and assure optimum medical care in the use of biosimilars among minority populations.” – From a June 10th letter to FDA signed by 22 of the leading U.S. organizations focused on minority health, including the National Alliance for Hispanic Health, National Hispanic Medical Association and National Medical Association.
“…For millions of female patients, any potential increase or decrease in effectiveness of a biologic, along with side effects and adverse reactions, will only be discovered after the treatment is approved and under active use…As states across the country look to the FDA for guidance on issues surrounding biosimilarity, interchangeability, and therapeutic substitution, the agency’s views on sex and genomic-based differences will be crucial…Distinguishable names will enable the gathering of sufficient data to ultimately allow providers to fully understand how all biologics – including biosimilars – are performing for both men and women.” – From a May 20th letter to FDA spearheaded by the Society for Women’s Health Research and signed by 45 other leading U.S. organizations focused on women’s health.
“Distinguishable names for biologics support the medical community’s vital post-approval learning curve about which medicines are best for their rare disease patients. Health care providers need to know that a prescribed medicine was actually given to the patient and whether a substitution was made and to what alternative product. This can’t be achieved unless biologic products—especially ones with similar therapeutic purposes—cannot be distinguished, tracked and studied.” – From a June 3rd letter to FDA by the National Organization for Rare Disorders (NORD), the umbrella organization representing the interests of the many advocacy groups that serve 30 million patients impacted by nearly 7,000 rare diseases.
By my estimate, the patient-focused organizations that have come out in support of distinguishable naming cover just about every single American family. Fully addressing all of the inaccuracies and agenda-driven language in the insurance-industry driven letter requires an extensive point-by-point rebuttal [link to one], but the key take-away is this: if you’re for patient safety, you can’t be against distinguishable naming.
As acknowledged by WHO and regulatory bodies of every developed nation, biologics are not chemical compounds (e.g., statins) — they’re infinitely more complicated. When it comes to biosimilars, we need to be extremely thoughtful about how we set policy and strike a balance that promotes health and safety, rather than forcing a binary response that is driven by profits rather than patients.“After years of timid, low-scoring play, that one word has become the theme of Brazil's World Cup. When the history of this tournament is written, the sport's cognoscenti will likely point to it as an event that changed the game. The finalists, Germany and Argentina, have survived the most offense-oriented tournament of the modern era, a series of games where playing defensively almost guaranteed an early exit.”
Pharma could learn a lot from the World Cup champion German club. Stay on offense.
Last night I attended a dinner hosted by Poppy McDonald the publisher of The National Journal to discuss what “value” means to various health care interests. Attendees included Chris Jennings, who advised both the Clinton and Obama administrations on health care reform, John Rother, the former head of policy for AARP (and now CEO of the National Coalition on Health Care), Nancy Ennis-Davenport who is the CEO of National Patient Advocacy Foundation and Alex Wayne, who writes about health care for Bloomberg. Julie Rovner led the discussion.
It was a lively group and the discussions were spirited and friendly. The conversation quickly turned to and focused on the price of Solvadi and whether it was reasonable or not.
I was struck by how, for the most part, few at the table thought in terms of what Solvadi would replace, how much money it would save relative to the cost of treating people with liver disease, the horrible side effects of current treatments and how a 12 week cure could and would affect productivity, disability costs, etc., etc.
And while there was a lot of moaning about drug prices, there was scant discussion about the price of liver transplants, bone marrow grafts, intensive care, etc.
Innovator drug firms have usually done a lousy job thinking about or making the case for the value of their products. But even when they are good at it, they are not consistently making the case. Too often they are on defense, using lobbyists to fend off regulation with apologies and explanations about the price of drugs.
And by playing defense, pharma, more than ever, is in danger of being booed and reviled. The audience expects both sides to mount an offense. Thus, “A team that dared to play passively for even the briefest period of a match was guaranteed to hear derisive howls from the Brazilian crowds, no matter how hot and humid it was or how tactically intelligent slowing down the game might have proven.
"Every team has realized you need a balance, that you need to attack and defend," said Avram Grant, the former manager of the English club Chelsea. "If all you do is defend, you lose."
All pharma does is play defense. At it’s peril. That’s what the dinner discussion about Solvadi and the World Cup showed me.
Imagine waking up in the morning and finding your beloved pet on the floor convulsing, motionless or dead.
Now stop imagining, because this was the real-life nightmare for horse trainers in both Lexington, Kentucky and Ocala, Florida when they found their horses experiencing seizures and thrashing in their stalls. In total, more than a dozen horses died or were severely injured – in some cases, paralyzed.
The cause of these horrific scenes – illegally compounded medicines.
These horses were prescribed illegal drug concoctions that contained unsafe levels of pyrimethamine. By one account 25 times the amount it was supposed to contain. A deadly overdose for innocent animals.
There is legal and appropriate animal drug compounding. All legally compounded product starts with an FDA-approved product. The product may then be modified by a trained pharmacist on the order of a veterinarian to treat the medical needs of an individual or group of animals such as adding flavorings, or turning tablets into an oral liquid for easier administration.
But some animal drug compounding pharmacies go far beyond those parameters – with deadly results. They mass produce and market drugs that attempt to mimic FDA-approved products, often using untested bulk active ingredients, imported from countries that may not enforce the strict controls on drug manufacturing that FDA requires for approved products. These copies carry a cheaper price tag than approved drugs, but none of the consumer protection.
Why does this black market exist? It’s both expensive and time-consuming to take a drug through the FDA approval process. For animal drugs, this can take up to 10 years and cost up to $100 million. But it is a process that protects consumers and their animals – by ensuring that the approved drug is both safe and effective at the labeled dose.
FDA permits a limited amount of necessary compounding from bulk ingredients in order to make sure medical needs can be met when there is no approved drug. But these compounding pharmacies have taken the proverbial inch and run for murderous miles. Despite their attempts to muddy the waters with lawsuits and rhetoric, the law is clear: FDA and three federal appeals courts have ruled that compounding animal drugs from bulk substances is illegal. Period.
Illegally compounded animal drugs have caused harm to more than just horses. One university veterinary hospital has reported that dogs and cats are brought in for medical care because their medicines aren’t working, only to find they were being treated with illegally compounded drugs. The literature is full of reports showing these compounded drugs contain far more or far less than the amount of advertised active ingredient. This is not acceptable.
As a former FDA Associate Commissioner (and a current dog owner), I know the agency has rigorous enforcement authority. Pharmacies that engage in illegal manufacturing cannot be allowed to ignore the law and put animal health at risk in the name of selling a cheaper product.
For several approved animal drugs, FDA has sent warning letters to these pharmacies, but often they were simply ignored and the illegal practices continued. Unfortunately there has been little to no follow up by the agency. The FDA must do more and commit to strong and sustained enforcement to protect animal health.
What can you do? It’s frightening to think a drug given to your pet might not carry the guarantee of safety and effectiveness that comes with FDA approval. The first step is to talk to your veterinarian about best treatment options for your pet. Ask if the drug being prescribed is FDA-approved. If there’s no approved drug and compounding is necessary, make sure the pharmacist preparing the compound has the credentials and license to do it safely and legally. Why that might sound obvious it is the only – and best – way to ensure the prescribed drug is what is best for your pet. If you have concerns about a pharmacy, check with your state Board of Pharmacy. At the same time, FDA must do its job of protecting our pets and animals by more regularly and aggressively enforcing the law and regulations.
Here is my commentary in the most recent edition of BioCentury.
Net/Net -- let's not do the wrong thing by trying to do the right thing.
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 princi
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