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From the pen of our friend and colleague Robert Popovian, Senior Director of Pfizer US Government Relations.
While the US spends more on healthcare per capita than any other developed country, it also drives innovation in healthcare. Most of the R&D in medicine is done in the US, physicians from around the world are trained in our universities, the NIH invests in transformative research and premier academic medical centers are within our borders. However, in terms of payment and delivery we are still using an outdated model, spending our valuable healthcare resources on administrative red tape; non-adherence to medicines; fraud and abuse; and unnecessary services.
It is time that US takes a leadership role in innovating how to pay for and deliver healthcare by paying for value rather than volume. Our current fee-for-service payment model encourages quantity not quality. Payments for outpatient services, hospital admissions, pharmaceuticals and provision of other healthcare services are based on individual budgets which only take into account cost rather than value and quality. This approach promotes an environment where decision-makers in one silo have little if any regard for the consequences of their choices on other aspects of healthcare consumption, including outcomes and impact on patient quality of care. Shifting healthcare spending is like squeezing a balloon – you squeeze one end and the other side pops up. If you inappropriately curtail one healthcare service, inevitably you will cause unintended consequences in others. For example, policies implemented to reduce biopharmaceutical expenditures have oftentimes led to increasing overall healthcare utilization and costs through increased hospitalizations and outpatient services. In addition, most published research supports the fact that curtailing pharmaceutical access through policies such as inordinately high cost sharing or administrative hurdles increases overall healthcare costs (including a paper that I researched and published investigating the impact of pharmaceutical capitation payments by a national insurer on patient outcomes and healthcare expenditures as a research fellow at University of Southern California).
As policymakers consider payment and delivery reform, a plethora of words, phrases and acronyms such as capitation, bundled payment, pay for performance, ACO or IPU are being thrown about as potential solutions. Each of these is simply an approach that aligns incentives to pay for value rather than volume. But determining the best payment reform approach requires the inclusion of some core principles.
So what are the principles of successful payment reform? Prioritize patient needs; support and promote sustainable high value care; examine health outcomes over a reasonably long term horizon; provide consumers and providers access to information and interconnected data; and encourage coordination of care. One example of a payment policy reform that did not incorporate these principles is the decision by some national Pharmacy Benefit Managers to remove certain medicines from their formularies without examining how such a decision would impact overall healthcare costs, or the burden on physicians or patient quality of life. Ideally, payers would instead follow the decision of United Healthcare which recently instituted a bundled payment model for cancer therapy and found out that payments tied to outcomes and physician flexibility to choose the right therapy for their patients resulted in reduction in overall healthcare costs.
Changing the payment scheme towards value-based reimbursement will align incentives and spur growth of new delivery models such as telemedicine, retail clinics and even change when and how physician practices are operating. Remember when a bank in the 1980’s operated on a Monday through Friday timeline with limited hours? Banks evolved to meet their customers’ needs through automation, changes in location of where customers could do their banking and most recently through technological advances that promote using online services. Those banks that did not evolve eventually perished. Currently, our healthcare delivery system operates much the same way the banks did in the 1980’s. In fact, healthcare is the only industry that keeps the fax machine industry alive!
Finally, we must implement payment reform with a “do-no-harm” priority towards innovation, managing the needs of patients who are very sick with hard to treat conditions, and guarding against decisions that are primarily based on short term financial gains at the expense of long term health. By instituting appropriate quality measures and ensuring availability of interconnected healthcare data we can ensure that we avoid such dilemmas for delivery of healthcare services.
There is risk for the biopharmaceutical industry in moving from a fee-for-service model towards payment reform which rewards the most efficient intervention. However, economic principles also establish that opportunities exist for interventions that produce efficiency in systems. Innovative biopharmaceuticals over time have proven to be the most efficient intervention in healthcare as their use commonly reduces overall healthcare costs and improves patients’ quality of care and life.
If payment reform fails as it has in the past, the consequences are dire. The only levers left to pull for policy makers to control the increase in healthcare costs will be draconian measures such as price and utilization management through mechanisms like the Independent Payment Advisory Board (IPAB). This approach won’t promote efficiency, value or a reduction in overall healthcare costs. Implementation of effective payment reform that results in new delivery model transformation will.Read More & Comment...
As John Adams said, “Facts are pesky things.” And facts that don't reinforce your cognitive mapping are pesky things. But that does not change the fact that nothing deserves truth and accuracy more than the public health.
According to Inside Health Policy:
“While some say an easy solution is to simply add a suffix to distinguish a biosimilar from the innovator product, the compendia group told FDA any change is a change, and regardless of the simplicity of the change, the associated coding would also have to shift. First data bank and two other databanks are sold to stakeholders who assemble them and put overlays on them and then the data are used for different purposes, including for reimbursement.”
But pay heed. As Deming warned, “Change is not required. Survival is not mandatory.”
Giving credit where credit is due, the good people at the USP understand that interoperability is important, but that naming is more of a philosohpical issue. That's why they support differentiation via discrete numerical suffix.
Per Inside Health Policy:
The drug compendia stakeholders told a group of 13 FDA drug policy experts, including drug center chief Janet Woodcock, that changing the traditional naming process would require that each piece of the compendia process be individually rebuilt in order to ensure patient safety and restore functionality to the system. Doing so, while possible, would be difficult and could lead to confusion, errors and misunderstanding, creating a "very real risk to patients," according to slides presented at the May 2 meeting and a June 6 follow-up letter, obtained by Inside Health Policy.
Here are some of the more egregious myths shared by the aforementioned group of compendia stakeholders along with the facts to debunk them.
We are concerned that distinguishable naming for every biologic, biosimilar and interchangeable biologic could confuse both providers and patients, and have the unintended effect of slowing the uptake of these cost saving drugs.
The patient and safety communities, as well as many physician organizations have weighed in on the same issue, and have come out on the opposite side – in favor of transparency, so that patients can know which medication is being put into their bodies and the whole system can quickly connect the dots to stem negative impact when an adverse event occurs. The scope of patient-focused organizations that have come out in support of distinguishable naming is so broad, it covers virtually every single American family.
While we agree that it is important to gather data that allows providers to better understand how biologics and biosimilars are performing among various patient groups and to assist in the tracking of adverse events, as we mention above, we believe that the current mechanisms in place (e.g., NDC code, lot number, brand name, manufacturer, etc.) are sufficient.
Traditional naming structures do a good job of tracking post market issues (NDC, lot number, brand name, manufacturer, etc.).
Other, complementary tracking systems do and should exist, however non-proprietary names are the backbone of pharmaceutical tracking within payment systems, not necessarily for tracking and tracing AEs. The National Drug Code, or NDC, system provides a unique 10- or 11-digit set of numbers for each medication, however payers do not universally use NDC codes.
A lot number alone is not sufficient enough to identify a product and its manufacturer. It is only useful when it is accompanied by an identifier that is linked to the manufacturer. While having brand names is useful for tracking and tracing AEs, they are not always used when prescribing or reporting AEs.
Additionally, there is a lack of standard use in medical benefit setting where the majority of biologics are administered and NDC are not necessarily present in patient records. When are entered there are many instances in patient care where NDC codes have been inaccurately entered.
Current approaches and systems do not allow for adequate collection of data relating to patient subpopulations, such as women, minorities and people with specific genetic problems; depending on the level of additional clinical research that will be required to bring a biosimilar to market, it is very likely there is much we won’t know about how a biosimilar might uniquely impact these subpopulations. Distinguishable names for biosimilars support the patient advocate and medical community’s vital post-approval learning curve to determine which medicines are best for patient subpopulations.
The clarity from distinguishable non-proprietary names will:
· Enable better safety monitoring.
· Promote timeliness in managing adverse events if they occur.
Provide physicians with more information to understand which products are likely to be more effective in specific patient subpopulations.
Requiring distinguishable names would segregate the safety data for brand and biosimilar products, making it more difficult to detect rare AEs across classes of products. (Study referenced: 2013 EMA report entitled “Traceability of Biopharmaceuticals in Spontaneous Reporting Systems: A Cross-Sectional Study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance Databases”)
The 2013 study referenced in this assertion did in fact find that 96.2% of adverse events could be traced back to biosimilars if either the brand name OR INN or company name were available. However, “…products for which only the INN was available were considered non-identifiable, except for epoetin zeta, for which product the INN differs from the innovator (epoetin alfa),” (pgs. 619-620). This is precisely why there needs to be distinguishable INN/ USAN names: so that products that can only be identified by INN/USAN can still be traced. Furthermore, the 2013 study cited actually found that 1 out of every 10 (90.4%) adverse events related to biosimilars can’t be traced back to a specific product if the biosimilar was given concomitantly or interacted with another medication.
WHO has already established a global naming convention, known as the International Non-proprietary Names (INN) system.
The INN system was established in the 1950’s to identify active ingredients in small molecule chemical compounds, well before highly complex biologics were developed.
Unlike traditional pharmaceutical medicines (small molecule, chemical entities), where the active ingredient of a generic and the originator compound are identical, the active ingredient for biologics (large molecule) is complex, and a biosimilar will not be an exact replica.
WHO has not announced how it may alter its existing INN program to effectively serve biologics including biosimilars, however the organization’s published deliberations on the issue indicate change is likely:
“Compared to a small chemical entity, biotherapeutic proteins are large and complex, with four levels of structure (primary, secondary, tertiary and quaternary). The complexity of their structure is often further augmented by glycosylation and other molecular modifications, whose variability can impact on bio-activity. There are already several different naming policies for SBPs amongst individual regulatory authorities and in some cases, alternative interpretation of INN policy has led different authorities to assign different non-proprietary names for the same product. If prescribers rely on regulatory authority names, this will lack global consistency and could lead to different SBPs having the same name in different countries.
Four approaches are suggested on how to deal with this situation:
· Continue with the status quo
· Treat all SBPs as unique products and provide them with a unique INN
· Create a biosimilar ‘identifier’ to be used for all SBPs (and not just glycosylated ones), e.g. use the original INN and add a fantasy code suffix
· Encourage regulatory authorities to provide an ‘identifier’ under the guidance of WHO”
“The last two approaches fulfill the need for a unique identifier of a biosimilar and it would be preferable for the WHO to perform this (i.e. the third option); if regulatory authorities are involved (fourth option), there is no guarantee that a name will be accepted and adopted globally. The naming of SBPs needs to be addressed globally and soon while the number of registered SBPs remains relatively small and with the INN programme being the best forum to achieve this.” (http://www.who.int/medicines/services/inn/55th_Executive_Summary.pdf)
Changing the traditional naming process would require that each piece of the compendia process be individually rebuilt in order to ensure patient safety and restore functionality to the system.
Comparing biologics to small molecule products that share identical active ingredients misses the crucial point that biosimilars are not generics. If the proper use of biosimilars requires modernizing the existing system of safety alerts, then it is imperative to do so.
Existing INN’s for small molecule medicines and their generic counterparts do not need new naming conventions, only biologics. This significantly reduces the alleged burden on the system.
As medicine and technology evolves, so should our naming and coding process. Patient therapies should be precise and traceable every step of the way; the cost of implementing computer upgrades should never be presented as an obstacle to ensuring the safety of patients.
There is already a precedent for shared names that has not resulted in any known issues and are used effectively in EU, Canada, Australia and Japan.
The non-proprietary naming system in Europe (INN) has mainly been used for first-generation biosimilars, as second-generation products have only recently been approved for marketing in the EU. Historical data that is collected from first generation biologics will be largely irrelevant and will not provide an accurate picture of potential pitfalls as complex second generation biologics enter the marketplace.
Canada has one biosmilar on the market and has stated that it will likely follow guidance issued by WHO as it establishes its naming nomenclature system for biosimilars. Australia and Japan have established their own systems to biosimilars naming, both of which take a distinguishable naming approach. Australia system includes a shared INN and suffix and early evidence indicates successful entry and uptake.
Not mentioned by the cost-centric/anti-safety crowd are the well-documented situation in Thailand, which resulted from the use of shared non-proprietary names. From the Citizen Petition filed January 7, 2014 by Johnson & Johnson with the FDA:
“Between 2004 and 2007, despite our switch to coated stoppers, adverse event reporters worldwide reported 15 cases of erythropoietin antibody-mediated PRCA in patients with chronic kidney disease who had been administered subcutaneous epoetin alfa. Of these 15 cases, 11 occurred in Thailand. The Thai market included multiple epoetin alfa products and hospitals and pharmacists frequently switched patients among them, often with incomplete documentation. Despite an extensive investigation, we were unable to determine which product(s) were responsible for the PRCA in the Thai patients because we could not determine which epoetin alfa product(s) a patient had received or which of several products that a patient had received had caused the problem.
In Thailand, several different erythropoietins were used, some of which shared the same nonproprietary name, and records did not reliably identify which specific product a patient had received. These factors confounded our ability to identify the product(s) responsible for the safety signal. To our knowledge, the product(s) responsible for the increased rate of PRCA in Thailand has never been identified.”
In the early 2000s, Thailand used non-distinguishable names for biological treatment of treat certain diseases, which lead to a dramatic increase in incidences of blood-related adverse events. Some of the products shared the same non-distinguishable name and records did not reliably identify which specific biosimilar a patient had received. These factors confounded the ability to identify the product responsible for the safety signal…When patients are switched between or among products, it can be difficult or impossible to identify the product responsible for an adverse event…contributing to the inability to identify the responsible product for cases of PRCA in the Thailand situation was the common practice of switching patients among the multiple epoetin alfa products available. And even where records identified which product(s) a patient received, it was often impossible to determine the particular product responsible for the PRCA because many patients had received more than one product.”
In order to prevent another life-threatening adverse event, more expensive registries were ultimately required in Thailand to better track these products and related outcomes.
Distinguishable names would be “Contrary to Sound Economic Healthcare Policy and Congressional intent in BPCIA.”
The patient and safety communities, as well as many physician organizations have weighed in on the same issue, and have come out on the opposite side – in favor of transparency, so that patients can know which medication is being put into their bodies and the whole system can quickly connect the dots to stem negative impact when an adverse event occurs. In the views of these stakeholders:
· “If untraceable biosimilars become the norm and should the hypothesis of biotherapeutic equivalency not prove to be correct it would likely cause significant morbidity and mortality and thus irreparably damage this market and consumer and practitioner confidence in this class of products.” – From January 30, 2014 comments submitted the FTC by Salvatore J. Giorgianni, Jr., PharmD, BSc, CMHE and chair of the American Public Health Association Caucus on Men’s Health and president of the Griffon Consulting Group, Inc.
· Distinguishable names can prevent delays in determining the cause of an AE by creating a more expeditious route back to the origin of the problem and may avoid the recall of an entire class of biologics (which would be necessary if the specific medicine causing the adverse effect could not be readily identified.)” - From a January 7, 2014 letter to the FDA signed by the Maryland State Medical Society.
Additionally, Australia opted for distinguishable codes for all biologics, and they appear to be experiencing successful rollout and uptake of biosimilars.
The incident surrounding ado-trastuzumab shows the risk of confusion with prefixes and can cause patient safety concerns.
Safety and quality experts concluded that the lesson learned by the ado-trastuzumab incident is not that prefixes present a patient safety risk but instead that strong coordination is needed between FDA, USAN, National Library of Medicine (NLM), USP, Compendia, and HIT stakeholders regarding naming for all biologics, including biosimilars.
Applying different names for the same biological drug ingredients:
• Introduces confusion and unnecessary complexity
• Is contrary to historical FDA practice and policy
• Is opposed by virtually all pharmacy association stakeholders because it conflicts with normal pharmacy practice - employing an electronic database to recognize products by identifiers
• Is unnecessary for product recall or other patient safety considerations
• Undervalues the ability of existing systems (NDC- and Lot- based recalls) and new regulatory structures (track and trace) to provide adequate safeguards
The patient and safety communities, as well as many physician organizations have weighed in on the same issue, and do not believe distinguishable naming would introduce confusion and complexity, nor do they believe distinguishable names would hinder product recalls. They have come out on the opposite side – in favor of transparency, so that patients can know which medication is being put into their bodies and the whole system can quickly connect the dots to stem negative impact when an adverse event occurs.
Due to the fact that the FDA will characterize its assessment of biosimilarity (based on comparative analytical data) into one of four levels -- not similar, similar, highly similar or highly similar with a fingerprint-like similarity – it will become even more critical to provide transparency as to which biologic or biosimilar is being prescribed. Additional pharmacologic studies would be required to show that the identified difference is "within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product." FDA said only products in the top two tiers would meet the statutory requirement for analytical similarity under the Biologics Price Competition and Innovation Act of 2009.
The American Society of Health-System Pharmacists in a February 27 letter to the FTC that “…we do not oppose the addition of suffixes (e.g., alpha, beta) to the INN name if experts believe this approach is needed to facilitate pharmacovigilance.”
The Hematology/Oncology Pharmacy Association (HOPA) has stated its support for distinguishable naming in a published position paper: “Health care providers, patients, manufacturers, and regulatory agencies must be able to identify that a product is biosimilar to the original branded medication, and they must be able to associate the medication with the appropriate therapeutic class to assure appropriate prescribing. Naming is important to avoid prescribing and dispensing errors. Further, biosimilars must be able to be easily tracked to monitor safety and quality. Pharmacists are uniquely positioned to understand the important role that naming will have in ensuring appropriate medication substitutions take place when biosimilars are used.”
Nowhere are the issues of safety, efficacy, and traceability more important than to those with Orphan Diseases. And nowhere are biologics more important for treatment. So let’s end this missive with the position of NORD.
In a letter submitted to FDA Commissioner Margaret Hamburg, NORD asks that the agency give serious consideration to the concerns of the rare disease community when setting policy regarding official names for biologics, including biosimilars. NORD President and CEO Peter L. Saltonstall writes,
With over 7,000 rare diseases identified and 30 million Americans affected, the patient population represented by NORD is extraordinarily heterogeneous, the letter notes. Without thoughtful and consistent naming protocols for biologics, there is the potential for significant confusion among treatment options and increased adverse events, both of which could jeopardize patient safety. Distinguishable naming of all biologics is imperative for health care professionals to deliver the degree of customized care that is routinely required for patients with complicated, uncommon and less well-studied diseases. Every patient deserves the care best suited for their medical situation and most likely to give them the best outcomes. Biologics are often the most advanced and effective treatments for patients we represent and everyone in the treatment continuum should be able to readily identify the specific drug product a patient was given.
… and you will know the truth, and the truth will make you free.Read More & Comment...
AHIP’s Deceptions and Distortions About Prescription Costs and Value : Part One
AHIP Deception: Drug costs are unsustainable.
Facts: In 2013 prescription drugs were 8.9% of health care spending. In 2022 they will be 9.1% of total health expenditures.
(This and other data was compiled from CMS statistics. National Health Expenditure (NHE) Amounts by Type of Expenditure and Source of Funds: Calendar Years 1965-2022 in PROJECTIONS format . The raw numbers are here: NHE Historical and Projections 1965-2022
The projections are based on the 2011 version of the NHE released in January 2013.)
Fact: In 2013 prescription drug spending by AHIP was 12 percent of the $962 billion it spent on health care. In 2022 it will be 12 percent of the $1.6 trillion private insurance will pay out for health care
And finally Rx spending by AHIP as percent of total US healthcare spending remains steady at 4 percent.
If you are going to lie, it has to have some element of truth to be effective..
Read More & Comment...
Today the House Energy & Commerce Committee’s 21st Century Cures Initiative tackles the FDA and “communications.”
According to the committee’s own white paper:
Communication about how certain treatments are working in certain patients is happening through a multitude of media around the globe. These conversations between and among doctors, patients, researchers, and scientists in academia and industry should be facilitated. This includes the free flow of data, research, and results related to what a therapy or combination of therapies does or does not do well and in what types of patients. We need to harness the power of the Internet and social networks.
That’s a big topic – but perhaps the most important issue within that big tent is that of off-label communications.
Perhaps the first thing to note is that there is distinction between off-label communications and off-label marketing. And is a distinction with a difference. Off-label marketing means sharing information with the intent to impact sales. Off-label communications means sharing information to improve and advance the public health. One well-known moniker for off-label communications is “the free and fair dissemination of scientific data.”
Let’s start here: Facts do not cease to exist because they are ignored.
According to a 2011 notice in the Federal Register:
The Food and Drug Administration (FDA) is announcing the establishment of a docket to assist with our evaluation of our policies on communications and activities related to off-label uses of marketed products, as well as communications and activities related to use of products that are not yet legally marketed for any use, we would like to obtain comments and information related to scientific exchange. FDA is interested in obtaining comments and information regarding scientific exchange about both unapproved new uses of products already legally marketed (“off-label” use) and use of products not yet legally marketed for any use.
And the issue of “scientific exchange” comes front and center. According to the FR notice, To assist with our evaluation of our policies on communications and activities related to off-label uses of marketed products, as well as communications and activities related to use of products that are not yet legally marketed for any use, we would like to obtain comments and information related to scientific exchange.
The FR notice puts this request into perspective:
On July 5, 2011, a citizen petition was submitted by Ropes & Gray and Sidley Austin LLP on behalf of seven product manufacturers (Petitioners): Allergan, Inc.; Eli Lilly and Co.; Johnson & Johnson; Novartis Pharmaceuticals Corp.; Novo Nordisk, Inc.; Pfizer, Inc.; and sanofi-aventis U.S. LLC under 21 CFR 10.30. The citizen petition requested that FDA clarify its policies for drug products and devices governing certain communications and activities related to off-label uses of marketed products and use of products that are not yet legally marketed for any use. Specifically, the petition requests clarification in the following areas:
1. Manufacturer responses to unsolicited requests;
2. Scientific exchange;
3. Interactions with formulary committees, payers, and similar entities; and
4. Dissemination of third-party clinical practice guidelines.
For some time, FDA has been considering these issues and is currently evaluating our policies on sponsor or investigator communications and activities related to off-label uses of marketed products and use of products that are not yet legally marketed for any use. We have been considering what actions to take in the areas specified by the petitioners with respect to manufacturer responses to unsolicited requests; interactions with formulary committees, payors, and similar entities; and the dissemination of third-party clinical practice guidelines.
Specifically, the FDA asks:
• How should FDA define scientific exchange?
• What types of activities fall under scientific exchange?
• What types of activities do not fall under scientific exchange?
• Are there particular types and quality of data that may indicate that an activity is, or is not, scientific exchange?
• In what types of forums does scientific exchange typically occur? Should the use of certain forums be given particular significance in determining whether an activity is scientific exchange or an activity that promotes the drug or device? If so, which forums?
• What are the distinctions between scientific exchange and promotion? What are the boundaries between scientific exchange and promotion?
• Generally, who are the speakers involved in scientific exchange, and who is the audience for their communications?
• Should the identity of the participants (either speakers or audience) be given particular significance in determining whether an activity is scientific exchange or an activity that promotes the drug or device? If so, which participants would be indicative of scientific exchange and which would be indicative of promotion?
• How do companies generally separate scientific roles and promotional roles within their corporate structures?
• How should the Agency treat scientific exchange concerning off-label uses of already approved drugs and new uses of legally marketed devices? Please address whether there should be any distinctions between communications regarding uses under FDA-regulated investigation (to support potential approval) and communications regarding uses that are not under express FDA-regulated investigation.
• How should the Agency treat scientific exchange concerning use of products that are not yet legally marketed (that is, products that cannot be legally distributed for any use outside of an FDA- or institutional review board (IRB)-approved clinical trial)?
• Should investigational new drugs and investigational devices be treated the same with respect to scientific exchange? Why or why not?
• Under 21 CFR 812.7(b), an investigational device is considered to be “commercialized” if the price charged for it is more than is necessary to recover the costs of manufacture, research, development, and handling. Similarly, FDA considers charging a price for an investigational drug that exceeds that permitted under its regulations (generally limited to cost recovery) to constitute “commercialization” of the drug (see 74 FR 40872 at 40890, August 13, 2009; 52 FR 19466 at 19467). What other actions indicate the commercialization of drug and/or device products? If there are differences in the steps taken to commercialize drug products and the steps taken to commercialize device products, either before or after approval, please explain these differences.
As PhRMA wrote in a June 2014 statement:
To get the best possible health outcome for patients, FDA should revise its regulations to allow companies to share truthful, scientifically accurate, and data-driven information with healthcare professionals to inform treatment decisions. Some examples of this kind of information include:
Observational data and “real world evidence” – Information on the safety and effectiveness of medicines taken from medical records based on actual use of approved medicines.
Sub-population data – Information on the safety and effectiveness of medicines in sub-populations including gender and race. Such information can help healthcare professionals tailor their treatment to meet the needs of individual patients.
Observational and comparative data – Information from the use of a medicine outside of randomized clinical trials, especially comparisons between two or more therapies.
Pharmacoeconomic information – Healthcare economic data and information on the economic value of medicines can improve the efficiency of patient care.
Information on medically accepted alternative uses of medicines – Information on new uses of approved medicines that are listed in major compendia and/or routinely reimbursed by the federal government and major payers. As the National Cancer Institute states, “Often, usual care for a specific type or stage of cancer includes the off-label use of one or more drugs.” Healthcare professionals help patients by applying new uses of approved drugs in “every specialty of medicine.” When patients are being prescribed medicines off-label, they deserve to know that their healthcare professionals have the latest information on these uses.
 See National Cancer Institute, Off-Label Drug Use in Cancer Treatment, available at http://www.cancer.gov/cancertopics/druginfo/offlabeldrug.
 Christopher M. Wittich, et; al., Ten Common Questions (and Their Answers) About Off-label Drug Use, Mayo Clinic Proceedings, available at http://www.mayoclinicproceedings.org/article/S0025-6196(12)00683-0/fulltext#sec3.
And it’s not just PhRMA – patient groups are keen to weigh in. Some examples:
At the same time, the government severely restricts what drug companies can say about new research and about off-label uses, thus cutting off information from the most knowledgeable sources. The Congress should seek new policies that permit drug companies to share appropriate information without fear of enforcement action.
Ovarian Cancer National Alliance
In ovarian cancer, as in many oncology settings, patients receive “off-label” therapies, which are legal and often part of practice guidelines. Access to these therapies is critical to providing patients with the best possible care...
The Alliance is deeply concerned that these revisions will chill off-label use of drugs and the dissemination of scientific information about non-approved uses. We strongly urge FDA to reconsider these changes and remove any language that may curb patient access to medically-accepted and life-saving medications.
And from BIO:
Current law deals with the important question of providing payers and others with meaningful information regarding the pharmacoeconomic benefits of medicines. However, implementation of Section 114 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) has undermined innovators’ ability to meet requests for such information. The committee could evaluate how this important provision could be implemented in a less restrictive way to allow manufacturers to discuss more fully the value to the healthcare system of their innovations.
More broadly, provision of other truthful and non-misleading information to providers, payers, and patients also should not be impeded by unnecessary and cumbersome regulatory restrictions or requirements. Such approaches hinder users of medicines from accessing information that can help them use the medicines most effectively.A lot of questions and, it seems, a lot of potential regulatory mission creep. All the more reason for both Congressional input .. and oversight. Read More & Comment...
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. Read More & Comment...
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.Read More & Comment...
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. Read More & Comment...
“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. Read More & Comment...
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.Read More & Comment...
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. Read More & Comment...
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.Read More & Comment...
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.
Read More & Comment...
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.Read More & Comment...
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
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 Read More & Comment...
A new European Commission working paper positions the pharmaceutical industry at the heart of the region’s economic growth prospects.
Pharmaceutical Industry: A Strategic Sector for the European Economy (available here) marks a significant turning point towards an integrated life sciences strategy for Europe. The working paper takes stock of the sector’s current situation, focusing on developments made over the last years as the first step in preparation for a new strategic agenda.
The paper highlights several points for strategic focus including:
- The presence of a viable pharmaceutical industry contributes to the health and the quality of life of citizens by providing remedies to an increasing number of patients, through a more timely, widespread and equal access to pharmaceuticals.
- Intellectual property rights related to pharmaceuticals have gained prominence in debates about intellectual property rights policy. They have been at the forefront in discussions about the impact of intellectual property rights in terms of the access to medicines, particularly in developing countries. In the light of these divergent views, European companies are often faced with significantly lower levels of intellectual property protection in third countries, particularly in emerging economies. The challenges range from a lack of or non-enforcement of patents to the disclosure or reliance on data submitted by the original manufacturer for obtaining a marketing authorization by regulatory authorities, thus depriving companies of the economic benefits of their investments.
- Assessing pharmaceutical expenditure also requires taking into account the effects on other health-related costs (like hospitalization, sick leave, pensions, etc.) as well as the overall implications for industrial competitiveness and external trade.
The paper suggests a comprehensive approach to streamlining the policy formulation processes impacting the pharmaceutical industry at European and Member States level. Against this backdrop, the European Commission will organize an event bringing together relevant EU and national public and private stakeholders: decision-makers from public bodies in charge of industrial competitiveness, health, pricing and reimbursement, research and innovation at Member States level, and their Commission counterparts, patients, healthcare professionals, trade unions and industry representatives.
The strengthening of the competitiveness of the European pharmaceutical industry requires actual implementation of innovation policies at EU and Member States level in order to create incentives and rewards for a sustainable, competitive pharmaceutical sector that addresses public heath needs.
On the intellectual property rights front, more than half of EU industries are considered IPR-intensive, providing for 35% of European jobs and 39% of total economic activity. It is crucial to ensure a strong and effective framework for IP protection and enforcement if we are to preserve the ability of EU industries to adequately grow and export. This also implies raising awareness as to the critical need for IP.
In related news, the new EU Action Plan of DG MARKT addresses infringements of intellectual property rights in the EU, strengthens the enforcement policy framework against commercial scale IP infringements, by defining a set of 10 innovative actions and tools. This action plan notably embodies the "follow the money” approach, which deprives infringers of their revenues.
The revised Strategy of DG TRADE for the protection and enforcement of IPRs in third countries rightly accounts for the current challenges which right-holders are faced with when trying to protect or enforce their intellectual property rights abroad. Addressing specifically the challenges of access to medicines worldwide, this new strategy recalls there are "many factors affecting access but mostly unrelated to IPRs". The Commission highlights the need to come up with a broad response to this complex and multifaceted problem, to ensure affordable access to medicines without undermining the incentives needed for continued pharmaceutical research.
The Commission documents are must-reads for all health and finance ministries from Pretoria to Beijing, to Delhi and elsewhere as they debate and consider the future roles of both IPR and strategic collegiality in the realm of pharmaceuticals and the public health.Read More & Comment...
(At least on paper.)
As reported in BioCentury, FDA has released a draft four-year plan for 2014-2018 that reiterates its emphasis on advancing regulatory science. The agency said it plans to increase the use and capacity of regulatory science -- which it defines as the science of developing tools, standards and approaches to assess the safety, efficacy, quality, toxicity, public health impact or performance of a food or medical product -- to inform standards development, analysis and decision-making and to effectively evaluate products.
In the agency's strategic priorities for 2011-2015, the advancement of regulatory science was listed as the top priority for the agency as a whole. FDA has since published a strategic plan for regulatory science, which details eight priority areas and calls on the agency to collaborate with stakeholders to develop and refine clinical trial designs.
Other priorities include addressing globalization; advancing safety and quality by reducing risks in the manufacturing, production and distribution processes; strengthening detection and surveillance of problems; and improving response to identified and emerging problems. The agency said it intends to increase the exchange of information with foreign sources by assembling global coalitions of regulators. Earlier this year, the agency launched an initiative to exchange information with EMA and the European Commission on foreign inspections, building on a three-year pilot launched in 2012. Comments are due July 31.Read More & Comment...
How important is the issue of opioids? Well, important enough that it was the very first panel offered at the 2014 BIO Convention’s regulatory affairs track. And it didn’t disappoint.
Moderated by yours truly, I was joined by three experts (Douglas Throckmorton, MD, Deputy Director of Regulatory Programs, FDA’s Center for Drug Evaluation and Research, Richard C. Dart, MD, PhD, Director of the Rocky Mountain Poison and Drug Center, and J. David Haddox, DDS, MD, Vice President of Health Policy for Purdue Pharma, L.P.) and a room full of engaged and inquisitive attendees. The session began with a question – Who lost opioids?
I reminded the audience of the old public relations maxim that, “Everything you read in the newspaper is true – except for those things you know about personally.” And today that means the preeminence of social media. Google “opioid abuse deterrence” and you’ll find a lot of hits from lawyers and elected officials in the mainstream media -- but you have to know where to look (or who to ask) to access expert thinking from the FDA.
There’s certainly no dearth of verbiage and suggested solutions from the law enforcement community. Alas, those fixes rely on the general philosophy that the only good opioid is a recalled opioid. And that results in strategies that require strict prescribing limitations, and severely limited access. Punishing the legitimate pain patient, all the panelists agreed, is the wrong way to go.
Then there’s the legislative solution – but what this really means is allowing politics to drive the agenda. The posturing and hyperbole that has surrounded the issue of opioids pain medicines hasn’t resulted in a single workable solution. And the premature promptitude of many attorneys general and chief executives such as Massachusetts Governor Deval Patrick has led to numerous headlines but, in the end, nothing but fruitless lawsuits.
As Mark Twain quipped, “For every complex problem there is usually a simple answer – and it is usually wrong.” What those seeking to solve the problem with one-shot solutions have ignored is that pain in America is a medical problem of enormous proportion.
100 million Americans are now living with chronic pain. That’s a third of the U.S. population. Ten million of those have pain so severe that the pain disables them. Pain costs the US economy about $600 billion dollars a year in lost productivity and healthcare cost. And lawsuits, recalls, and police actions won’t change those dire statistics.
But just as opioids aren’t the problem, neither are they a panacea. Yet payers often implement barriers to the use of branded, on-label non-opioid pain medicines, relegating these treatments to second line options. 52% of patients diagnosed with osteoarthritis receive an opioid pain medicine as first line treatment, as do 43% of patients diagnosed with fibromyalgia, and 42% of patients with diabetic peripheral neuropathy.
Aren’t abuse deterrent opioids the magic bullet we’ve all been looking for? Not really. First of all, what does “abuse deterrence” even mean? As FDA Commissioner Peggy Hamburg testified to Congress, “It doesn’t do any good to label something as abuse deterrent if it isn’t actually abuse deterrent, and right now, unfortunately, the technology is poor.” Abuse deterrence is a goal. And at present, it’s an elusive one.
Abuse deterrence also raises some very important and difficult regulatory questions for the FDA. What type of 21st regulatory science will be required to review abuse deterrent applications? How will the agency approach the approval of non-abuse deterrent generics? What about more sophisticated pharmacovigilance programs? And, last but not least, how can the FDA better protect the public health while simultaneously preserving innovative development programs?
Dr. Throckmorton’s presentation noted that both FDA and other government epidemiologists are working to improve the surveillance databases and tools used to assess impact of abuse deterrent formulations in US market. He specifically mentioned the “DAWN” (Drug Abuse Warning Network) database replacement, measuring appropriate access to opioids by pain patients. The development and broad adoption of successful abuse-deterrent formulation remains an important priority for FDA. But we’re in the early days of the science, with much important work to be done.
But what else can be done?
As former Canadian Prime Minister Pierre Trudeau once said, “There's no place for the state in the bedrooms of the nation.” But what’s the appropriate place for the state in our nation’s pharmacies and medicine chests – particularly for opioids? As CDER Deputy Director (and the FDA’s point-man on opioids) Dr. Douglas Throckmorton said, “We are challenged with determining how to best balance the need to ensure continued access to patients who need these medications while addressing concerns about abuse and misuse.”
While scene-stealing members of Congress, some governors, and a gaggle of state attorneys general are trying to run roughshod over science-based regulation to great attention from the media, the FDA has been quietly doing the right thing without anybody noticing. In the immortal words of Don Draper, “If you don't like what is being said, then change the conversation.
The FDA must play a lead role in facilitating physician education, not only through labeling language but physician education. The FDA has, of late, repeatedly discussed enhancing continuing medical education (CME) and working to develop (with a broad constituency) validated tools for physicians to use in determining which patients may be more prone to slide into abuse so they can choose their therapeutic recommendations more precisely.
In the words of FDA Commissioner Hamburg, “It all comes back to provider education.” Amen.
Provider education – the Hamburg Manifesto.
That’s not regulatory mission creep; it’s the appropriate application of the agency’s Safe Use of Drugs initiative. The way you make a drug “safer” is to ensure that it is used by the right patient in the proper manner.
Abuse deterrence is a worthy goal and will evolve when all the players work together in a more regular and synchronistic fashion. Fortunately, all panelists agreed this was the reality.
As the Japanese proverb goes, “Don’t fix the blame, fix the problem.”Read More & Comment...
The Massachusetts Senate has passed legislation to allow pharmacists to substitute a biosimilar for a biological medicine when the United States Food and Drug Administration has determined that the two biological products are interchangeable and the prescriber has not instructed otherwise.
Following a substitution, the bill requires pharmacists to notify the prescribing practitioner and the patient. The bill will now go to the Governor for his signature.
Sounds good, right? Physician notification. But the bill was obviously drafted before the FDA expanded the types of biosimilars it will consider. Once upon a time there were two categories: biosimilar and interchangeable. But today there are four: not similar, similar, highly similar or highly similar with a fingerprint-like similarity -- depending on the type, nature and extent of any structural and functional differences revealed.
The reality is that “interchangable” is a thing of the past – even before it was a thing of the present.
In keeping with the spirit of the Massachusetts legislation (as well as that in many other states), the nomenclature should be reconsidered to reflect the realities of the evolving regulatory science.Read More & Comment...
First-Ever Patient-Initiated “Guidance for Industry” for Duchenne Muscular Dystrophy Submitted to FDA
Parent Project Muscular Dystrophy-led guidance seeks to address unmet clinical needs of individuals with Duchenne muscular dystrophy and accelerate development of safe and effective therapies
Washington, DC–June 25, 2014 -- Parent Project Muscular Dystrophy (PPMD) and a broad coalition of stakeholders today submitted the first-ever patient advocacy-initiated draft guidance for a rare disease to the U.S. Food and Drug Administration (FDA) to help accelerate development and review of potential therapies for Duchenne muscular dystrophy (Duchenne).
“This landmark guidance represents a major milestone for the Duchenne community and may open the way for other rare disease groups to incorporate the patient perspective in a well-documented and quantifiable way, moving beyond any one family’s experience,” said PPMD President Pat Furlong. “By working closely with the FDA to provide industry and other clinical trial sponsors with clearer guidance from the patient perspective, we will increase the likelihood that clinical trials will be designed to better match the unique needs of Duchenne patients. It is our profound hope that this, in turn, will lead to the approval of much needed treatments for all people living with Duchenne muscular dystrophy.”
Duchene, the most common lethal genetic disorder diagnosed in childhood, is a progressive and degenerative condition with no cure or disease-modifying treatments available in the United States.
Clinical trials for rare diseases like Duchenne are difficult to design and implement because of challenges such as small study populations, incomplete and evolving understanding of rare diseases, and effective ways to measure clinical impact of therapies being studied. Last year, FDA collaborated with PPMD and its scientific advisors to convene a policy forum that informed the process for developing the Duchenne community’s suggested guidance.
“The U.S. Food and Drug Administration is appreciative of the input of Duchenne patients and patient advocates. Their input will enhance the essential data-driven process and evaluation of new therapies,” said Janet Woodcock, M.D., Director of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.
About The Suggested Guidance
More than 80 representatives of the Duchenne community - including parents and patients, medical experts, academics, and biopharmaceutical industry representatives -- participated in seven working groups that met over the past six months to draft the guidance.
The cornerstone of the guidance encourages the FDA and trial sponsors to engage patients and their families at all stages of trial development and to take into account what they consider acceptable risk in clinical trials. A recent PPMD study published in the journal Clinical Therapeutics* shows that parents of children with Duchenne will accept substantial risk when balanced with noncurative slowing or stopping of the progression of muscle weakness, even with no improvement in life expectancy. The results came from the first-ever scientific survey of benefit/risk perspectives that PPMD conducted last year involving 120 Duchenne parents.
“As the FDA evaluates new drug applications for Duchenne therapies, it is imperative to take into consideration the value that parent decision makers place on even moderate benefits to function and mobility, and their tolerance for considerable risk and uncertainty,” said Furlong. “Parents and caregivers of Duchenne children know firsthand that every day without treatment is another day closer to their child losing essential activities of daily living such as walking, feeding oneself, and eventually, breathing. When your child is living with Duchenne, you find yourself willing to take significant risk for even the hope of modest benefit. Parents can make these decisions thoughtfully and the FDA must recognize that. They cannot protect us from what we think is important in the drugs we need now.”
Each section of the guidance includes extensive published or in-press peer-reviewed articles and focuses on six areas aimed at overcoming the challenges in trial design and implementation:
* Benefit/Risk Assessment – providing a community-centered approach for the benefit-risk framework fundamental to the regulatory process and reflecting the community’s tolerance of potential risks or uncertainty of benefit associated with new treatment options.
* Diagnosis – referring sponsors to guidance produced by the American Academy of Pediatrics (AAP) on a diagnostic algorithm, as well as, providing context on diagnostic delay and importance of genetic analysis using modern technologies, including access to genetic testing.
* Natural History – accurately characterizing the clinical course of Duchenne to reflect the timing of the loss of certain abilities based on current medical management practices, including how Duchenne affects cardiac and pulmonary function.
* Clinical Trial Designs, Outcome Measures and Considerations – ensuring that trials – to the degree possible – are inclusive of Duchenne patients of all ages and disease stages.
* Muscle Biopsy-Based Biomarkers – addressing key considerations when performing muscle biopsies, including the ethical imperative to perform them only when needed and precautions to assure usable specimens; sponsors are also referred to an international effort to standardize methodologies and emerging technologies.
* Non-Muscle Biopsy-Based Biomarkers – exploring the ability to bring non-invasive imaging techniques to replace biopsy (e.g., MRI/MRS skeletal muscle imaging) and eventually reach the goal of being a surrogate endpoint for treatment trials.
The suggested FDA guidance represents the culmination of PPMD’s 20 year history of improving care and developing urgently needed therapies for Duchenne. PPMD led the effort to pass the MD-CARE Act, which created the Senator Paul Wellstone Muscular Dystrophy Cooperative Research Centers. The draft guidance builds on PPMD’s effort to shape federal policy that reflects the needs of families living with Duchenne, including the release of “Putting Patients First” which calls on the FDA to act more flexibly when reviewing applications for Duchenne therapies. PPMD also ensured that the FDA Safety & Innovation Act of 2012 (FDASIA) responded to the needs of the community; recently published a groundbreaking benefit/risk study which documented the willingness of families to live with risk; and held a national PPMD-FDA Duchenne Policy Forum where the community made its needs and preferences in drug development known to the Agency.
*[EDITOR’S NOTE – Peay H.L. et al: A community-engaged approach to quantifying caregiver preferences for the benefits and risks of emerging therapies for Duchenne muscular dystrophy; Clinical Therapeutics, Vol. 36, No. 5, 2014; available for access: http://www.clinicaltherapeutics.com/article/S0149-2918(14)00209-4/abstract.]Read More & Comment...
The New York Times has written quite a lot lately on the cost of drugs – without a word on either the value of new medicines or the cost of investing in innovation. On the up side, the Gray Lady has finally discovered the cost of poor medicines quality.
For years, Dr. Harry Lever, a cardiologist at the Cleveland Clinic, has been warning nearly anyone who would listen of his growing suspicions about generic versions of a widely used heart drug, Toprol XL.
Patient after patient, he said, would visit his office complaining of chest pains or other symptoms after switching from the brand-name version, made by AstraZeneca, to a generic product, often one made in India. When he switched them back to the brand — or to another generic — the symptoms disappeared, he said. Dr. Lever wrote a letter outlining his concerns to the Food and Drug Administration in 2012, and this year, he traveled to Washington to try to get the attention of Congress.
Dr. Lever could not prove that the generic drugs were to blame. “You see enough people and you get a feel, but it’s anecdotes,” he said in an interview Monday. “It’s not science.”
This is in keeping with a March Reuter’s story on the same topic:
Some U.S. doctors are becoming concerned about the quality of generic drugs supplied by Indian manufacturers following a flurry of recalls and import bans by the Food and Drug Administration.”
"I'm just beginning to realize the gravity of the problem," said Dr. Steven Nissen, head of cardiology at the Cleveland Clinic. "It's terrible and it is starting to get a lot of traction among physicians."
Hopefully the Times story will provide further traction because, as Dr. Lever said (in the Reuter’s story),
We are losing control over what people are swallowing," said Dr. Harry Lever, a cardiologist at the Cleveland Clinic who is trying raise awareness of the matter among U.S. lawmakers. "Now, when a patient comes in who is not doing well, the first thing I do is look at their drugs and find out who makes it."
It’s too simplistic to call these “quality” problems. There’s a range from sub-standard API and manufacturing issues, to excipient changes and, most importantly, bioequivalence and bioavailability standards.
Bioequivalence does not always equal therapeutic equivalence – and that’s as true for Toprol XL as it is for Wellbutrin. According to the Times story, Two large Indian manufacturers, Wockhardt and Dr. Reddy’s Laboratories, have announced recalls over the last two months totaling more than 100,000 bottles of Toprol XL because their products were not dissolving properly — therefore probably not working as they should. The drug is a beta blocker that treats high blood pressure and heart ailments. Not good.
FDA’s recent draft guidances on bioequivalence for both generic and innovator products, as well as the move towards independent labeling for generic products are additional steps the agency has recently taken to address the issue of drug quality beyond safety and efficacy. And the implications for biosimilars is obvious
(Something else to consider is for the FDA to report BE and BA and PK data in generic labels.)
Small is the new Big means we must think differently about pharmacovigilance. While we must continue to capture adverse event data, we must also strive to capture Substandard Pharmaceutical Events (SPEs). SPEs occur when a product does not perform as expected—perhaps because of API or excipient issues. SPEs can arise because of an issue related to therapeutic interchangeability. When it comes to 21st-century pharmacovigilance, we have to both broaden and narrow our views about bioequivalence to the patient level.
Where's the Times editorial on that?