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WASHINGTON DC, June 4, 2014 – In a letter submitted today to the U.S. Food and Drug Administration (FDA), the National Organization for Rare Disorders (NORD) urged Commissioner Margaret Hamburg to give serious consideration to the concerns of the rare disease community when setting policy regarding official names for biologics, including biosimilars.
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,” said NORD President and CEO Peter L. Saltonstall. “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.”
The letter raises a number of concerns specific to rare disease patients. Rare disease patients usually have unique treatment courses and, while similar medications might work equally well, such a judgment can only be made through tracking of outcomes made possible through distinguishable names.
According to the letter, distinguishable names for biologics would:
* Support the medical community’s vital post-approval learning curve regarding which medicines are best for their rare disease patients;
* Support surveillance and tracking of adverse events given that rare disease patients often do not respond to medications in the same way as other individuals might; and
* Reinforce a critical distinction in the biosimilars law between biosimilars (similar not identical) and interchangeable biosimilars (similar but demonstrated to have comparable clinical results).
Next up: Vote at the AMA House of Delegates.
The FDA has publicly released a huge amount of data on drug side effects that it hopes will lead to new applications and research.
Under its open FDA project, the agency has released more than 3 million reports on adverse drug events and medication errors recorded between 2004 and 2013. These kinds of reports were only available before through lengthy Freedom of Information Act requests.
Before releasing the information, the agency removed patient identification and other sensitive information. It has also been formatted to let researchers, mobile applications and Web developers easily analyze the data and present it in a way that can help improve how people take drugs.
Eventually the agency plans to release more reports on recalls and labeling, as well as other information it thinks can be useful to developers and researchers.
The move to make medical data more transparent isn’t limited to the FDA. Several drug makers working with the National Institutes of Health have begun releasing clinical trial data in a limited fashion to help find new uses for old drugs.
Obvious by its absence is any mention of greater clinical trial transparency. But that's a whole other can of worms. (For more on this issue, see "Cry Havoc, and let slip the Dogs of Data Transparency.")
A good next step would be for the FDA to be the coordinating body for all relevant e-tized information from both public and private sources. But that’ll take resources. It would be money well spent.
Speaking of transparency – how about an OpenFDA program for the agency’s risk/benefit decision-making process?
There’s a difference between off-label communications and off-label marketing – and it’s more than a finesse. It’s one of those 800-pound gorilla issues we’ve been pussyfooting around for too long. And now, at long last, it’s time for a serious conversation.
Here’s a bit of outreach send out by PhRMA. It’s well said. It’s brief. And it's a call to action. Take it seriously.
FDA Restrictions on Medical Communications Can Negatively Impact Patient Care
Some of the regulations and guidances of the Food and Drug Administration (FDA) have a more direct impact on patient care than others. The FDA’s restrictions on biopharmaceutical companies’ ability to share authoritative, regulated data about prescription medicines limits healthcare professionals’ access to information that can help them make informed decisions based on their patients’ individual healthcare needs and preferences.
Biopharmaceutical companies have the most complete and up-to-date information about the medicines that they research, develop and manufacture for use by patients. However, companies are often unable to proactively share valuable information about their medicines, especially for information that is not contained in the FDA-approved prescribing information (the package insert you often receive with a prescription), with physicians and other healthcare providers.
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.”[1] Healthcare professionals help patients by applying new uses of approved drugs in “every specialty of medicine.”[2] When patients are being prescribed medicines off-label, they deserve to know that their healthcare professionals have the latest information on these uses.
You Can Help. Patients need their healthcare professionals to have timely, authoritative, FDA-regulated information about available medical treatments. Currently, the House Energy and Commerce Committee is soliciting comments from patients, providers and other stakeholders about how they learn about new treatments and cures.[3] If you believe that physicians and other healthcare professionals should have access to sound, evidence-based information that biopharmaceutical companies have about their medicines in order to help patients make informed healthcare decisions, please send a comment to cures@mail.house.gov by June 13, 2014.
[1] See National Cancer Institute, Off-Label Drug Use in Cancer Treatment, available at http://www.cancer.gov/cancertopics/druginfo/offlabeldrug.
[2] 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.
[3] See
It seems that every day there’s another headline about a serious issue involving generic drug quality. And how to improve the agency’s evaluation of these products drugs was a top priority when the agency recently compiled its regulatory science goals.
In a new Broad Agency Announcement (BAA), the FDA has announced a roadmap that will be funded from a pot of up to $50 million, and it reveals some of the difficulties facing the agency as it works to get a handle on an industry riddled with unanswered questions as companies start to produce more-and-more complex products.
In the BAA, the FDA lays out five broad areas (Post-market Evaluation of Generic Drugs; Equivalence of Complex Products; Equivalence of Locally Acting Products; Therapeutic Equivalence Evaluation and Standards; Computational and Analytical Tools) in which it wants to improve its generic evaluation capabilities and invites organizations to submit proposals detailing how they can help. Many of the specific goals focus on the equivalence between generics and their innovator forbearers. The FDA is particularly interested in methods to compare the bioavailability of complex and locally-acting products. Questions about the bioavailability of generic drugs and its impact on therapeutic effects are as old as the industry itself, but the industry's expansion into new dosage forms--such as sustained release injections and inhaled products--throws up fresh concerns.
Per a report in Fierce Pharma, the FDA is also looking at more human aspects of switching from innovative to generic drugs, with the agency keen to know what patients think about the quality and effectiveness of copycats and how tablet size affects substitution. High-profile quality failings at Ranbaxy, Sun Pharma and Wockhardt could have tainted the public's perception of generics, a possibility the FDA wants to understand while also working to get better at spotting problems early.
Other, less generic-focused aspects of the roadmap also deal with this goal. The FDA wants to develop sensitive, rapid, high-throughput methods to spot microbes, and assess ways other than sterilization to remove such contaminants. The technology is one of several ways the FDA wants to retool its capabilities and those of the industry, with the document also calling for investigations into continuous manufacturing, process analytical technologies and Quality-by-Design.
21st century pharmacovigilance must also include tighter and more regularly monitored post-approval bioequivalence measures. Recent recalls of products such as Budeprion (Wellbutrin) and Metoprolol (Toprol) offer vivid examples. "We are losing control over what people are swallowing," said Dr. Harry Lever, a cardiologist at the Cleveland Clinic. It’s a new and difficult task and calls for better validated methodologies for both data collection and signal prioritization.
Another key regulatory question is the appropriate role of regulators in coordinating input from crucial partners such as physicians, nurses, pharmacists, disease organizations, patients, and pharmaceutical manufacturers. “Real World” event monitoring must become as specific and informing as in a clinical trial environment. To borrow a term from the nuclear disarmament discussion, 21st century pharmacovigilance must work with its various colleagues to “trust, but verify.”
From the pages of the Orange County Register:
Foreign meds, quality control
In the past year, several major foreign pharmaceutical companies have been forced to recall thousands of medications sold in the United States. The problems with their products were myriad, including packaging defects, dosage errors, and bacterial contamination. In one especially egregious instance, epilepsy medications were found in a bottle of diabetes drugs, resulting in the recall of more than 2,000 bottles produced by a company based in India.
Given these dangerous errors, it's little wonder that American physicians are growing increasingly worried about the safety of prescription medications imported from foreign pharmaceutical companies. Compromised medications jeopardize the health of their patients.
We must strengthen America's "pharmacovigilance." The federal government should bulk up its drug import oversight apparatus and implement a tracking system that monitors the entire life cycle of medications.
Right now, 40 percent of America's over-the-counter and generic drugs come from Indian suppliers. The World Health Organization has estimated that around 20 percent of the drugs manufactured in that country are counterfeit.
As the New York Times recently noted, at one hospital in Kashmir, fake drugs likely lead to the deaths of hundreds of infants. In January, the Indian health ministry identified at least 32 medicines being sold in Indian stores that didn't meet basic safety and quality standards. Earlier this year, the FDA's commissioner, Margaret Hamburg, expressed her dismay about "recent lapses in quality at a handful of [Indian] pharmaceutical firms.
To protect against dangerous drug imports, the FDA has established the Office of Pharmaceutical Quality, which will more meticulously monitor the quality of brand-name, generic, and over-the-counter drugs.
Congress also enacted legislation in 2012 mandating that foreign pharmaceutical manufacturers be subjected to more intense scrutiny. This bill lead to 160 FDA-conducted inspections at Indian drug manufacturers in 2013, an enormous increase over the number of site visits in previous years.
What American inspectors discovered was often profoundly disturbing.
For example, at one plant owned by the Indian pharmaceutical manufacturer Ranbaxy, the FDA found flies "too numerous to count." Ranbaxy has since been hit with half a billion dollars in fines and has plead guilty to felony charges.
These developments are all the more discouraging once situated within the broader context of the global economy. Pharmaceutical manufacturing is a $14 billion industry in India. When its firms are permitted to push sub-par medications into the U.S. health care market, they often end up displacing American companies.
Such displacement can hurt our economy. Drug firms currently support 810,000 jobs throughout the United States. More than 20 percent of the sector's domestic sales are directed back into local research and development projects.
The American pharmaceutical industry has already proven its commitment to ensuring the quality and safety of the medicines it produces. It has vigorously pushed for the federal adoption of a track-and-trace system, which would monitor a drug's journey from manufacturer to packager to distributer to pharmacy and, ultimately, to patients.
Such a system would significantly strengthen the security of America's drug supply chain.
In contrast, India is simply shrugging off its gross failures in drug production. The Indian Medical Association's secretary-general recently said: "Our drugs are being sold in many countries and being accepted, so we have no issues. How do I know that Western drugs are better than our drugs?"
That casual attitude is unacceptable. American consumers are being put at direct risk by India's malfeasance. If Indian authorities won't take responsibility, the United States must step in and ensure that proper vigilance is in place throughout the entire life cycle of a drug.
A global pharmaceutical market benefits consumers only when the appropriate safeguards are in place. The recent spate of recalls should prompt renewed dedication to pharmacovigilence.
For the sake of both American drug companies and American patients, federal regulators must work harder to ensure that all drug imports meet basic standards for quality and safety.
Peter Pitts, a former FDA Associate Commissioner, is president of the Center for Medicine in the Public Interest.
According to report in BioCentury, the U.S. District Court for the District of Columbia vacated HHS' July 2013 final rule that discounted Orphan drugs when used in non-Orphan indications under Medicare's 340B program. The court said HHS lacked authority to make the rule.
The 340B program requires manufacturers to deeply discount outpatient drugs to hospitals and clinics bearing the brunt of healthcare for low income and other special populations. In 2010, Congress amended 340B to exclude Orphan drugs from discounting, but the law was unclear on whether the exclusion applied when the drugs were used for non-Orphan indications. In 2013, HHS issued the final rule saying the drugs were to be discounted when used in non-Orphan indications, and the Pharmaceutical Research and Manufacturers of America subsequently sued to challenge it.
In the decision, the court said that while the rule "seems like the most reasonable way for implementing the orphan drug exclusion, unfortunately Congress did not delegate to HHS broad rulemaking authority as a means of doing so," noting Congress limited HHS's 340B rulemaking authority to three purposes -- establishing a dispute resolution process, setting methodology for price calculations and imposing monetary civil sanctions. Plaintiff PhRMA said in a statement it is "extremely pleased" with the ruling.
The 340B program has been scrutinized for expanding margins. In June, HHS' Health Resources and Services Administration (HRSA) plans to publish a proposed rule addressing eligibility criteria. HRSA declined to comment on implications of the decision on that rule.
Part two of my interview from Context Matters:
Anti-Infectives
In 2010, Representative Henry Waxman voiced concern about non-inferiority trials – but when he was confronted with the science he backed down. That’s a good thing. When politicians start to dabble in science, they generally get badly burned.
Today the FDA is trying to expedite reviews of anti-infectives. The need for these products and that in itself changes the benefit / risk profile. And that will allow for approvals based on less data – and in an expedited fashion.
There are multiple ways to get an important new therapy to market quicker – but that has to be based on a public health need, not a marketing strategy.
Pediatric Trials
Pediatric trials bring both public health and IP benefits, but they are hard to design, hard to recruit for, and hard to field. They’re especially important for anti-depressants and anti-psychotics. We also will be seeing more precise clinical trials in minority and genotype populations. From a perspective of companion diagnostics we’re developing more medicines for small, more precisely identifiable patient populations – clearly the wave of the present and this will continue for the foreseeable future. It’s all about personalized medicine.
The best way to address benefit/risk profile is to make sure that the right patient gets the right medicine in the right dose at the right time. That will result in more positive clinical outcomes and huge cost savings. That’s where you’re going to see the greatest increase in adaptive clinical trials, whether in children, pregnant women, certain genotypes, women, men, African-Americans, Asians, etc.
The benefit/risk profile of a product that’s proven to be more beneficial within an identifiable sub-population is a key for expedited review, because you can more precisely define who it works for and, just as importantly, who should not be using it.
Conditional Approval
As far as so-called “conditional approval” goes, I wouldn’t look for it any time soon in the US. The last time I spoke with senior members of the FDA, I heard comments like, “What does that even mean?” And, then again, do drug developers really want conditional approval? You invest a lot of time and money to get a conditional approval and then the agency decides to take the product off the market? Is that something to roll the dice on?
Unless and until the FDA can ramp up its pharmacovigilance prowess, any kind of provisional approvals will remain problematic. At the moment, the FDA doesn’t have an eye in the sky.
Political Impact
And there’s the issue of Congress politicizing the FDA process. Plan B, Avandia, Zohydro. As Mark McClellan used to say, “If people are saying we’re approving drugs too slowly, and others are saying we’re approving drugs too quickly. We must be doing something right.”
That’s my story… and I’m sticking to it!
Facts that don’t reinforce your cognitive mapping are pesky things.
When it comes to the value of innovative medicines, keywords such as welfare impact, cost-effectiveness, innovative drugs, economic evaluation, quality-adjusted life year are often used to explain why both licensure and reimbursement is deferred or denied.
The opposite is true.
In fact, those very key words are tagged in a new Frontiers in Public Health article, Estimating the potential annual welfare impact of innovative drugs in use in Switzerland
In this new study, Swiss academics have estimated that the introduction of innovative pharmaceuticals provided substantial welfare gains to Swiss patients and the health system.
The authors find that "The introduction of innovative pharmaceuticals since 2000 onward to the Swiss market led to a potential welfare gain of about CHF 781 million in the year 2010."
Here’s the abstract:
Expenditure of health care systems are increasing from year to year. Therefore, this study aimed to estimate the difference in costs and benefits of innovative pharmaceuticals launched 2000 onward compared to standard treatment on the national economy of Switzerland in 2010. The approach and formula described in the pilot study by Tsiachristas et al., which analyzed the situation of welfare effects in the Netherlands, served as a model for our own calculations. A literature search was performed to identify cost–utility or cost-effectiveness studies of drugs launched 2000 onward compared to standard treatment. All parameters required for the calculation of welfare effects were derived from these analyses. The base-case threshold value of a quality-adjusted life year was set to CHF 100,000. Overall, 31 drugs were included in the welfare calculations.
The introduction of innovative pharmaceuticals since 2000 onward to the Swiss market led to a potential welfare gain of about CHF 781 million in the year 2010. Univariate sensitivity analysis showed that results were robust. Probably because of the higher benefits of new drugs on health and quality of life compared to standard treatment, these drugs are worth the higher costs. The literature search revealed that there is a lack of information about the effects of innovative pharmaceuticals on the overall economy of Switzerland.
Our study showed that potential welfare gains in 2010 by introducing innovative pharmaceuticals to the Swiss market were substantial. Considering costs and benefits of new drugs is important.
Nations such as South Africa (where the Medicines Control Council is taking 4-5 years to approve medicines that are globally commercialized) should take notice. If innovative medicines aren’t even licensed within months of their globalization, talking about prices is just a hypothetical exercise.
Imagine all the mortality, morbidity and … costs that could be avoided if people had access to innovative medicines.
Facts do not cease to exist because they are ignored. -- Aldous HuxleyStudy Design and the Drug Development Process
To the Editor
A Viewpoint by Dr Djulbegovic and colleagues1 claimed not only that randomized clinical trials (RCTs) aremore ethical but that greater use of randomized designs throughout the drug development process would “improve the efficiency, ie, enable faster development ofnew, successful treatments.” However,RCTs are outdated for several reasons. First,RCTs are inadequate to evaluate cancer therapies. Genomic analysis is uncovering the tremendous heterogeneity of what previously were considered single diseases. Genomic analysis of cancers of individual patients is disclosing the large number of mutations, and thus targets, within one person. Developing RCTs for targeted therapies would be difficult and timeconsuming, prolonging the wait for effective treatments.
Second, RCTs are a less efficient and accurate method of establishing which treatments work.
A recent study demonstrated that RCTs fail to predict or improve outcomes when evaluating multicausal diseasenetworks or treatments orwhen assessing which particular interactions are relevant.2 Rather than increase the use of RCTs, we propose an increase in the use of N-of-1 studies, which are based on simulations that rapidly sort through billions of possible interactions
at the clinical, genomic, and biological levels to arrive at predictive models of multicausality. This approach has identified candidate markers, which have been successfully used in clinical trials.3 These studies also have predicted the most effective treatments for patients based on a particular genotype
and medical history when RCTs have not.4 Increasing the use of RCTs would add to the cost and time required to developand use new products. Other analytic methods more quickly and precisely match patients to treatment.
1. Djulbegovic B, Hozo I, Ioannidis JPA. Improving the drug development
process: more not less randomized trials.JAMA. 2014;311(4):355-356.
2. Eppstein MJ, Horbar JD, Buzas JS, Kauffman SA. Searching the clinical fitness
landscape.PLoS One. 2012;7(11):e49901.
3. Wu C-C, D’Argenio D, Asgharzadeh S, Triche T. TARGETgene: a tool for
identification of potential therapeutic targets in cancer.PLoS One.
2012;7(8):e43305.
4. Garnett MJ, Edelman EJ, Heidorn SJ, et al. Systematic identification of
genomic markers of drug sensitivity in cancer cells.Nature.
2012;483(7391):570-575.
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
