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Scrutiny of the high list price of the drug EpiPen, used for the emergency treatment of certain allergic reactions, exposed some of the craziness and inefficiency in how drugs are priced. But it also reveals problems with how certain medicines are developed.
Drugs like EpiPen fall into a category of products that one might classify as complex generic medicines. As widely noted, the active ingredient in the EpiPen is a very old drug – epinephrine. What makes the EpiPen unique is its delivery vehicle – an auto-injector that’s packaged in a convenient, pen-like device. The product’s key attribute is its ability to reliably deliver accurate doses of the essential medicine.
The product’s ease and reliability has allowed EpiPen to capture a substantial portion of the market for injected epinephrine. But why is it almost the only game in town?
Over the years, EpiPen’s manufacturer, Mylan, made meaningful modifications to its auto-injector pen. The company maintains some important intellectual property around these revisions. Mylan rightly argues that these features differentiate its device.
But this should not – and has not – prevented other companies from developing their own pen-like devices for auto-injecting epinephrine. However, the way that FDA administers its generic drug regulatory process has left the Agency tied in some policy knots when it comes to approving these similar products as generic substitutes for EpiPen. At the same time, other regulations make it hard for competitors to EpiPen to get their products approved as new, branded alternatives to EpiPen through the new drug approval pathway.
Those looking to develop alternatives to EpiPen can get caught in a regulatory Catch 22.
One issue relates to the existing generic drug law, and FDA regulations that govern the generic approval process and the Abbreviated New Drug Application (ANDA) that a generic drug maker must file with FDA. Under the Agency’s interpretation of those rules, if a patient has to be re-trained to use a generic alternative to a branded product, then the alternative product cannot bear the same labeling as the drug it seeks to copy. As a result, it can’t meet the burden of the ANDA process and be approved as a generic equivalent.
In other words, the generic drug can’t be considered the “same” as the branded version that it seeks to copy, and serve as a fully substitutable alternative.
This means that an alternative to a complex drug or a complex drug and device combination like EpiPen would have to function in the precise manner as EpiPen. To the extent that EpiPen’s manufacturer, Mylan, maintains some intellectual property around some of the functions of its device that also correlate to some of the unique instructions on how to use the product, this can be an impediment to the entry of generic competitors to EpiPen — even if most of the fundamental IP on the drug and the device has lapsed.
At the same time, it could be difficult under FDA’s existing rules, for a competitor to EpiPen to seek approval under the longer and costlier new drug approval process, as a branded alternative to EpiPen. This is the Catch 22. A competitor to EpiPen might not be able to get through the generic drug route. But it also might not qualify as a new drug.
EpiPen is not unique. It falls into a category of old drugs, many of which should have long been subject to generic competition. Only the generic drug law, which was crafted more than 30 years ago, didn’t contemplate these “complex” drugs, and so it doesn’t provide for an efficient and predictable path for enabling generic entrants to them.
There is no official regulatory definition of “complex” generics. But one can broadly define complex drugs as those for which it’s particularly hard to establish therapeutic equivalence as defined by FDA in its official “Orange Book” on drug equivalents.
Some complex generics present significant challenges in establishing pharmaceutical equivalence due to problems related to characterizing the drugs. So it can be especially hard to develop generic alternatives. For some complex drugs, a simple bioequivalence study (the backbone of the generic approval process) is not enough to establish that the copy drug will have the same clinical and safety profile as the reference listed drug.
Many complex drugs are injectables. It’s many of these old “parenteral” medicines that have recently been in shortage, and have seen some enormous price increases. This is, in large measure, a consequence of the lack of brisk, generic competition to these drugs.
Complex generic drugs can also involve situations where the drug’s mode of action in the body makes it hard to determine, under FDA’s current standards, whether a copy drug has the same penetration on (and activity at) the biological site that it’s targeting.
This might involve, for example, a drug that acts locally on tissue lining the gut or an inhaled drug that acts directly on the lungs (like an asthma inhaler). Complex drugs might also be one that’s delivered through a complicated delivery mechanism like EpiPen. Or to take another and similar example, a drug delivered through a controlled release patch.
FDA has faced policy challenges, in part of its own making, when it has tried to “genericize” a growing number of these complex drugs through its traditional pathway.
The problem is that the generic drug approval process was crafted at a time when most drugs were simple, small molecule pills. The process for copying these drugs was relatively straightforward. The system for proving sameness largely turned on the ability to show that a copy of a drug can get into the blood at the same levels, and in the same timeframe as the branded drug that it was seeking to emulate. It could then be postulated — based on these “bioequivalence” and “bioavailability” studies — that the generic alternative would have the same profile as the branded drug that it sought to copy.
This classical generic pathway was sufficient for many well-defined, low molecular weight drugs where the analytical testing could fully characterize the product and was able to show pharmaceutical sameness to the reference list drug. Together with a proof of bioequivalence to the reference drug, this information allowed for the submission of an abbreviated file with a waiver for efficacy and safety studies. FDA would nonetheless be able to declare that the copy drug was fully substitutable for the reference medicine.
When it comes to complex drugs, the ability to determine sameness based on bioequivalence and bioavailability alone is sometimes not as straightforward.
For example, the FDA delayed for years the approval of a generic alternative to long acting heparin — years after the legitimate intellectual property on that medicine had lapsed.[iii] Similar delays challenged the approval of complex generic formulations such as oral vancomycin, liposomal Doxorubicin HCl injection, and topical Acyclovir ointment. Many of these drugs persist as branded, and costly medicines, even though the law intended for them to be subject to brisk competition from lower-cost generic alternatives.
In other cases, FDA made errors when it tried to approve generic alternatives to complex drugs like IV iron, requiring its decisions to be revisited. Or FDA established regulatory principles that were widely criticized and ultimately rescinded, such as when FDA tried to address the generic approval of certain eye drops that act topically on the eye.
These missteps underscore more systemic problems with the regulatory process that governs the review and approval of generic copies of complex drugs.
Congress should modernize the generic drug framework to accommodate complex drugs. It could start by giving FDA more discretion to rely on a broader complement of data for evaluating generic copies to complex drugs. This could mean granting FDA the ability to ask for more than just bioequivalence and bioavailability data when it comes to making judgments around sameness as it relates to complex drugs.
Congress could also give FDA more discretion to allow generic copies to have minor differences in their labeling, to account for small variations between a branded drug and the proposed generic copy. This could address situations where the instructions for use might be marginally different, but where FDA has reviewed data to demonstrate that these differences would not trigger patient confusion or present other public health risks.
Complex drugs comprise a growing and important portion of our therapeutic armamentarium. Generic entry of important copies of these medicines, once the legitimate IP has lapsed on branded alternatives, has sometimes been needlessly delayed.
This is largely because FDA lacks the scientific and regulatory framework to efficiently approve copies to complex drugs under its existing rules. But the Agency insists on trying to force these drugs down its traditional, misapplied, and dead-end approval routes.
This article is adapted from testimony that Dr. Gottlieb delivered on October 7th before a hearing of the Senate Help Committee, Subcommittee on Children and Families.
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