Shortly before Alex Azar’s confirmation hearing (to be Secretary of HHS), a reporter called me with questions.  She had an angle she wanted to pursue: that Lilly had “gamed” a patent, using pediatric exclusivity, under Azar’s watch.  I explained pediatric exclusivity – what it was designed for, how it works, and how Lilly seemed to have used it precisely as designed. I mentioned the constraints that apply to company requests for pediatric exclusivity and told her that they were meaningful, mentioning Amgen’s ongoing litigation against FDA regarding exclusivity for Sensipar.

My explanation had little impact; the story ran as initially conceived.  Judge Moss ruled in the Sensipar dispute in late January, however, and Amgen has confirmed that it plans to appeal the ruling.  This is therefore the first of two posts on the issue of pediatric exclusivity.  Below I explain how pediatric exclusivity works; in the next post I will explain the Sensipar dispute.

Why do we need to encourage pediatric studies of drugs?

There are two reasons.

First, we need information about the safety and effectiveness of approved drugs in children.  Once a drug is approved, doctors may prescribe the drug for a child with the condition in question — even if the labeling doesn’t provide any guidance about dosing for children.  And children are not simply smaller versions of adults.  Their bodies are physiologically different, and they metabolize drugs differently.  We need studies, to know whether these drugs are safe and effective for them, and at what dose.  Depending on the drug, for instance, a child might require lower dosing (per pound of body weight) because she is less able to clear the drug from her body, or she might require higher dosing if it clears more quickly in immature bodies.  For these reasons, since enactment of the Pediatric Research Equity Act (PREA) in 2003, the law has required companies to study their new drugs in children — to develop information on safety, effectiveness, dosing, and administration in pediatric populations.  PREA just requires testing of the indication already planned.  In other words, if the company is studying the drug for approval to treat disease A, the company must study disease A in children.

Second, we have a continuing need for treatments for pediatric diseases and conditions.  Consider Duchenne muscular dystrophy; this disease is usually diagnosed between the ages of 3 and 5 and usually leads to death in the 20s.  Or osteogenesis imperfecta, in which the bones break easily; one type can be lethal at birth, but some children have milder types and survive for years — even into adulthood.  Or diffuse intrinsic pontine glioma (DIPG), a highly aggressive brain tumor that is invariably fatal and swiftly, too.

Before Congress enacted pediatric exclusivity in 1997, few companies studied drugs specifically for pediatric diseases.

Why is this?  In many cases, there aren’t enough children with a condition to populate a clinical trial that will be powered adequately to detect effectiveness.  Even if there are technically enough children for a trial, there may be many fewer children than adults, making it hard to recruit subjects, particularly if they are widely scattered.  Parents may not want to enroll their children in the trials, children may not want to participate, and issues like informed consent can be trickier to navigate.  Some pediatric groups present additional challenges — neonates (four weeks old or younger) can be especially challenging, for instance because the amount of blood that can be drawn is limited, and because they are heterogeneous (depending on the gestational age at birth).  And then there’s the technological challenge (and cost) of making a formulation suitable for children.  Younger ones, in particular, may need a liquid, chewable tablets, or (my five-year-old’s favorite) an orange-flavored powder.  Most important, the market for any resulting product is typically very small — and the lack of a commercial upside discourages companies from investing in trials.

Pediatric exclusivity provides the incentive to do this research.

How does a company earn pediatric exclusivity?

Section 505A of the FDCA has been amended quite a few times since 1997 — including in the 2002 Best Pharmaceuticals for Children Act which gives pediatric exclusivity its acronym (BPCA) — but the gist is that a company receives a reward in exchange for testing its drug in children.

First, FDA sends the company a “written request” for the studies needed.  This document describes the studies and the time frame for their completion.  The agency allows companies to ask for written requests, and it is not uncommon for companies to make detailed written proposals based on their understanding of the drug and its possible uses in children.  But FDA holds the pen in the end.  It is responsible for the terms of the actual request.

Second, the company performs the studies in accordance with the written request and within the specified time frame.  Following this, it submits the study report or reports to FDA — typically in a supplement to its approved application.

Finally, FDA determines whether the company qualifies for the exclusivity.  For the company to earn exclusivity, the study reports must satisfy the written request, with respect to both timing and the actual conduct of the studies.  Amgen’s dispute with FDA relates to whether it satisfied the written request.

Does the study have to show the drug is safe and effective in children?

No.  A company earns exclusivity if it performs studies that satisfy the terms of the written request.  It doesn’t matter whether the study resulted in a new pediatric indication, or generated additional labeling information about pharmacokinetics in children, or failed to find safety and effectiveness.  The scheme is designed to encourage research rather than to reward particular study results.  This is why it is so important that FDA holds the pen on the written requests.

And what exactly does the company get?

The company gets six months of exclusivity.  It’s frequently misunderstood as a six-month extension of the patent, but this is wrong.

• The FDCA has rules governing the timing of generic drug applications and approvals. Some of these timing rules relate to the patents on the brand product, and some are instead regulatory exclusivity.
• For instance, if there is a patent on the brand product that the generic company doesn’t want to challenge, FDA cannot approve the generic drug until the patent expires. To give another example, if the brand drug was a “new chemical entity,” a generic company cannot submit its application until five years after the brand drug’s approval — unless it wants to challenge a patent.  (If it wants to challenge a patent, it can submit its application at the four year mark.)
• If a company receives pediatric exclusivity, then each of these dates is extended by six months. So, for instance, FDA could not approve the generic drug until six months after the patent expired.

Moreover, as FDA explained in a guidance document issued in 1998 and reissued in 1999, the exclusivity attaches to all of the company’s products that contain the same active moiety, not just the particular product it tested in children.  Thus, if a new drug were approved in pill form for treatment of disease A in adults, the company could study the active moiety in solution form for treatment of disease B in children.  The pediatric exclusivity would give the pill for disease A another six months of exclusivity in the market.  Lilly markets tadalafil for erectile dysfunction under the name Cialis.  When it studied tadalafil for potential use in treatment of Duchenne muscular dystrophy, in order to earn six months of exclusivity on Cialis, it was doing exactly what the statute was intended to encourage.

It’s perfectly reasonable to argue that the law should be changed because we don’t need or want to encourage pediatric research this way.  We can have that discussion.  But it is important to be clear-headed about the scheme and about the research that companies are performing; this is exactly how it was meant to work.

And does it work?

It seems to, yes.  As of January 2018, FDA had issued 530 written requests.  As of December 2017, the agency had granted exclusivity to 229 new drugs.  The qualifying studies had looked at a range of conditions ranging from osteogenesis imperfecta to ulcerative colitis, non-disseminated intrinsic diffuse brain stem gliomas, HIV-1 infections, community-acquired pneumonia, and partial seizures.  On the FDA website here, you can find a list of all pediatric labeling changes resulting from either pediatric exclusivity (the BPCA) or the mandatory testing requirement (PREA) — including 181 labeling changes that resulted from exclusivity alone.  Put another way, FDA has approved 181 labeling changes reflecting research that was encouraged by the carrot of exclusivity and that could not have been required under the statute.

But, blockbusters?

Some people are unhappy that companies earn pediatric exclusivity on their blockbuster drugs — for instance, suggesting that it is inappropriate for a company to earn an enormous reward for conducting a small trial in a small population, particularly if the results are not positive.  (This is why you see words like “windfall” and “exploitation”  and “gamed the patent system.”)

But here are things to remember.

First, FDA issues the written request.  Without question, it would refuse a proposed written request if it believed the study lacked merit.  Indeed, according to FDA, only about half of the proposals from companies result in written requests.

Second, the entire scheme is designed to hold out an extremely attractive carrot for research that would not otherwise be done.  This works only if the exclusivity is awarded regardless of outcome; the prize is for research, not for results.

Third, the merit of the research is purely a scientific question.  The revenue from the drug’s approved indications has nothing to do with the scientific question whether the active moiety might have safety or effectiveness for a particular use in a pediatric population.  And as a public policy matter, we would not want potential pediatric uses overlooked simply because the drug was already a best-seller for some other use.

Finally, FDA polices the scientific merit of the pediatric research in question.  It plays this role by deciding whether to issue a written request and — even more important — deciding exactly what will be required from the company and when.  Not only does it decline to issue written requests about half the time it is asked, but half of the time the companies that receive written requests end up not performing the studies or asking for exclusivity (here) — which suggests the FDA’s requirements are rigorous.  And when FDA receives study reports from companies that have invested in studies and believe they have responded fairly to the written requests, the agency still rejects nearly 10 percent (here) — denying exclusivity.

Again, it is perfectly reasonable to have a serious discussion about the policy choices reflected in the pediatric exclusivity scheme.  Indeed, we should have that discussion.  But it is not reasonable to suggest there is gaming, or exploitation, when the scheme works precisely as designed.

That brings me to FDA’s denial of exclusivity for Sensipar.  I will describe Amgen’s suit against FDA in another post soon.