Pediatric Exclusivity (2 of 3): Amgen v. Hargan

A prior post provided an overview of pediatric exclusivity — how it works and why it was designed this way.  This is the first of two posts describing Amgen’s suit against FDA regarding the agency’s denial of pediatric exclusivity for Sensipar (cinacalcet hydrochloride).  I’ll start, today, with the back story — the facts and Amgen’s complaint.


The parathyroid gland regulates calcium in the blood.  Patients with secondary hyperparathyroidism (HPT) have too much parathyroid hormone in their blood because their parathyroid glands are overactive.

FDA approved Amgen’s Sensipar in March 2004, for treatment of secondary HPT in patients with chronic kidney disease on dialysis and for treatment of hypercalcemia in patients with parathyroid carcinoma.  Amgen now has approval also for treatment of hypercalcemia in adult patients with primary HPT for whom parathyroidectomy (removal of the gland) would be indicated on the basis of serum calcium levels but who are unable to undergo the procedure.

In December 2009 Amgen proposed that FDA issue a written request to study cinacalcet hydrochloride for treatment of secondary HPT in children.

FDA’s Written Request

After discussions with Amgen and after Amgen performed some additional preclinical research, FDA issued a written request in May 2010, asking that the company study the drug in pediatric patients on dialysis with chronic kidney disease and secondary HPT.

The request specified four studies.

  • Study 1 was to be a single dose study of pharmacokinetics and pharmacodynamics in pediatric patients ages 28 days to 6 years. Pharmacokinetics study how the body acts on a drug —absorption, distribution, metabolism, and excretion.  Pharmacodynamics study how the drug acts on the body — one is not assessing clinical effect but changes in various other measurements.  The subjects of this trial were to have secondary HPT and chronic kidney disease and to be receiving dialysis.
  • Study 2 was to be a 30-week, randomized, placebo-controlled, double-blinded safety and efficacy study in pediatric patients ages 6 years to 18 years. These subjects were to have secondary HPT and chronic kidney disease and to be receiving dialysis.
  • Study 3 was to be a 26-week (or time-until-transplantation, whichever came first) open-label safety study in patients ages 28 to 6 years. “Open label” means that no one is blinded; the investigators and subjects know exactly what the subject is receiving.  These subjects were to have secondary HPT and to be receiving dialysis.
  • Study 4 was to be a 20-week, randomized, open-label, controlled study in pediatric patients ages 6 years to 18 years. These subjects were to have secondary HPT and chronic kidney disease and to be receiving either hemodialysis or peritoneal dialysis.

The deadline for completion of the trials was November 25, 2016.

Completion of the Studies

Amgen submitted its reports by the deadline.  FDA denied pediatric exclusivity, though, citing Amgen’s “failure to meet one element of one study.”  Specifically, Amgen had not enrolled 15 patients in Study 3.

Why didn’t Amgen enroll 15 patients? 

The company held enrollment open from January 2012 to June 2016 and says it made “Herculean” efforts to meet the 15-patient target.  At any given time there are only about 300 patients under the age of 6 on dialysis in the United States.  These patients are prioritized for kidney transplants, which means that they may not stay on dialysis long enough for 26-week trials.  Also, for more than a year — from February 2013 to April 2014 — FDA prohibited Amgen from enrolling patients in the study (and from dosing patients already enrolled in the study), while it figured out how to respond to the death of a child in Study 2.  During this year, six of the eight enrolled patients dropped out (for one reason or another —  one had a transplant).  Amgen eventually managed to enroll another 10 subjects, but only three stayed enrolled for all 26 weeks, and one other stayed for the minimum 12 weeks required.  In the end, 17 children received the drug, 11 completed at least 12 weeks, but only four met all the trial criteria.

Amgen actually proposed stopping the studies, but FDA said it wanted the studies continued, because it would learn from the data analysis.  At the same time, though, the agency refused to modify the written request to reflect the difficulty that Amgen was facing in meeting the 15-patient target.  FDA made other adjustments to the written request at Amgen’s request, but it refused to make this one.

Amgen ultimately managed to submit safety data from 63 patients under the age of 6 who received Sensipar, thanks to Study 1 and two other studies it performed that were not part of the written request.  But it did not enroll 15 patients in Study 3.

The Dispute

Section 505A of the FDCA states that FDA must accept or reject study reports within 180 days of their submission.  FDA’s “only responsibility” in doing so “shall to be determine”

  • whether the studies “fairly respond” to the written request;
  • whether they were conducted in accordance with commonly accepted scientific principles and protocols; and
  • whether they were reported in accordance with the agency’s requirements.

As Judge Moss notes, FDA’s “approach” to the phrase “fairly respond” has evolved over the years.  Before 2001, the agency required that companies precisely satisfy every term of the request.  In 2001, a court rejected this approach as inconsistent with the statute.  FDA’s subsequent approach was not made public.  While its decisions on pediatric exclusivity are public, the agency’s analysis is generally shared only with the companies seeking exclusivity.

In its May 2017 ruling on Amgen’s request, FDA set forth “its most recent interpretation” of the provision (I am quoting Judge Moss).  Under this interpretation of the statute, a sponsor “fairly responds” if either of the following is true:

  • The studies “are carried out in accordance with the trial’s plans and objectives, as expressed” in the written request.
  • The “specific terms” of the written request are not met, but FDA, “apply[ing] its scientific expertise,” determines that the underlying “objectives of the [written request] have … been met.”  Put another way, FDA determines that the studies yielded information that is “clinically meaningful across all age groups and uses cited in the” written request.

Amgen did not enroll 15 patients in Study 3, as specified in the written request, so FDA applied the second standard — the “clinically meaningful information” standard.  The agency then denied exclusivity on the ground that (a) the goal of the study was to characterize the risks of the drug, and (b) it could not draw any clinical conclusions from the safety data that had been provided.

In its papers, Amgen argued that:

  • The new interpretation of “fairly respond” is inconsistent with the statute. FDA responded that its interpretation is entitled to deference under Chevron.
  • Denial of exclusivity was arbitrary and capricious, because FDA treated Amgen differently from others and because it refused to consider Amgen’s evidence about the enrollment challenges. FDA responded that it applied the standard correctly, though — as we will see — it didn’t engage enough on the question of inconsistent prior decisions.
  • FDA’s application of the new “fairly respond” interpretation to Amgen was inconsistent with due process and APA principles, mainly because the agency sprung a new standard on the company without notice. FDA responded that Amgen was well aware of the new standard.

My final post in this series will discuss Judge Moss’s handling of Amgen’s arguments.

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