Chart: Long-Term Commitments: The First Mandatory Post-Marketing Trials

Long-Term Commitments: The First Mandatory Post-Marketing Trials
FDA used its new authority to mandate post-marketing studies four times in the month of April. The trials seem very typical of Phase IV commitments of the past. But they appear tougher now that there will be consequences for failure to follow through, thanks to new authorities included in the FDA Amendments Act signed into law in 2007. The imposition of mandatory studies is formally communicated to sponsors in the approval letter for their applications. Each letter includes a section entitled, "POST-MARKETING REQUIREMENTS UNDER 505(o)." Each includes a formal finding by the agency that post-marketing studies are required based on a specific risk-either a known risk of the product or class, a signal of risk associated with the product or class or a basis for concern about an unexpected risk. The letter then justifies the need for the specific type of trial, explaining why spontaneous adverse event reports and the as-yet unrealized plan for an active surveillance system will not suffice. The initial group of post-marketing study requirements varies considerably. Two of the four sponsors have just one commitment. One has two commitments. But the fourth, UCB, has five. The types of the trials vary considerably as well, ranging from ongoing open-label extensions to case-control studies to randomized placebo-controlled trials. (In each case, the approval letter justifies the reason for the type of study requested.) And the length of the commitments also varies, from two years to 12. In fact, the variety of post-marketing commitments in the first four FDAAA approvals seem little different from any random selection of four drugs approved over the past decade. But now there are consequences for not completing the work. That makes the initial list of commitments worthy of careful study. Here are the commitments of each of the four sponsors affected by FDAAA, excerpted from the FDA approval letters for each application:
CV Therapeutics' Lexiscan (regadenoson) - Approved April 10 as a pharmacologic stress agent
Protocol Due: October 2008	Trial Start: April 2009		Final Report: April 2011
Justification for Trials: "Signals of serious risk of pulmonary adverse effects in patients with bronchoconstrictive disease following administration of Lexiscan ... Signals of serious risk of adverse effects in patients with moderate or worse kidney disease following administration of Lexiscan." Commitments: (1) "Clinical trial to examine the pulmonary adverse effects of a single 0.4 mg dose of Lexiscan in approximately 600 patients with a broad severity of bronchoconstrictive disease (300 with asthma, 300 with COPD). Patient follow-up for the detection of adverse reactions will extend over a time period of at least 24 hours following Lexiscan administration." (2) "Clinical trial to examine the serious adverse effects of a single 0.4mg dose of Lexiscan in approximately 300 patients with moderate (or worse) chronic kidney disease (Stage 3 or greater/using NKF GER definitions). Patient follow-up for the detection of adverse reactions will extend over a time period of at least 24 hours following Lexiscan administration."
Pozen's Treximet (sumatriptan/naproxen) - Approved April 15 for treatment of acute migraines
Final Report: Within 24 months of the approval date
Justification for trials: "The known serious risk of hypertension associated with exposure to sumatriptan and naproxen." Commitment: "A randomized, double-blind, active comparator clinical trial of Treximet in adults with episodic migraine dosed with either Treximet, naproxen sodium 500 mg, or sumatriptan 85 mg to further assess the hypertensive effects of Treximet relative to each of its two active ingredients."
Alcon's Patanase (olopatadine) nasal spray - Approved April 15 for seasonal allergic rhinitis
Protocol Due: July 2008	Trial Start: November 2008		Final Report: November 2012
Justification for Trials: "Signal of a serious risk of nasal septal perforation, which has been associated with the use of an earlier formulation of olopatadine hydrochloride nasal spray containing povidone." Commitment: "A one-year, controlled clinical trial in patients with perennial allergic rhinitis to assess the long term safety of povidone-free olopatadine hydrochloride nasal spray with respect to nasal septal perforation. We also request that you assess the long term safety of this product with respect to local nasal adverse effects, including epistaxis and nasal ulceration, as well as systemic effects. Include at least the following three treatment groups: povidone-free olopatadine hydrochloride nasal spray, vehicle placebo with pH matching olopatadine hydrochloride nasal spray, and vehicle placebo with normal pH to evaluate if the low pH of the formulation has an effect on local nasal safety."
UCB's Cimzia (certolizumab) - Approved April 22 for treatment of Crohn's disease
Justification for trials: "The TNF blocker class, of which this product is a member, has been associated with known serious risks of serious infections, including opportunistic infections, development of lymphoma and other malignancies, and development of demyelinating disorders and autoimmune disorders in Crohn's disease patients. In addition, available data suggest that members of the TNF blocker class may impair a patient's ability to mount an appropriate immune response to B cell- and T cell-mediated immunization and thereby subject the patient to unexpected serious risks."
Protocol Amendment: September 2008		Trial Start: February 2009		Final Report: March 2020
Commitment: "Long-term observational study in the U.S. that will include approximately 2,000 Cimzia-treated Crohn's disease patients and 2,000 matched controls receiving other treatments for Crohn's disease. Patients will be monitored for 10 years."
Protocol Amendment: October 2008		Trial Start: Ongoing		Final Report: May 2013
Commitment: "CDP870-033, an ongoing open-label trial to assess the long-term safety of Cimzia in patients with Crohn's disease who have previously completed trials CDP870-031 or CDP870-032. The objectives of this trial include measurement of pharmacokinetics and antibody response in Cimzia-treated patients. Patient follow-up will be extended to seven years from the start of treatment."
Protocol Amendment: October 2008		Trial Start: Ongoing		Final Report: May 2013
Commitment: "CDP870-034, an ongoing open-label trial to assess the long-term safety of re-exposure to Cimzia after a variable interval in patients with Crohn's disease who were previously withdrawn from completed trials CDP870-031 or CDP870-032 due to an exacerbation of Crohn's disease. The objectives of this trial include measurement of and antibody response in Cimzia-treated patients. Patient follow-up will be extended to seven years from the start of treatment."
Protocol Amendment: October 2008		Trial Start: May 2008		Final Report: May 2015
Commitment: "CDP870-088, an open-label trial to assess the long-term safety of Cimzia in patients with Crohn's disease who have either completed trial CDP870-085 or were withdrawn from CDP870-085 due to an exacerbation of Crohn's disease. The objectives of this trial include measurement of pharmacokinetics and antibody response in Cimzia-treated patients. Patient follow-up will be extended to five years from the start of treatment."
Protocol Amendment: October 2008		Trial Start: October 2009		Final Report: March 2011
Commitment: "A placebo-controlled trial designed to assess the effects of Cimzia treatment on antibody responses to a B cell-mediated immunization, using pneumococcal vaccine immunization, and to a T cell-mediated immunization, using influenza vaccine, in patients with active rheumatoid arthritis. The study will measure both antibody titers and rates of clinical response in approximately 100 placebo- and 100 Cimzia-treated patients who will be given polyvalent pneumococcal polysaccharide vaccine and influenza vaccine."