A determination letter slapping the lead university in a federally funded neonatal trial resulted in a government watchdog calling on the Department of Health and Human Services (HHS) to suspend enrollment in similar trials until it gets an independent review to ensure that parents will be adequately informed of potential risks to their babies.

In a letter this week to HHS Secretary Kathleen Sebelius, Public Citizen specifically requested a suspension of seven randomized trials being funded by the National Institutes of Health and conducted by the Neonatal Research Network (NRN). The trials are either enrolling or about to enroll infants, most of whom are premature or with an extremely low birth weight. Together, the trials are expected to enroll about 4,500 babies.

The trials range from comparisons of feeding, warming and surgical procedures to a study of the effect of hydrocortisone on survival without bronchopulmonary dysplasia in premature infants and a comparison of a liberal red blood cell transfusion strategy with a restrictive strategy to improve survival of infants with extremely low birth weights.

Although the advocacy group is focused on the NRN trials, the issues it raised could have drugmakers reassessing their informed consent forms for neonatal trials, especially if they involve discrete aspects of standard-of-care therapies.

The concerns stem from the informed consent used in part of the SUPPORT trial, conducted by the NRN from 2004 to 2009 to study the appropriate oxygen saturation level in infants with extremely low birth weight.

Older studies had found that lower oxygen saturation could lead to death and higher levels could increase the risk of retinopathy of prematurity (ROP), which can result in blindness.

Building on previous research that led to a standard of care ranging from 85 percent to 95 percent oxygen saturation levels, the SUPPORT trial was designed to help physicians determine exactly how much oxygen to provide to minimize ROP without contributing to undue increases of other risks, according to the HHS Office of Human Research Protection (OHRP).

The study randomized infants into two groups – one with 85 percent to 89 percent oxygen saturation and the other with 91 percent to 95 percent. Because both ranges were within the standard of care, the informed consent said, "There is no predictable increase in risk for your baby." However, the form, which was approved by several institutional review boards (IRBs), did point out potential benefits to the infant, specifically a decreased risk of developing severe ROP.

In minimalizing the risk, the study violated informed consent requirements because it failed "to describe the reasonably foreseeable risks of blindness, neurological damage and death," OHRP said in a letter last month to the University of Alabama at Birmingham, the lead site for the study.

Trial results showed that 8.6 percent of the 475 infants in the low oxygen group developed severe ROP, as compared with nearly 18 percent of the 509 babies in the high oxygen group. But nearly 20 percent of the infants in the low oxygen group died, compared with about 16 percent in the other group. The results echoed those from previous studies.

OHRP noted that similar trials being conducted in Australia and the UK were ended early because of the survival rates.

In making it clear that risks must be disclosed when a study compares discrete aspects of standard care, the determination letter serves as OHRP's response to a commentary published last year in Pediatrics that faulted the 18 IRBS that required consent for the SUPPORT trial, "even though these interventions are routinely provided without specific consent in everyday practice."

Endo Adcom to Look at Safety

Safety is the primary issue two advisory committees will be asked to consider Thursday when they weigh in on Endo Pharmaceuticals Solutions Inc.'s new drug application for its extended-duration testosterone undecanoate injection, Aveed, in men with hypogonadism.

The discussion, which will focus on reports of oil microembolism in the lungs and potential anaphylactic reactions, won't be limited to Aveed, the FDA said in its briefing documents. The Advisory Committee for Reproductive Health Drugs and Drug Safety and the Risk Management Advisory Committee are likely to look at similar adverse events reported for other approved testosterone injectable products.

The committees also will be asked to evaluate Endo's proposed risk evaluation and mitigation strategy (REMS).

The serious post-injection reactions have stymied previous attempts to get Aveed approved in the U.S., even though it has been approved in 90 other countries. In 2009, Endo, of Chadds Ford, Pa., received a complete response letter, requesting information about the rare but serious adverse events. The complete response also noted that the company's REMS was not sufficient.

Aveed, known as Nebido outside the U.S., was acquired in Endo's $637 million purchase of Lexington, Mass.-based Indevus Pharmaceuticals Inc. Prior to the 2009 acquisition, Nebido had received an approvable letter, with the FDA asking for additional safety data. (See BioWorld Today, June 5, 2008, and Jan. 7, 2009.)

Sterile Drugs Recalled

The FDA's crackdown on compounding pharmacies has led to another recall of sterile drugs. The agency issued a MedWatch Tuesday warning that sterile drugs, including injectables, made by ApotheCure Inc. and sterile lyophilized products made by NuVision Pharmacy may be contaminated.

The warning stems from an ongoing inspection of the drugmakers' facilities in Dallas.