The U.S. Food and Drug Administration has stopped applying a safety program for two drugs - Nplate and Promacta – because the program's data was not useful for determining and distinguishing between the effects of the drugs and underlying medical conditions in patients using them.

The agency has monitored the safety of Nplate and Promacta since 2008 using the Risk Evaluation and Management Strategy (REMS). At the time of approval, experience with both drugs was limited, so for safety reasons, the FDA decided to monitor the drug through the agency’s REMS program. After an evaluation, the agency concluded that the REMS program was inadequate.

FDA spokeswoman Erica V. Jefferson told Medical Daily the FDA had taken similar action against other drugs.

“This is the first time the agency has removed requirements for a more restrictive REMS for an oncology product, but it is not the first time the agency has removed restrictive requirements from a REMS for a drug, or determined that a REMS with restrictive requirements is no longer necessary to ensure that the benefits of a drug outweigh its risks,” said Erica V. Jefferson, a spokeswoman for the FDA.

Side-Effects Prompted Safety Concerns

The clinical trials upon which the approvals were based consisted of small pools of participants and were relatively short in duration, the FDA said, but they identified several safety concerns for both drugs including evidence of bone marrow changes of collagen deposition (reticulin), higher risk for blood clots, increased risk of developing hematological malignancies resulting from the stimulation of bone marrow cells, worsening low blood platelet count, and the risk for bleeding shortly after discontinuing the drugs. Promacta may also cause liver injury.

Both Nplate and Promacta were both approved in August of 2008 to treat adult patients with chronic immune thrombocytopenia (ITP) who responded inadequately to corticosteroids, immunoglobulins, or splenectomy.

ITP is a rare blood disorder where patients are have a low number of platelets in their bloodstream, and can lead to serious and uncontrolled bleeding. The treatments stimulate the bone marrow to produce more platelets.

FDA Program’s Data ‘Inherently Confounded’

According to the FDA, the harmful side effects that come with the drugs can also be part of the natural history of ITP and other serious medical conditions in patients who use the drug, consequently the confounding data from the REMS safety programs were challenging to interpret and rendered inadequate.

Amgen, the pharmaceutical company that makes Nplate, also released a statement that states that its researchers, working with the FDA, "have determined that the safety information collected through the REMS, which is based on individual case safety reports, is inherently confounded by underlying medical conditions in the treated patient population and thus cannot be used to determine the precise role of Nplate in the development of the adverse events."

An FDA-initiated review of the current information has determined that while safety risks for both Nplate and Promacta still exist, certain restrictive requirements of the [risk evaluation and management strategy (REMS)] programs are no longer necessary to ensure that the benefits of the drugs outweigh their risks," the agency said in a press release.

Instead, FDA decided that regular clinical trials, post-approval studies, and post-marketing adverse event reports should provide the necessary data to continue monitoring the long-term safety of Nplate and Promacta and dropped their safety precautions that require anyone using, prescribing, or providing Nplate (Romiplostim) of Promacta (eltrombopag) to enroll in a monitoring program, on Tuesday.

Previously, the agency required healthcare professionals, pharmacies, hospitals, specialty care facilities, and patients to enroll in a special access program to prescribe, dispense, or receive the drugs.

The goals of the REMS were to promote informed risk-benefit decisions before initiating treatment and while patients are on treatment to ensure appropriate use of the drugs and to establish the overall long-term safety and safe use of the drugs through periodic monitoring of all patients who receive them, the agency said.

Specific Changes

Doctors, hospitals, specialty care facilities, and patients are no longer required to be enrolled in the Nplate NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) Program or the Promacta CARES Program to prescribe, dispense, or receive these products.

Doctors are no longer required to complete periodic safety forms for patients receiving Nplate or Promacta.

Pharmacies and pharmacists are no longer required to enroll in the Promacta CARES Program or verify prescriber and patient enrollment before dispensing Promacta.

Instead, the modified REMS programs will include a communication plan that will inform healthcare professionals about the changes to the REMS and the risks associated with each product.

Past Changes

Jefferson says that the agency removed one of the safe use conditions for Letairis (ambrisentan), because further evaluation led the FDA to conclude that the risk of liver injury in patients treated with this drug was lower than previously thought. It lifted requirements for monthly serum liver enzyme testing for patients taking Letairis, in March 2011.

“Sucraid (sacrosidase), an enzyme replacement therapy, had requirements for healthcare providers to report events of allergic reactions,” said Jefferson. The agency removed safe use conditions when data from REMS showed that there were no reports of allergic reactions from patient mailings, telephone surveys, and physician surveys, in December 2010.