Gattex Review Shows FDA Approach On MedGuides Outside REMS

FDA said a Medication Guide need not be encompassed within NPS Pharma’s proposed Risk Evaluation and Mitigation Strategy for teduglutide due to the extensive interactions between short bowel syndrome patients and their health care providers and the inclusion of other patient-directed materials.

The Gastrointestinal Drugs Advisory Committee’s Oct. 16 review of NPS Pharmaceuticals Inc.’s short bowel syndrome drug Gattex (teduglutide) provided a look into how FDA decides whether a Medication Guide should be placed within the purview of a Risk Evaluation and Mitigation Strategy or outside of it.

FDA’s views on whether a MedGuide fits within a REMS are shaped, in part, by the degree of patient interaction with health care providers for a given disease. In the case of short bowel syndrome, where patients often have extensive dealings with a multidisciplinary team of medical professionals, the MedGuide need not be included under the formal REMS but, rather, as part of labeling, the agency said.

Patients’ understanding of teduglutide’s risks should be evaluated in the REMS assessment, panelists said.

Incorporating patient-directed educational materials, for use by physicians, within the REMS further negates the need to put a MedGuide under the REMS umbrella, FDA said.

The majority of advisory committee members endorsed NPS’ proposed REMS containing a prescriber-directed communication plan and timetable for assessment. However, some panelists said the REMS assessment should not be limited to prescribers but also should take into account patients’ understanding of the drug’s risks.

Panel members also raised concerns that NPS’ plans for a voluntary patient registry outside the REMS would not be comprehensive enough to provide useful data on long-term safety (Also see "FDA Panel Backs NPS Pharma’s Gattex But Questions Registry Plans" - Pink Sheet, 16 Oct, 2012.).

Efficacy In An Orphan Indication

Short bowel syndrome results from surgical resection of some or all of the small or large intestine. Excessive loss of the small intestine can lead to difficulty absorbing protein, fluid, electrolytes and micronutrients, which can force patients to become dependent upon parenteral nutrition and intravenous fluids.

NPS is seeking approval for teduglutide, a recombinant analogue of human glucagon-like peptide-2, as supportive treatment for short bowel syndrome patients who are dependent upon parenteral nutrition and intravenous fluids. This is an orphan indication with an estimated population of 10,000-15,000 U.S. patients.

Advisory Committee Votes

• 12-0 that teduglutide has demonstrated a clinically meaningful benefit in adult patients with SBS
• 10-1, with 1 abstention, that the proposed REMS element, a communication plan directed to prescribers, is adequate to address safety concerns
• 11-1 that the benefits of teduglutide outweigh the potential risks in patients with SBS (the lone dissenter said his vote was in error and he favored approval)

In the pivotal study, twice as many patients in the teduglutide 0.05 mg/kg/day arm experienced a 20% or greater reduction in parenteral nutrition volume at weeks 20 and 24 compared to those in the placebo group. This was a statistically significant result and one that both FDA and the advisory committee deemed to be clinically meaningful.

Teduglutide also was associated with statistically significantly greater reductions in both the percentage change and actual change from baseline in parenteral nutrition/intravenous fluid volume at week 24 compared to placebo. Across the placebo-controlled and open-label extension trials, a total of 15 patients who received teduglutide have been completely weaned off parenteral nutrition and intravenous fluids, the company told the advisory committee.

Managing Potential Risks

With no major qualms about efficacy, safety and risk management were the primary focus of FDA’s questions to the advisory committee.

Teduglutide’s potential risks include the acceleration of neoplastic growth including intestinal polyps, gastrointestinal stenosis and intestinal obstruction, cholecystitis, pancreatic disease, increased fluid absorption and risk of hypervolemia, and hypersensitivity reactions.

FDA said that although it believed a REMS was necessary for teduglutide, restrictive distribution measures (in the form of elements to assure safe use) were not appropriate due to the clinical expertise of subspecialists who manage short bowel syndrome patients. Distribution restrictions also would create an additional burden and an unnecessary barrier to access for patients, who generally receive close follow-up from surgeons, gastroenterologists, primary care providers and nutritionists, FDA said.

NPS proposed a REMS based upon a communication plan aimed at informing prescribers about the risks of acceleration of neoplastic growth and enhancement of colon polyp growth, GI obstruction, and biliary and pancreatic disorders. As originally proposed, the communication component comprised a Dear Healthcare Professional letter targeted at gastroenterologists and gastrointestinal surgeons, and a Dear Professional Society letter directed to select professional organizations (Also see "NPS Pharma’s REMS For Gattex Will Face FDA Panel Scrutiny" - Pink Sheet, 12 Oct, 2012.).

At the advisory committee meeting, NPS presented a revised communication plan that incorporated several new elements recommended by FDA review staff. These included an educational slide deck for face-to-face presentations by medical science liaisons to prescribers and patient-directed educational materials for use by prescribers.

The company’s REMS assessment plan includes surveying health care providers about their knowledge of teduglutide’s risks. Roger Garceau, NPS senior vice president and chief medical officer, said there currently are no plans to survey patients about their understanding of the drug’s risks, “but we can consider that.”

NPS also proposed a Medication Guide and a voluntary patient registry, both outside of the REMS.

Where To Put The MedGuide?

The FDA Amendments Act of 2007 gave FDA authority to require a MedGuide as part of a REMS. When the law’s drug safety provisions took effect in March 2008, the agency initially considered any new MedGuide, or safety-related changes to an existing MedGuide, to come under the risk management programs.

However, with several years of FDAAA experience under its belt the agency began looking for a way around requiring that MedGuides always be a part of REMS (Also see "FDA Seeks To Write MedGuides Outside REMS Process" - Pink Sheet, 21 Jun, 2010.).

In a February 2011 draft guidance, the agency said that in most cases a MedGuide would be incorporated into a REMS only when elements to assure safe use are needed. However, a MedGuide could still be part of an ETASU-less REMS if the agency determines that such an approach is necessary to ensure a drug’s benefits outweigh its risks (Also see "MedGuide-Only REMS Will Be The Exception, Not The Norm, As FDA Relaxes Policy" - Pink Sheet, 25 Feb, 2011.). The agency affirmed this approach in a November 2011 final guidance (Also see "Final Guidance Clarifies Distribution Requirements For MedGuides" - Pink Sheet, 21 Nov, 2011.).

Discussion at the Gattex meeting about the intersection of MedGuides and REMS provided further clarity as to how the agency has been applying the principles of this guidance document.

Temporary voting member Elaine Morrato, Colorado School of Public Health, said that while she agreed that restricted distribution was not appropriate, “I’m trying to understand the rationale and justification of when a Medication Guide for patients is part of a REMS or not part of a REMS.”

Morrato is a member of the Drug Safety and Risk Management Advisory Committee, with expertise in risk communication and epidemiology. She asked Division of Risk Management Senior Medical Officer Carolyn Yancey what considerations go into the agency’s determination that a MedGuide can exist outside a REMS, because “it looks like when it’s not in the REMS they don’t have to evaluate patient knowledge and understanding.”

“We felt that a medication guide within the REMS would not be necessary due to the intense interaction … and complex, vigilant care that these patients receive,” DRISK Senior Medical Officer Yancey said.

Yancey pointed to the highly intensive and often interdisciplinary approach to treating short bowel syndrome patients.

“Because patients with short bowel syndrome are usually managed in a collaborative provider environment with many follow-up visits, there is repeat discussion from experts – gastroenterologists, colorectal surgeons … nutritionists, dietitians – with these patients constantly,” Yancey said. “We felt that a Medication Guide within the REMS would not be necessary due to the intense interaction … and complex vigilant care that these patients receive.”

Yancey noted that NPS had adopted FDA’s suggestion to include within the REMS educational materials that prescribers can use to inform patients about teduglutide’s risks. “We felt because of that it wouldn’t be necessary to include the Medication Guide as a separate element,” she said.

“I think that’s very important learning as other REMS are considered across other categories because that understanding of the interaction of patients is an important consideration,” Morrato said. However, she went on to question why another drug approved to treat short bowel syndrome, EMD Serono’s (Merck KGAA) human growth hormone Zorbtive (somatropin [rDNA origin]), does not have a REMS even though it, too, is associated with various risks.

Approved in 2003, Zorbtive is contraindicated in patients with active neoplasia, and labeling carries precautions about pancreatitis and impaired glucose tolerance, among other risks. “I’m just trying to make sure we think of REMS consistently,” Morrato said, adding later that she did not want to see one drug placed at a disadvantage to another due to the presence of a REMS.

Yancey said that Zorbtive’s approval predates FDAAA and “there’s been no new safety data that has prompted the agency to change risk mitigation strategy for this product at this time.”

Seeking to further distinguish Zorbtive from Gattex, Division of Gastroenterology and Inborn Errors Products Deputy Safety Director Joyce Korvick said teduglutide is a new molecular entity, unlike Zorbtive, and the latter’s labeling is comparable to that of other growth hormone products, which also do not have REMS.

A Call For Patient Surveys

Morrato was the lone “no” vote on the question of whether NPS’ communication plan under the REMS was adequate.

“I think what they’ve outlined for prescribers is very good,” she said. “I’m just a little worried that they don’t include … informing the patients as something that’s part of the evaluation” of the REMS’ effectiveness.

Acting committee chairman Richard Grand, Children’s Hospital Boston, took up Morrato’s cause on this point. “I do think it’s appropriate for perhaps [providing] a questionnaire to patients to see whether or not their knowledge of this agent is appropriate, and that is something the company needs to decide with the FDA,” he said.