FDA Considers Infliximab for Pediatric Ulcerative Colitis Maintenance

The Food and Drug Administration has questions about whether a pediatric indication for infliximab to treat ulcerative colitis can include the maintenance claims featured in the adult indication for the disease, according to briefing material for the Gastrointestinal Drugs Advisory Committee’s July 21 review.

"Infliximab appears to induce clinical response as well as clinical remission at week 8, but the long-term efficacy data provide limited support that the proposed dose of infliximab will result in persistent efficacy through week 54," the FDA says.

Centocor, which markets the drug as Remicade, is seeking to add pediatric patients to Remicade’s ulcerative colitis indication. The current indication is for "reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adults with moderately to severely active disease who have had an inadequate response to conventional therapy."

The Supplemental Biologics License Application is supported by a single ulcerative colitis (UC) pediatric study (T72), an open-label, randomized, parallel-group multicenter study to assess the safety and efficacy of infliximab. Sixty patients aged 6-17 received infliximab 5 mg/kg at weeks 0, 2, and 6. Those with a clinical response at week 8 were randomized in a 1:1 ratio to one of two maintenance doses, 5 mg/kg every 8 weeks or 5/mg/kg every 12 weeks.

The two Phase III double-blind, randomized, placebo-controlled ACT 1 and ACT 2 trials in adults with UC are referenced to support extrapolation of efficacy from adults to children. That is possible due to sufficient similarity in disease characteristics for adult and pediatric patients, the FDA says.

The primary endpoint of clinical response at week 8 was achieved by 73% (44 of 60) of patients in T72, compared with 67% of adults in the combined ACT trials. Clinical response equates to reducing signs and symptoms of UC.

Data also suggest infliximab induces clinical remission at week 8, which was measured by two instruments – the Mayo and Pediatric UC Activity Index (PUCAI) – and mucosal healing at week 8, the FDA says.

Insufficient Long-Term Data

The agency’s concerns center on the long-term findings. At week 54, 38% (8/21) of patients receiving 5 mg/kg every 8 weeks, and 18% (4/22) in the 5 mg/kg every 12 weeks group, were in clinical remission. Those percentages decline when patients who received step-up therapy or did not have PUCAI data are included and considered as failures.

A larger proportion of patients who achieved clinical remission at week 8 maintained remission at week 54, compared to those who achieved only clinical response at week eight. Based on this data, as many as 50% of those in remission maintained remission. "However," the FDA notes, "this result should be interpreted in the context of a very small sample size and the use of two different scoring instruments at week 8 (Mayo) and week 54 (PUCAI) for most comparisons."

The claims for maintenance of mucosal healing and elimination of corticosteroid use were not prespecified endpoints in T72.

For the mucosal healing claim, only nine patients had data suitable for analysis, a "very small" sample size on which to base the claim, the FDA notes.

As to the claim for elimination of corticosteroid use, the FDA points out that not only is the data limited, but the baseline level of use was substantially lower than that routinely used in the UC clinical setting with children. Low baseline use raises the possibility that enrolled patients’ disease was not severe enough to call for corticosteroid therapy, or that they already were being weaned off the drug and would have ceased its use regardless of infliximab treatment, the FDA says.

Although the observed trends for these two claims appear favorable, "the very small sample size makes it difficult to conclude that the proposed dosing regimen for pediatric UC should carry these additional indications," the FDA points out.

Questions about Maintenance Dosing

Post hoc exposure-response analyses conducted by the FDA found that the 5 mg/kg induction dose is supported by the similar exposure-response relationship between pediatric and adult patients.

However, the agency says, limited pharmacokinetic data (PK) on pediatric patients with clinical remission prevents definitive conclusions about the maintenance dose. "The limited PK data in T72 suggest that exposures in pediatric patients with UC might be less than adults with UC. This apparent difference, however, may be secondary to the small sample size."

The FDA says two clinical observations could potentially support the proposed maintenance dose: (1) fewer T72 participants in the every 8 weeks group required step-up therapy or discontinued treatment than in the every 12 weeks group, and (2) the pediatric clinical remission rate at week 54 for the every 8 weeks dose appears similar to adults receiving the same dose in ACT 1 despite lower trough concentrations.

No new safety concerns were identified in T72, the FDA says. Existing safety issues with infliximab and other tumor necrosis factor inhibitors include fungal infections and lymphoma. In April, the FDA requested labeling changes to notify users about the risk of hepatosplenic T-Cell lymphoma (HSTCL).

HSTCL has occurred mostly in adolescent or young adult males treated with infliximab and concomitant azathioprine or 6-mercaptopurine. It is therefore especially important, the FDA says, to consider this safety data when making treatment decisions involving children.

In its briefing material, Centocor notes that it has an extensive education program to inform users and physicians about the drug’s risk. Its safety in treating pediatric patients with inflammatory bowel disease, including UC, is being assessed in two ongoing prospective registries.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration has questions about whether a pediatric indication for infliximab to treat ulcerative colitis can include the maintenance claims featured in the adult indication for the disease, according to briefing material for the Gastrointestinal Drugs Advisory Committee’s July 21 review.

"Infliximab appears to induce clinical response as well as clinical remission at week 8, but the long-term efficacy data provide limited support that the proposed dose of infliximab will result in persistent efficacy through week 54," the FDA says.

Centocor, which markets the drug as Remicade, is seeking to add pediatric patients to Remicade’s ulcerative colitis indication. The current indication is for "reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adults with moderately to severely active disease who have had an inadequate response to conventional therapy."

The Supplemental Biologics License Application is supported by a single ulcerative colitis (UC) pediatric study (T72), an open-label, randomized, parallel-group multicenter study to assess the safety and efficacy of infliximab. Sixty patients aged 6-17 received infliximab 5 mg/kg at weeks 0, 2, and 6. Those with a clinical response at week 8 were randomized in a 1:1 ratio to one of two maintenance doses, 5 mg/kg every 8 weeks or 5/mg/kg every 12 weeks.

The two Phase III double-blind, randomized, placebo-controlled ACT 1 and ACT 2 trials in adults with UC are referenced to support extrapolation of efficacy from adults to children. That is possible due to sufficient similarity in disease characteristics for adult and pediatric patients, the FDA says.

The primary endpoint of clinical response at week 8 was achieved by 73% (44 of 60) of patients in T72, compared with 67% of adults in the combined ACT trials. Clinical response equates to reducing signs and symptoms of UC.

Data also suggest infliximab induces clinical remission at week 8, which was measured by two instruments – the Mayo and Pediatric UC Activity Index (PUCAI) – and mucosal healing at week 8, the FDA says.

Insufficient Long-Term Data

The agency’s concerns center on the long-term findings. At week 54, 38% (8/21) of patients receiving 5 mg/kg every 8 weeks, and 18% (4/22) in the 5 mg/kg every 12 weeks group, were in clinical remission. Those percentages decline when patients who received step-up therapy or did not have PUCAI data are included and considered as failures.

A larger proportion of patients who achieved clinical remission at week 8 maintained remission at week 54, compared to those who achieved only clinical response at week eight. Based on this data, as many as 50% of those in remission maintained remission. "However," the FDA notes, "this result should be interpreted in the context of a very small sample size and the use of two different scoring instruments at week 8 (Mayo) and week 54 (PUCAI) for most comparisons."

The claims for maintenance of mucosal healing and elimination of corticosteroid use were not prespecified endpoints in T72.

For the mucosal healing claim, only nine patients had data suitable for analysis, a "very small" sample size on which to base the claim, the FDA notes.

As to the claim for elimination of corticosteroid use, the FDA points out that not only is the data limited, but the baseline level of use was substantially lower than that routinely used in the UC clinical setting with children. Low baseline use raises the possibility that enrolled patients’ disease was not severe enough to call for corticosteroid therapy, or that they already were being weaned off the drug and would have ceased its use regardless of infliximab treatment, the FDA says.

Although the observed trends for these two claims appear favorable, "the very small sample size makes it difficult to conclude that the proposed dosing regimen for pediatric UC should carry these additional indications," the FDA points out.

Questions about Maintenance Dosing

Post hoc exposure-response analyses conducted by the FDA found that the 5 mg/kg induction dose is supported by the similar exposure-response relationship between pediatric and adult patients.

However, the agency says, limited pharmacokinetic data (PK) on pediatric patients with clinical remission prevents definitive conclusions about the maintenance dose. "The limited PK data in T72 suggest that exposures in pediatric patients with UC might be less than adults with UC. This apparent difference, however, may be secondary to the small sample size."

The FDA says two clinical observations could potentially support the proposed maintenance dose: (1) fewer T72 participants in the every 8 weeks group required step-up therapy or discontinued treatment than in the every 12 weeks group, and (2) the pediatric clinical remission rate at week 54 for the every 8 weeks dose appears similar to adults receiving the same dose in ACT 1 despite lower trough concentrations.

No new safety concerns were identified in T72, the FDA says. Existing safety issues with infliximab and other tumor necrosis factor inhibitors include fungal infections and lymphoma. In April, the FDA requested labeling changes to notify users about the risk of hepatosplenic T-Cell lymphoma (HSTCL).

HSTCL has occurred mostly in adolescent or young adult males treated with infliximab and concomitant azathioprine or 6-mercaptopurine. It is therefore especially important, the FDA says, to consider this safety data when making treatment decisions involving children.

In its briefing material, Centocor notes that it has an extensive education program to inform users and physicians about the drug’s risk. Its safety in treating pediatric patients with inflammatory bowel disease, including UC, is being assessed in two ongoing prospective registries.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration has questions about whether a pediatric indication for infliximab to treat ulcerative colitis can include the maintenance claims featured in the adult indication for the disease, according to briefing material for the Gastrointestinal Drugs Advisory Committee’s July 21 review.

"Infliximab appears to induce clinical response as well as clinical remission at week 8, but the long-term efficacy data provide limited support that the proposed dose of infliximab will result in persistent efficacy through week 54," the FDA says.

Centocor, which markets the drug as Remicade, is seeking to add pediatric patients to Remicade’s ulcerative colitis indication. The current indication is for "reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adults with moderately to severely active disease who have had an inadequate response to conventional therapy."

The Supplemental Biologics License Application is supported by a single ulcerative colitis (UC) pediatric study (T72), an open-label, randomized, parallel-group multicenter study to assess the safety and efficacy of infliximab. Sixty patients aged 6-17 received infliximab 5 mg/kg at weeks 0, 2, and 6. Those with a clinical response at week 8 were randomized in a 1:1 ratio to one of two maintenance doses, 5 mg/kg every 8 weeks or 5/mg/kg every 12 weeks.

The two Phase III double-blind, randomized, placebo-controlled ACT 1 and ACT 2 trials in adults with UC are referenced to support extrapolation of efficacy from adults to children. That is possible due to sufficient similarity in disease characteristics for adult and pediatric patients, the FDA says.

The primary endpoint of clinical response at week 8 was achieved by 73% (44 of 60) of patients in T72, compared with 67% of adults in the combined ACT trials. Clinical response equates to reducing signs and symptoms of UC.

Data also suggest infliximab induces clinical remission at week 8, which was measured by two instruments – the Mayo and Pediatric UC Activity Index (PUCAI) – and mucosal healing at week 8, the FDA says.

Insufficient Long-Term Data

The agency’s concerns center on the long-term findings. At week 54, 38% (8/21) of patients receiving 5 mg/kg every 8 weeks, and 18% (4/22) in the 5 mg/kg every 12 weeks group, were in clinical remission. Those percentages decline when patients who received step-up therapy or did not have PUCAI data are included and considered as failures.

A larger proportion of patients who achieved clinical remission at week 8 maintained remission at week 54, compared to those who achieved only clinical response at week eight. Based on this data, as many as 50% of those in remission maintained remission. "However," the FDA notes, "this result should be interpreted in the context of a very small sample size and the use of two different scoring instruments at week 8 (Mayo) and week 54 (PUCAI) for most comparisons."

The claims for maintenance of mucosal healing and elimination of corticosteroid use were not prespecified endpoints in T72.

For the mucosal healing claim, only nine patients had data suitable for analysis, a "very small" sample size on which to base the claim, the FDA notes.

As to the claim for elimination of corticosteroid use, the FDA points out that not only is the data limited, but the baseline level of use was substantially lower than that routinely used in the UC clinical setting with children. Low baseline use raises the possibility that enrolled patients’ disease was not severe enough to call for corticosteroid therapy, or that they already were being weaned off the drug and would have ceased its use regardless of infliximab treatment, the FDA says.

Although the observed trends for these two claims appear favorable, "the very small sample size makes it difficult to conclude that the proposed dosing regimen for pediatric UC should carry these additional indications," the FDA points out.

Questions about Maintenance Dosing

Post hoc exposure-response analyses conducted by the FDA found that the 5 mg/kg induction dose is supported by the similar exposure-response relationship between pediatric and adult patients.

However, the agency says, limited pharmacokinetic data (PK) on pediatric patients with clinical remission prevents definitive conclusions about the maintenance dose. "The limited PK data in T72 suggest that exposures in pediatric patients with UC might be less than adults with UC. This apparent difference, however, may be secondary to the small sample size."

The FDA says two clinical observations could potentially support the proposed maintenance dose: (1) fewer T72 participants in the every 8 weeks group required step-up therapy or discontinued treatment than in the every 12 weeks group, and (2) the pediatric clinical remission rate at week 54 for the every 8 weeks dose appears similar to adults receiving the same dose in ACT 1 despite lower trough concentrations.

No new safety concerns were identified in T72, the FDA says. Existing safety issues with infliximab and other tumor necrosis factor inhibitors include fungal infections and lymphoma. In April, the FDA requested labeling changes to notify users about the risk of hepatosplenic T-Cell lymphoma (HSTCL).

HSTCL has occurred mostly in adolescent or young adult males treated with infliximab and concomitant azathioprine or 6-mercaptopurine. It is therefore especially important, the FDA says, to consider this safety data when making treatment decisions involving children.

In its briefing material, Centocor notes that it has an extensive education program to inform users and physicians about the drug’s risk. Its safety in treating pediatric patients with inflammatory bowel disease, including UC, is being assessed in two ongoing prospective registries.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.