FDA sends out a letter to Merck regarding the company's alleged failure to comply with a post marketing study. Here is the letter in full:
Merck Sharp and Dohme Corp.
Attention: Lou Ann Eader, Ph.D.Director, Worldwide Regulatory Affairs
P.O. Box 1000, UG2C-50
North Wales, PA 19454-1099
Dear Dr. Eader:
The U.S. Food and Drug Administration (FDA) has determined that your firm failed to comply with the milestone dates, within a previously agreed-upon timetable for completion, to conduct a required postmarketing study (PMR) for the purpose of investigating a safety issue associated with the use of Januvia® and Janumet® under New Drug Applications (NDA) 021995 and 022044, respectively. Failure to comply with the milestone dates, and to demonstrate good cause for your noncompliance, is in violation of section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 355].
This violation is concerning from a public health perspective because the PMR milestone dates (as described below) constitute part of a written agreement between you and the FDA to conduct additional testing to further assess a signal of a serious risk of acute pancreatitis, including necrotizing forms, associated with the use of sitagliptin.
Background
On October 16, 2009, FDA sent you a Complete Response letter in which we stated, in pertinent part:
We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk of acute pancreatitis, including necrotizing forms, associated with the use of Januvia® (sitagliptin).
Furthermore, the new pharmacovigilance system that FDA is required to establish under section 505(k)(3) of the FDCA has not yet been established and is not sufficient to assess this serious risk.
Therefore, based on appropriate scientific data, FDA has determined that you will be required, pursuant to section 505(o)(3) of the FDCA, to conduct the following study if your application is approved:
3- month pancreatic safety study in a diabetic rodent model treated with sitagliptin.
The specific details of this required postmarketing study will be described more fully in the approval letter for these applications, if they are approved.
On December 21, 2009, as a response to FDA’s Complete Response letter, you submitted a proposal for a pancreatic study in a rodent model of diabetes, which FDA reviewed. Then, on January 21, 2010, you committed to perform the PMR study described above and to adhere to the timetable below, should your supplemental new drug applications be approved:
Final Protocol Submission June 15, 2010
Study Completion Date March 15, 2011
Final Report Submission June 15, 2011
On February 26, 2010, FDA sent you Supplemental NDA (sNDA) approval letters under NDAs 021995 and 022044, in which you were notified that, as a condition of these sNDA approvals, the following study was required for both PMR 1602 (under NDA 021995) and PMR 1603 (under NDA 022044), pursuant to section 505(o) of the Act:
3-month pancreatic safety study in a diabetic rodent model treated with sitagliptin.
Noncompliance With Timetable for Completion of PMR and Milestone Dates
On May 17, 2010, FDA conveyed to you comments on and deficiencies of a completed study protocol you proposed in your December 21, 2009, submission, and reminded you that a new protocol for PMRs 1602 and 1603 needed to be finalized and submitted by June 15, 2010. You responded on July 6, 2010, with a submission that included responses to the comments and deficiencies, and stated that you would have additional information by “the third quarter of 2010.” On September 22, 2010, FDA stated in correspondence the following: “Unless exposure to sitagliptin at 280 mg/kg achieves at least a 10-fold multiple of clinical exposure, based on AUC, it is likely that this set of studies will not satisfy the postmarketing requirement.” You were reminded on September 24, 2010 to submit a new protocol.
On November 8, 2010, you responded that you had an ongoing second preclinical pancreatic safety study, for which you expected to have data by “the end of 2010.”
In your December 14, 2010, annual report PMR/PMC status update, you noted that you were on target for completing PMRs 1602 and 1603 by June 15, 2011. However, on February 7, 2011, you submitted a REMS assessment in which you proposed to satisfy the PMRs by submitting study data from another independently conducted investigator-initiated study, the second preclinical pancreatic safety study that you had referenced on November 8, 2010.
On March 25, 2011, you provided information about this independently conducted investigator-initiated study and indicated that some results would be available in the third quarter of 2011. On April 26, 2011, FDA requested that you provide a complete and detailed study report for the ongoing independent study and indicated that the adequacy of the study to satisfy PMR 1602/1603 would be determined following a review of the study by FDA. On June 21, 2011, you notified FDA via email that the study would be completed by August 2011.
In a teleconference on June 30, 2011, FDA expressed continuing concerns as to whether the results of this study would be sufficient to satisfy the PMR, in part because the protocol for this study had not been submitted to the FDA for review and agreement before study initiation. You were informed that because you had not yet submitted a protocol for review, the status for these PMRs for Januvia and Janumet was officially delayed, and that this information may be posted on the relevant FDA website in the near future.
On November 7, 2011, FDA formally notified you in a Failure to Respond letter that you had missed milestone dates for the final protocol submission (June 15, 2010) and final report submission (June 15, 2011) as described in the timetable you committed to on January 21, 2010 for completion of PMRs 1602 and 1603. You were also notified that this postmarketing requirement is considered delayed. You were asked to submit a written response providing your reason(s) for failing to perform the required actions by the milestone dates.
FDA notes that your November 21, 2011 written response to the Failure to Respond letter failed to acknowledge that FDA had not agreed that the ongoing independent study could be used to satisfy PMRs 1602 and 1603, and that the adequacy of the independent study to satisfy PMRs 1602 and 1603 would be determined only when a complete detailed study report was submitted to FDA for review. Your response focused entirely on the independent study. You included a brief description of the protocol for the ongoing independent study and an interim report and tables of interim results. You did not provide a final protocol submission for a new study that would fulfill the PMRs, as requested by FDA.
Following review of your written response, FDA determined on November 30, 2011 that you had not demonstrated good cause for failing to adhere to the agreed upon timetable for completion of postmarketing requirements 1602 and 1603.
FDA notes that on January 6, 2012, you submitted data from the now-completed proposed independent rodent study to the IND. However, this submission is not considered a final study report. Further, FDA has not been provided sufficient information to determine whether the proposed independent study is adequate to satisfy the PMRs.
Therefore, you have submitted neither a study protocol for a new rodent study, nor a final study report for the independent study that you proposed would satisfy the PMRs. You have not provided an adequate explanation for the cause of the delay of either of the milestones in the timetable for completion of the postmarketing requirement, nor did you propose to revise the agreed-upon timeline.
As a result, you are more than 20 months late in achieving the June 15, 2010 final protocol submission milestone and more than 8 months late in achieving the final protocol submission milestone in the timetable, and you have not demonstrated good cause for these delays.
Conclusion and Requested Action
Under section 502(z) of the Act [21 U.S.C. 352(z)], your product is considered misbranded because you are in violation of a postmarketing requirement (PMR) established under section 505(o)(3) of the Act. You have failed to comply with the approved timetable and periodic report submissions of section 505(o)(3)(E)(ii) of the Act and failed to show good cause for not conducting the additional testing required to further assess whether a signal of a serious risk of acute pancreatitis, including necrotizing forms, associated with the use of sitagliptin, represents a public health risk.
Failure to promptly correct this violation may result in regulatory actions by the FDA without further notice. These actions include, but are not limited to, civil money penalties. Other federal agencies may take this Warning Letter into account when considering the award of contracts. In addition, civil money penalties under section 303(f)(4) of the Act [21 U.S.C. 333(f)(4)] could be levied for a maximum of $250,000 per violation, with the possibility of additional penalties if the violation continues uncorrected.
Within thirty (30) calendar days from the date of this letter, submit to your NDA a final study protocol for a new 3-month rodent study that will satisfy PMRs 1602 and 1603 and a proposed revised timetable for completion of the study. Within 6 months from the date of this letter,we expect you to have obtained agreement with FDA on an adequate study protocol and to have initiated the study.
Submit your protocol to your IND, with a cross-reference letter to this NDA. Prominently identify the submission with the following wording in bold capital letters at the top of the first page of the submission, as appropriate:
- Postmarketing Commitment Protocol
- Postmarketing Commitment Correspondence
Send an additional desk copy of your written response to the following address:
Food and Drug Administration
Office of Scientific Investigations
Attention: Hee (Sheila) LianosBuilding 51, Room 5337
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
If you have any questions, you may call Sheila Lianos, CDER Office of Scientific Investigations PMR Coordinator, on (301) 796-4147.
Sincerely yours,
{See appended electronic signature page}
Leslie K. Ball, M.D.
Acting Office Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
Attention: Lou Ann Eader, Ph.D.Director, Worldwide Regulatory Affairs
P.O. Box 1000, UG2C-50
North Wales, PA 19454-1099
Dear Dr. Eader:
The U.S. Food and Drug Administration (FDA) has determined that your firm failed to comply with the milestone dates, within a previously agreed-upon timetable for completion, to conduct a required postmarketing study (PMR) for the purpose of investigating a safety issue associated with the use of Januvia® and Janumet® under New Drug Applications (NDA) 021995 and 022044, respectively. Failure to comply with the milestone dates, and to demonstrate good cause for your noncompliance, is in violation of section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 355].
This violation is concerning from a public health perspective because the PMR milestone dates (as described below) constitute part of a written agreement between you and the FDA to conduct additional testing to further assess a signal of a serious risk of acute pancreatitis, including necrotizing forms, associated with the use of sitagliptin.
Background
On October 16, 2009, FDA sent you a Complete Response letter in which we stated, in pertinent part:
We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk of acute pancreatitis, including necrotizing forms, associated with the use of Januvia® (sitagliptin).
Furthermore, the new pharmacovigilance system that FDA is required to establish under section 505(k)(3) of the FDCA has not yet been established and is not sufficient to assess this serious risk.
3- month pancreatic safety study in a diabetic rodent model treated with sitagliptin.
The specific details of this required postmarketing study will be described more fully in the approval letter for these applications, if they are approved.
On December 21, 2009, as a response to FDA’s Complete Response letter, you submitted a proposal for a pancreatic study in a rodent model of diabetes, which FDA reviewed. Then, on January 21, 2010, you committed to perform the PMR study described above and to adhere to the timetable below, should your supplemental new drug applications be approved:
Final Protocol Submission June 15, 2010
Study Completion Date March 15, 2011
Final Report Submission June 15, 2011
On February 26, 2010, FDA sent you Supplemental NDA (sNDA) approval letters under NDAs 021995 and 022044, in which you were notified that, as a condition of these sNDA approvals, the following study was required for both PMR 1602 (under NDA 021995) and PMR 1603 (under NDA 022044), pursuant to section 505(o) of the Act:
3-month pancreatic safety study in a diabetic rodent model treated with sitagliptin.
Noncompliance With Timetable for Completion of PMR and Milestone Dates
On November 8, 2010, you responded that you had an ongoing second preclinical pancreatic safety study, for which you expected to have data by “the end of 2010.”
On March 25, 2011, you provided information about this independently conducted investigator-initiated study and indicated that some results would be available in the third quarter of 2011. On April 26, 2011, FDA requested that you provide a complete and detailed study report for the ongoing independent study and indicated that the adequacy of the study to satisfy PMR 1602/1603 would be determined following a review of the study by FDA. On June 21, 2011, you notified FDA via email that the study would be completed by August 2011.
In a teleconference on June 30, 2011, FDA expressed continuing concerns as to whether the results of this study would be sufficient to satisfy the PMR, in part because the protocol for this study had not been submitted to the FDA for review and agreement before study initiation. You were informed that because you had not yet submitted a protocol for review, the status for these PMRs for Januvia and Janumet was officially delayed, and that this information may be posted on the relevant FDA website in the near future.
On November 7, 2011, FDA formally notified you in a Failure to Respond letter that you had missed milestone dates for the final protocol submission (June 15, 2010) and final report submission (June 15, 2011) as described in the timetable you committed to on January 21, 2010 for completion of PMRs 1602 and 1603. You were also notified that this postmarketing requirement is considered delayed. You were asked to submit a written response providing your reason(s) for failing to perform the required actions by the milestone dates.
FDA notes that your November 21, 2011 written response to the Failure to Respond letter failed to acknowledge that FDA had not agreed that the ongoing independent study could be used to satisfy PMRs 1602 and 1603, and that the adequacy of the independent study to satisfy PMRs 1602 and 1603 would be determined only when a complete detailed study report was submitted to FDA for review. Your response focused entirely on the independent study. You included a brief description of the protocol for the ongoing independent study and an interim report and tables of interim results. You did not provide a final protocol submission for a new study that would fulfill the PMRs, as requested by FDA.
Following review of your written response, FDA determined on November 30, 2011 that you had not demonstrated good cause for failing to adhere to the agreed upon timetable for completion of postmarketing requirements 1602 and 1603.
FDA notes that on January 6, 2012, you submitted data from the now-completed proposed independent rodent study to the IND. However, this submission is not considered a final study report. Further, FDA has not been provided sufficient information to determine whether the proposed independent study is adequate to satisfy the PMRs.
Therefore, you have submitted neither a study protocol for a new rodent study, nor a final study report for the independent study that you proposed would satisfy the PMRs. You have not provided an adequate explanation for the cause of the delay of either of the milestones in the timetable for completion of the postmarketing requirement, nor did you propose to revise the agreed-upon timeline.
As a result, you are more than 20 months late in achieving the June 15, 2010 final protocol submission milestone and more than 8 months late in achieving the final protocol submission milestone in the timetable, and you have not demonstrated good cause for these delays.
Conclusion and Requested Action
Under section 502(z) of the Act [21 U.S.C. 352(z)], your product is considered misbranded because you are in violation of a postmarketing requirement (PMR) established under section 505(o)(3) of the Act. You have failed to comply with the approved timetable and periodic report submissions of section 505(o)(3)(E)(ii) of the Act and failed to show good cause for not conducting the additional testing required to further assess whether a signal of a serious risk of acute pancreatitis, including necrotizing forms, associated with the use of sitagliptin, represents a public health risk.
Failure to promptly correct this violation may result in regulatory actions by the FDA without further notice. These actions include, but are not limited to, civil money penalties. Other federal agencies may take this Warning Letter into account when considering the award of contracts. In addition, civil money penalties under section 303(f)(4) of the Act [21 U.S.C. 333(f)(4)] could be levied for a maximum of $250,000 per violation, with the possibility of additional penalties if the violation continues uncorrected.
Within thirty (30) calendar days from the date of this letter, submit to your NDA a final study protocol for a new 3-month rodent study that will satisfy PMRs 1602 and 1603 and a proposed revised timetable for completion of the study. Within 6 months from the date of this letter,we expect you to have obtained agreement with FDA on an adequate study protocol and to have initiated the study.
Submit your protocol to your IND, with a cross-reference letter to this NDA. Prominently identify the submission with the following wording in bold capital letters at the top of the first page of the submission, as appropriate:
Send an additional desk copy of your written response to the following address:
Food and Drug Administration
Office of Scientific Investigations
Attention: Hee (Sheila) LianosBuilding 51, Room 5337
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
If you have any questions, you may call Sheila Lianos, CDER Office of Scientific Investigations PMR Coordinator, on (301) 796-4147.
Sincerely yours,
{See appended electronic signature page}
Leslie K. Ball, M.D.
Acting Office Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
