ANDA Submissions-Refuse to receive: Industry perspective
ANDA SUBMISSIONSREFUSE TO RECEIVE: INDUSTRY PERSPECTIVE May 18, 2016
Aloka Srinivasan, Ph.D.
CONFIDENTIAL
© 2016 PAREXEL INTERNATIONAL CORP.
REFUSE TO RECEIVE (RTR) GUIDANCE FOR ANDAS
RTR guidance was mandated by GDUFA: “FDA will develop enhanced refusal to receive standards for ANDAs and other related submissions by the end of year one of the program and will publish such standards in advance of implementation.” -Generic Drug User Fee Act Program Performance Goals and Procedures
2 © 2016 PAREXEL INTERNATIONAL CORP.
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CONFIDENTIAL
IMPACT OF REFUSE TO RECEIVE GUIDANCE ON ANDA QUALITY • Information provided in the guidance has helped the generic industry understand the FDA’s thought process regarding “high quality” ANDA submissions. • Information in the finalized guidance has helped resolve some of the issues, for which OGD’s perspective was not clear, prior to GDUFA. Examples – Inactive ingredient limits and the total daily intake – Stability requirement for transdermal patches – Validation/verification of analytical methods – Fill volumes – Microbial process validation considerations
• The guidance has also proved to be a challenge to the industry in some ways. © 2016 PAREXEL INTERNATIONAL CORP. / 3
CONFIDENTIAL
RTR DEFICIENCIES THAT HAVE AFFECTED THE GENERIC INDUSTRY: EXAMPLE 1 Stability data does not cover the recommended 6 month (180 days) minimum hold time, in accordance with ANDA Submissions – Refuse-toReceive Standards. • Sponsors have received this deficiency when the data submitted covered as much as 176 days and the drug product has not shown any adverse trend under accelerated or long term conditions • The established SOP for most manufacturers include minor excursions: Example: “Pull the stability samples within ± five (5) days of the scheduled pull date for one (1), two (2), and three (3) month stability samples; ± seven (7) days for six (6) month stability samples; and ± two (2) weeks for stability samples stored over nine (9) months”.
• The sites where the stability studies are done are regularly inspected by the FDA and the SOPs related to withdrawal of stability samples have been found to be satisfactory. © 2016 PAREXEL INTERNATIONAL CORP. / 4
CONFIDENTIAL
CHALLENGES TO THE INDUSTRY RELATED TO 180 DAYS STABILITY DATA • The ICH Q1A(R2) and the FDA Guidance to the Industry ANDAs: Stability Testing of Drug Substances and Products Questions and Answers state the stability requirement in months (not days or weeks), which in turn is reflected in the SOPs of facilities, which manufacture new drugs, generic drugs, OTCs and drugs for other ICH regions. • Also, just as excursions are allowed to the ICH storage conditions (temperature, humidity), it is desirable to have reasonable excursions for the time period covered by the stability studies and FDA’s compliance has taken this into consideration in many occasions. • The rigid interpretation of the 180 days stability data in the RTR guidance, without provision for any excursion has lead to numerous ANDAs being rejected at filing, though the deviation had no impact on product quality. • This has required the industry, in some cases, to have a separate SOP for monitoring the stability generic products versus new drugs and OTCs (a contradiction to “one quality voice”)
© 2016 PAREXEL INTERNATIONAL CORP. / 5
CONFIDENTIAL
EXAMPLE 1: POSSIBLE REMEDIATION STRATEGIES
• Discuss with the FDA as industry, regarding the possibility of a “reasonable” excursion to the stability data requirement for generics based on science. Or • Change your current stability related SOPs to assure that a sample is never removed prior to 180 days.
© 2016 PAREXEL INTERNATIONAL CORP. / 6
CONFIDENTIAL
RTR DEFICIENCIES THAT HAVE AFFECTED THE GENERIC INDUSTRY: EXAMPLE 2: In vitro dissolution comparison to the RLD has not been provided
• In several cases, performing the dissolution comparison with the RLD is difficult due the fact that the sufficient amount of RLD samples is not available based on REMS. • On many occasions, the sponsor have tried to overcome this problem by performing the in vitro comparison with a non-U.S. comparator, when the innovator for the RLD and the non-U.S. comparator are the same company, and they have comparable formulations and are manufactured in facility(ies) licensed and inspected by a regulatory authority that has similar scientific and regulatory standards as FDA (e.g., ICH countries) - however this is not acceptable;
© 2016 PAREXEL INTERNATIONAL CORP. / 7
CONFIDENTIAL
CHALLENGES WITH PERFORMING IN-VITRO COMPARISON WITH RLD SUBJECT TO REMS
• The sharp increase in the number of new drugs approved with REMS requirements in the last few years has made access to samples of these drugs difficult for the generic industry. • Based on the Guidance to the Industry: How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD, an ANDA sponsor may acquire sufficient RLD to perform bio-studies but not the other in vitro studies.
• There is no obligation on the part of the innovator to provide the samples in a timely manner which causes delays in generic product development. © 2016 PAREXEL INTERNATIONAL CORP. / 8
CONFIDENTIAL
EXAMPLE TWO: POSSIBLE REMEDIATION STRATEGIES • Discuss in advance with FDA (may be through a meeting request or controlled correspondence) regarding possible alternatives when there are REMS related challenges in acquiring enough RLD samples to perform in vitro studies
Or • Wait for the Fair Access for Safe and Timely Generics Act of 2015 (FAST Generics Act) to pass.
Submission of dissolution comparison with non-US comparator will count towards Refuse to Receive
© 2016 PAREXEL INTERNATIONAL CORP. / 9
CONFIDENTIAL
CONCLUSIONS
The FDA Guidance to the Industry, ANDA Submissions ― Refuseto-Receive Standards has helped improve the general quality of ANDA submissions.
The guidance has also presented the generic industry with several challenges.
The Generic Industry may initiate a dialogue with FDA providing them clarity regarding some of the hurdles presented by this guidance and collaboratively work towards a possible solution.
Ultimate Goal
Smooth filing of ANDAs and one cycle approval © 2016 PAREXEL INTERNATIONAL CORP. / 10
CONFIDENTIAL
THANK YOU
© 2016 PAREXEL INTERNATIONAL CORP. / 11
CONFIDENTIAL
Aloka Srinivasan, Ph.D.
CONFIDENTIAL
© 2016 PAREXEL INTERNATIONAL CORP.
REFUSE TO RECEIVE (RTR) GUIDANCE FOR ANDAS
RTR guidance was mandated by GDUFA: “FDA will develop enhanced refusal to receive standards for ANDAs and other related submissions by the end of year one of the program and will publish such standards in advance of implementation.” -Generic Drug User Fee Act Program Performance Goals and Procedures
2 © 2016 PAREXEL INTERNATIONAL CORP.
/ 2
CONFIDENTIAL
IMPACT OF REFUSE TO RECEIVE GUIDANCE ON ANDA QUALITY • Information provided in the guidance has helped the generic industry understand the FDA’s thought process regarding “high quality” ANDA submissions. • Information in the finalized guidance has helped resolve some of the issues, for which OGD’s perspective was not clear, prior to GDUFA. Examples – Inactive ingredient limits and the total daily intake – Stability requirement for transdermal patches – Validation/verification of analytical methods – Fill volumes – Microbial process validation considerations
• The guidance has also proved to be a challenge to the industry in some ways. © 2016 PAREXEL INTERNATIONAL CORP. / 3
CONFIDENTIAL
RTR DEFICIENCIES THAT HAVE AFFECTED THE GENERIC INDUSTRY: EXAMPLE 1 Stability data does not cover the recommended 6 month (180 days) minimum hold time, in accordance with ANDA Submissions – Refuse-toReceive Standards. • Sponsors have received this deficiency when the data submitted covered as much as 176 days and the drug product has not shown any adverse trend under accelerated or long term conditions • The established SOP for most manufacturers include minor excursions: Example: “Pull the stability samples within ± five (5) days of the scheduled pull date for one (1), two (2), and three (3) month stability samples; ± seven (7) days for six (6) month stability samples; and ± two (2) weeks for stability samples stored over nine (9) months”.
• The sites where the stability studies are done are regularly inspected by the FDA and the SOPs related to withdrawal of stability samples have been found to be satisfactory. © 2016 PAREXEL INTERNATIONAL CORP. / 4
CONFIDENTIAL
CHALLENGES TO THE INDUSTRY RELATED TO 180 DAYS STABILITY DATA • The ICH Q1A(R2) and the FDA Guidance to the Industry ANDAs: Stability Testing of Drug Substances and Products Questions and Answers state the stability requirement in months (not days or weeks), which in turn is reflected in the SOPs of facilities, which manufacture new drugs, generic drugs, OTCs and drugs for other ICH regions. • Also, just as excursions are allowed to the ICH storage conditions (temperature, humidity), it is desirable to have reasonable excursions for the time period covered by the stability studies and FDA’s compliance has taken this into consideration in many occasions. • The rigid interpretation of the 180 days stability data in the RTR guidance, without provision for any excursion has lead to numerous ANDAs being rejected at filing, though the deviation had no impact on product quality. • This has required the industry, in some cases, to have a separate SOP for monitoring the stability generic products versus new drugs and OTCs (a contradiction to “one quality voice”)
© 2016 PAREXEL INTERNATIONAL CORP. / 5
CONFIDENTIAL
EXAMPLE 1: POSSIBLE REMEDIATION STRATEGIES
• Discuss with the FDA as industry, regarding the possibility of a “reasonable” excursion to the stability data requirement for generics based on science. Or • Change your current stability related SOPs to assure that a sample is never removed prior to 180 days.
© 2016 PAREXEL INTERNATIONAL CORP. / 6
CONFIDENTIAL
RTR DEFICIENCIES THAT HAVE AFFECTED THE GENERIC INDUSTRY: EXAMPLE 2: In vitro dissolution comparison to the RLD has not been provided
• In several cases, performing the dissolution comparison with the RLD is difficult due the fact that the sufficient amount of RLD samples is not available based on REMS. • On many occasions, the sponsor have tried to overcome this problem by performing the in vitro comparison with a non-U.S. comparator, when the innovator for the RLD and the non-U.S. comparator are the same company, and they have comparable formulations and are manufactured in facility(ies) licensed and inspected by a regulatory authority that has similar scientific and regulatory standards as FDA (e.g., ICH countries) - however this is not acceptable;
© 2016 PAREXEL INTERNATIONAL CORP. / 7
CONFIDENTIAL
CHALLENGES WITH PERFORMING IN-VITRO COMPARISON WITH RLD SUBJECT TO REMS
• The sharp increase in the number of new drugs approved with REMS requirements in the last few years has made access to samples of these drugs difficult for the generic industry. • Based on the Guidance to the Industry: How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD, an ANDA sponsor may acquire sufficient RLD to perform bio-studies but not the other in vitro studies.
• There is no obligation on the part of the innovator to provide the samples in a timely manner which causes delays in generic product development. © 2016 PAREXEL INTERNATIONAL CORP. / 8
CONFIDENTIAL
EXAMPLE TWO: POSSIBLE REMEDIATION STRATEGIES • Discuss in advance with FDA (may be through a meeting request or controlled correspondence) regarding possible alternatives when there are REMS related challenges in acquiring enough RLD samples to perform in vitro studies
Or • Wait for the Fair Access for Safe and Timely Generics Act of 2015 (FAST Generics Act) to pass.
Submission of dissolution comparison with non-US comparator will count towards Refuse to Receive
© 2016 PAREXEL INTERNATIONAL CORP. / 9
CONFIDENTIAL
CONCLUSIONS
The FDA Guidance to the Industry, ANDA Submissions ― Refuseto-Receive Standards has helped improve the general quality of ANDA submissions.
The guidance has also presented the generic industry with several challenges.
The Generic Industry may initiate a dialogue with FDA providing them clarity regarding some of the hurdles presented by this guidance and collaboratively work towards a possible solution.
Ultimate Goal
Smooth filing of ANDAs and one cycle approval © 2016 PAREXEL INTERNATIONAL CORP. / 10
CONFIDENTIAL
THANK YOU
© 2016 PAREXEL INTERNATIONAL CORP. / 11
CONFIDENTIAL
