US FDA•United StatesAL•Approval Letter

Approval Letter Other 208288 (Jan 1, 2018)

Issued January 1, 2018

Issued

January 1, 2018

Application

Other • 208288

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due January 1, 2019Product may be marketed.

Summary

The FDA issued two Complete Response letters for New Drug Application (NDA) 208288 for SoluPrep™ to 3M Health Care. The letters detail reasons for non-approval, including nonclinical deficiencies related to impurity qualification and systemic toxicity assessment, requirements for a comprehensive safety update, and clinical deficiencies regarding replicative efficacy in pivotal studies and insufficient financial disclosure information for subinvestigators. The application cannot be approved in its present form, and specific actions are required for resubmission.

Key points

Provide an adequate qualification study in a single animal species (e.g., a single extended dose study) or otherwise adequately address the systemic exposure to impurities.
Alternatively, control the level of impurities to that of a relevant approved product using the total daily exposure resulting from four 26 mL applicators per day.
If choosing the alternative pathway, provide updated stability specifications consistent with your justification.
Provide justification that your dosing regimen reflects the expected clinical use of your product.
Ensure that the time and extent of application of your product in your animal studies is sufficient to address the anticipated maximal duration and extent of application in humans if your product is approved.
To address systemic toxicity after dermal administration, assess a full battery of tissues.
Animals may be dosed by the dermal route, with assessments for mortality, clinical signs, body weights, organ weights, food consumption, gross pathology, histopathology, and toxicokinetic parameters of the impurities after a single administration, with further evaluations conducted 2 weeks (14 days) later to assess delayed toxicity and/or recovery.
In the absence of clinical pharmacokinetic data, ensure that the study addresses adequate exposure using body surface area conversion of doses, and a complete assessment of local and systemic effects.

Cited reasons

Inadequate impurity qualification and systemic toxicity assessment
Failure to demonstrate replicative efficacy in clinical simulation studies
Insufficient financial disclosure information for clinical investigators
Requirement for comprehensive safety update
The application cannot be approved due to inadequate nonclinical data for impurity qualification and systemic toxicity assessment, failure to demonstrate replicative clinical efficacy for the inguinal site, and missing financial disclosure information for subinvestigators. A comprehensive safety update is also required for resubmission.

Recommended actions

Provide an adequate qualification study in a single animal species (e.g., a single extended dose study) or otherwise adequately address the systemic exposure to impurities.
Alternatively, control the level of impurities to that of a relevant approved product using the total daily exposure resulting from four 26 mL applicators per day.
If choosing the alternative pathway, provide updated stability specifications consistent with your justification.
Provide justification that your dosing regimen reflects the expected clinical use of your product.
Ensure that the time and extent of application of your product in your animal studies is sufficient to address the anticipated maximal duration and extent of application in humans if your product is approved.
To address systemic toxicity after dermal administration, assess a full battery of tissues.
Animals may be dosed by the dermal route, with assessments for mortality, clinical signs, body weights, organ weights, food consumption, gross pathology, histopathology, and toxicokinetic parameters of the impurities after a single administration, with further evaluations conducted 2 weeks (14 days) later to assess delayed toxicity and/or recovery.
In the absence of clinical pharmacokinetic data, ensure that the study addresses adequate exposure using body surface area conversion of doses, and a complete assessment of local and systemic effects.

Deficiency summary

The application cannot be approved due to inadequate nonclinical data for impurity qualification and systemic toxicity assessment, failure to demonstrate replicative clinical efficacy for the inguinal site, and missing financial disclosure information for subinvestigators. A comprehensive safety update is also required for resubmission.

Findings

Inadequate impurity qualification and systemic toxicity assessment

Severity: major

Proposed impurity specifications exceed qualification thresholds per ICH Q3B(R2). The dermal rabbit study lacks a sufficient tissue battery for systemic toxicity assessment and the administered doses do not adequately support proposed impurity specifications for the 26 mL applicator. Clinical pharmacokinetic data, animal toxicokinetic data, or human pharmacokinetic data from a maximal use trial (MUsT) are needed to establish exposure margins or demonstrate minimal systemic absorption of impurities.

Recommended response: Provide an adequate qualification study in a single animal species (e.g., a single extended dose study) or otherwise adequately address systemic exposure. Alternatively, control impurity levels to that of a relevant approved product and provide updated stability specifications. Ensure the study addresses adequate exposure using body surface area conversion and a complete assessment of local and systemic effects, including a full battery of tissues for systemic toxicity.

Cited: ICH guidance for industry Q3B(R2) Drug Product Impurities, ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals

Failure to demonstrate replicative efficacy in clinical simulation studies

Severity: critical

Replicative efficacy was not demonstrated for the inguinal site in Study EM-05-013260, as it failed to meet the pre-specified primary endpoint. Previously proposed alternative primary efficacy analyses were deemed unacceptable.

Recommended response: Conduct a repeat study of the inguinal region with adequate controls that meets the pre-specified primary endpoint.

Insufficient financial disclosure information for clinical investigators

Severity: major

Financial disclosure information is missing for 11 of 20 subinvestigators in pivotal study EM-05-012760 and for one subinvestigator in study EM-05-013260.

Recommended response: Provide the missing financial disclosure information for all subinvestigators.

Requirement for comprehensive safety update

Severity: info

A safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), must be included with the resubmission. This update should detail significant changes in the safety profile, provide combined and comparative tabulations of new and original safety data, retabulate reasons for premature trial discontinuations, include case reports for deaths/serious adverse events, describe changes in common adverse events, update exposure information, summarize worldwide safety experience, and provide English translations of current approved foreign labeling.

Recommended response: Prepare a comprehensive safety update according to 21 CFR 314.50(d)(5)(vi)(b) for inclusion in the resubmission.

Cited: 21 CFR 314.50(d)(5)(vi)(b)

Regulatory context

Submission stage: final decision
Regulatory pathway: 505(b)(2) of the Federal Food, Drug, and Cosmetic Act

Impact

Impact score: 0.95
Estimated delay: 545 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The application requires substantial additional nonclinical data to qualify impurities and assess systemic toxicity, a repeat clinical study to demonstrate replicative efficacy for a key indication, and resolution of administrative deficiencies related to financial disclosures. A complete safety update is also mandated for resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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