3M Health Care (Infection Prevention Division)SoluPrep™ (2% chlorhexidine gluconate and 70% isopropyl alcohol), solution

NDA 208288 COMPLETE RESPONSE

3M Health Care (Infection Prevention Division) Attention: Dianne Gibbs

Regulatory Affairs Director, IPD Division Building 275-5W-06

St. Paul, MD 55144-1000

Dear Ms. Gibbs:

Please refer to your New Drug Application (NDA) dated March 3, 2017, received March 3, 2017, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for SoluPrep™ (2% chlorhexidine gluconate and 70% isopropyl alcohol), solution.

We acknowledge receipt of your amendment dated March 3, 2017, which constituted a complete response to our May 6, 2016, action letter.

We also acknowledge receipt of your major amendment dated July 31, 2017, which was not reviewed for this action per your request on August 22, 2017, to withdraw the July 31 submission. You may incorporate applicable sections of the amendment by specific reference as part of your response to the deficiencies cited in this letter.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

NONCLINICAL The proposed specifications of NMT {3% for the impurity, © and NMT) (9% for the impurity ®@ are above the qualification threshold per the ICH

guidance for industry Q3B(R2) Drug Product Impurities. The dermal rabbit study (#16-014) submitted on March 3, 2017, does not include a sufficient tissue battery to assess systemic toxicity.

We also note that the doses administered in your rabbit dermal study do not appear to support your proposed impurity specifications for the 26 mL applicator, using the available data. This relies upon your proposed maximal use for the 26 mL applicator, the proposed impurity stability specifications, and conversion of the doses administered to animals to human equivalent doses. As an alternative to human equivalent doses, clinical pharmacokinetic data and animal

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toxicokinetic data can be used to provide animal-to-human exposure margins. In addition, human pharmacokinetic from an adequate maximal use trial (MUsT) can demonstrate minimal systemic absorption of the impurities of concern. Absent these data, you have not provided adequate qualification data to support your proposed impurity specifications.

To resolve this deficiency, 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 © "As discussed during a teleconference on August 22, 2017, data from a Franz Cell assay does not supplant clinical pharmacokinetic data for informing the animal-to-human exposure margin, or demonstrating minimal absorption of the impurities of concern. In such cases the in vivo assessment of exposure (through a MUsT) is considered the definitive demonstration.

Alternatively, you can 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. This relies upon your proposed use for the 26 mL applicator, which results in higher estimated patient exposures than the anticipated use of the 10 mL applicator. If you choose this pathway, provide updated stability specifications consistent with your justification.

For a description of extended single dose studies, refer to ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. Briefly, one group of animals should be sacrificed on the day following dosing and an additional group on day 14 post-dose. Provide justification that your dosing regimen reflects the expected clinical use of your product. Specifically, 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, sa 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. Provide justification for your study design in your submission.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at

21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the product under consideration regardless of indication, dosage form, or dose level.

1. Describe in detail any significant changes or findings in the safety profile.

2. When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

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e Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

e Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

3. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

4. Provide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

5. Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.

6. Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

7. Provide a summary of worldwide experience on the safety of this product. Include an updated estimate of use for product marketed in other countries.

8. Provide English translations of current approved foreign labeling not previously submitted.

CHEMISTRY, MANUFACTURING AND CONTROLS

We acknowledge that you have accepted the Agency’s recommendation for the drug product impurity levels and updated specifications (dated 21 August, 2017). Since the qualification of impurities is still inadequate, updated specifications for the drug product will remain as “tentative specifications”.

OTHER Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. If you do not take one of these actions, we may consider your

lack of response a request to withdraw the application under 21 CFR 314.65. You may also request an extension of time in which to resubmit the application.

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A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider this resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products,” March 2015 at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm 43743 | pdf.

The drug product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, call Celia Peacock, Regulatory Project Manager, at (301)796-4154. Sincerely, {See appended electronic signature page} Theresa Michele, MD Director Division of Nonprescription Drug Products

Office of Drug Evaluation IV Center for Drug Evaluation and Research

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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

THERESA M MICHELE 09/01/2017

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