CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICATION NUMBER:
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`210875Orig1s000
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`OTHER ACTION LETTERS
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
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`Silver Spring MD 20993
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` NDA 210875
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`COMPLETE RESPONSE
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`Sunovion Pharmaceuticals Inc.
`Attention: Sonya A. Roeloffzen
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`Director, Global Regulatory Affairs
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`84 Waterford Drive
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`Marlborough, MA 01752
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`Dear Ms. Roeloffzen:
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`Please refer to your New Drug Application (NDA) dated March 29, 2018, received March 29,
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`2018, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug,
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`and Cosmetic Act for Kynmobi (apomorphine) sublingual film 10 mg, 15 mg, 20 mg, 25 mg, and
`30 mg.
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`We have completed our review of this application, and have determined that we cannot approve
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`this application in its present form. We have described our reasons for this action below and,
`where possible, our recommendations to address these issues.
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`HUMAN FACTORS (HF)
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`As communicated to you in a November 21, 2018, Discipline Review (DR) letter, the human
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`factors (HF) validation study conducted for Kynmobi does not provide sufficient evidence to
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`demonstrate that the proposed product can be used safely and effectively by intended users for its
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`intended uses and use environments. Your HF study identified several use errors and close calls
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`that occurred on critical tasks. Additionally, you have not provided data to demonstrate that your
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`proposed mitigations are effective and do not introduce new use-related risks. Furthermore, your
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`HF study did not evaluate the final intend-to-market user interface, i.e., your proposed
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` packaging. Thus, you have not provided sufficient data to demonstrate whether
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`the intended users can open and close the packaging.
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`We acknowledge your December 7, 2018, formal response to the DR letter, and note that your
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`response provided additional information and your plan to address the Agency’s concerns about
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`your human factors (HF) validation study results and the
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`acknowledge that you have evaluated this product in the clinical environment. However, the
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`intend-to-market outer carton
` packaging) was not part of the user interface
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`evaluated in the HF validation study. While we acknowledge your proposed plan to submit a
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`petition for exemption from the child-resistant (CR) packaging requirement post-approval
`, it is not clear whether such exemption will be granted.
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`Reference ID: 4383056
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 210875
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`Page 2
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` The specific deficiencies identified in your HF validation study include the following:
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`1. Your study results showed several use errors and close calls that occurred on critical
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`tasks. We note that you implemented revisions to the Instructions for Use (IFU) and film
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`pouch (container label) to address the use errors and close calls. However, you did not
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`validate the revisions to the user interface. Furthermore, our evaluation of the proposed
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`user interface, label and labeling identified areas of vulnerability that may lead to
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` medication errors, and we provided additional recommendations in our November 21,
` 2018, Discipline Review letter. We acknowledge that you have implemented our IFU,
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`container label, and carton labeling recommendations.
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` 2. We note that the
`packaging requires a push-pull technique to open,
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`which may pose concerns for the intended user population (i.e., patients with Parkinson’s
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`disease) due to dexterity and motor impairments that occur in the OFF period. We also
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`note that Kynmobi is intended for the acute, intermittent treatment of “OFF” episodes
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`associated with Parkinson’s disease; therefore, delay in therapy (e.g., due to difficulty
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`opening the
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`We are concerned that if users experience difficulty opening or closing the
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`packaging, they might remove the foil pouches from the packaging permanently or alter
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`the packaging to eliminate the child-resistant features, which may increase the risk of
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` packaging was not part of the user interface
`secondary exposure. As the
`evaluated in the HF validation study and the intended user population has clinical
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`manifestations that might impact interaction with the
`packaging, we find
`that the study results are not representative of real-world use.
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`A human factors validation study using the intend-to-market user interface (i.e.,
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`packaging) is needed to demonstrate that the mitigations are effective and do not introduce new
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`risks. You should evaluate the use-related errors observed in the HF study, employ additional
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`mitigation strategies, and update your use-related risk analysis prior to conducting that study.
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`We recommend you submit your HF validation study protocol for feedback before commencing
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`your study. Note that submission of a protocol for review is not a requirement.
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`Please refer to our draft guidance titled “Contents of a Complete Submission for Threshold
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`Analyses and Human Factors Submissions to Drug and Biologic Applications” for the content of
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`a human factors validation study protocol submission. The guidance is available online at
`https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
`UCM621902.pdf
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`Place the requested information in eCTD Section 5.3.5.4 – Other Study reports and related
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`information.
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`Guidance on human factors procedures to follow can be found in: Applying Human Factors and
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`Usability Engineering to Medical Devices, available online at:
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`Reference ID: 4383056
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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` NDA 210875
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` Page 3
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`http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocu
`ments/ucm259760.pdf
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`Guidance on Safety Considerations for Product Design to Minimize Medication Errors and can
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`be found online at:
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM331810.pdf
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`Note that we recently published two draft guidance documents that, while not yet finalized,
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`might also be useful in understanding our current thinking and our approach to human factors for
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`combination products, product design, and labeling:
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`Human Factors Studies and Related Clinical Study Considerations in Combination
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`Product Design and Development and can be found online at:
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`http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM484345.pdf
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`Safety Considerations for Container Labels and Carton Labeling Design to Minimize
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`Medication Errors and can be found online at:
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`http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
`es/ucm349009.pdf
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`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
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`Complete Study CTH-203 and provide the final report for Study CTH-203, which is necessary to
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`justify the relevance of comparative data with your proposed product (Kynmobi) and Apo-go to
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`support the scientific appropriateness of reliance on FDA’s finding of safety for Apokyn. In
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`addition, clearly describe the data and information that supports the scientific bridge between
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`your proposed product (Kynmobi) and the listed drug relied upon (Apokyn), which may include
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`data and information supporting a bridge between Kynmobi and Apo-go and between Apokyn
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`and Apo-go.
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`SAFETY
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`You have not adequately characterized the oropharyngeal adverse events that were observed in
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`patients treated with Kynmobi. These events were reported under multiple terms, such as
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`oropharyngeal pain, oropharyngeal swelling, pharyngeal erythema, gingivitis, oral pain, lip
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`swelling, gingival edema, mouth edema, lip ulceration, oral mucosal erythema, stomatitis, mouth
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`ulceration, oral discomfort, oral hypoesthesia, mouth swelling, glossodynia, tongue discomfort,
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`lip blister, dysgeusia, angular cheilitis, oropharyngeal pain, leukoplakia oral, lip exfoliation, oral
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`mucosal blistering, agueusia, throat irritation, oral allergy syndrome, pharyngeal edema, soft
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`palate swelling, and others.
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`Taken together, and according to our analyses, oropharyngeal adverse events were reported in
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`over 25% of patients treated with Kynmobi in the maintenance phase of Study 300, compared to
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`4% of patients on placebo. Oropharyngeal adverse events were also commonly observed in
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`Study 301, and were a common reason for discontinuation in both studies.
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`Reference ID: 4383056
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` NDA 210875
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` Page 4
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`You will need to provide a comprehensive discussion and summary of oropharyngeal adverse
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`events with Kynmobi, including an expert review from a qualified dermatologist. For both Study
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`300 and Study 301, reexamine your safety database, and pool all related oropharyngeal adverse
`events in appropriate clusters (e.g., oropharyngeal edema, pain, ulceration, hypoesthesia, etc.).
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`Identify the number of oropharyngeal adverse events, and the number of unique patients
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`reporting at least one of the adverse events in the cluster. Identify the number of discontinuations
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`in both studies for each of these events and each cluster of events. Provide analyses of these
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`events by severity. Present this information for each study phase (e.g., titration and
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`maintenance) and for all patients in the overall safety population. Present analyses of the time to
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`onset of the events after treatment initiation, evolution, time course, time to resolution after
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`treatment discontinuation, and relationship to the dose of Kynmobi. Present analyses of the
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`association between oropharyngeal adverse events and systemic hypersensitivity, including the
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`temporal relationship between oropharyngeal and systemic hypersensitivity events, if any.
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`Send all patients reporting new oropharyngeal adverse events in ongoing Study CTH-301 to a
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`qualified dermatologist, and obtain photographs of all relevant oral and skin abnormalities
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`associated with the event. Submit a copy of the dermatologist’s diagnosis, the investigator’s
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`assessment, a case summary and the photographs of the relevant abnormalities.
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`SAFETY UPDATE
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`When you respond to the above deficiencies, include a safety update as described at
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`21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and
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`clinical studies/trials of the drug under consideration regardless of indication, dosage form, or
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`dose level.
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`1. Describe in detail any significant changes or findings in the safety profile.
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`2. When assembling the sections describing discontinuations due to adverse events, serious
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`adverse events, and common adverse events, incorporate new safety data as follows:
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` Present new safety data from the studies/clinical trials for the proposed indication
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`using the same format as in the original submission.
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` Present tabulations of the new safety data combined with the original application
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`data.
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`Include tables that compare frequencies of adverse events in the original application
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`with the retabulated frequencies described in the bullet above.
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` For indications other than the proposed indication, provide separate tables for the
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`frequencies of adverse events occurring in clinical trials.
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`3. Present a retabulation of the reasons for premature trial discontinuation by incorporating
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`the drop-outs from the newly completed trials. Describe any new trends or patterns
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`identified.
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`Reference ID: 4383056
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` NDA 210875
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` Page 5
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`4. Provide case report forms and narrative summaries for each patient who died during a
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` provide narrative summaries for serious adverse events.
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`5. Describe any information that suggests a substantial change in the incidence of common,
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`but less serious, adverse events between the new data and the original application data.
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`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
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`subjects, person time).
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`7. Provide a summary of worldwide experience on the safety of this drug. Include an
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`updated estimate of use for drug marketed in other countries.
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`8. Provide English translations of current approved foreign labeling not previously
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`submitted.
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`ADDITIONAL COMMENTS
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`We have the following comments/recommendations that are not approvability issues:
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`1. You will need to conduct in vitro studies to evaluate drug-drug interaction (DDI)
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`potential of the two major metabolites from Kynmobi, apomorphine glucuronide and
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`norapomorphine glucuronide.
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`2. For the ISS, submit a new set of ADaM datasets that are fully compliant with the CDISC
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`standard. For example, the USUBJID should be uniform throughout the submitted data,
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`with every patient in the development program having the same unique identifier in every
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`dataset. The datasets should include all patients in the safety population from initiation of
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`clinical studies through an appropriate cut-off date for your re-submission.
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`3. The Summary of Clinical Safety should be updated with attention to all adverse events of
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`special interest, especially those suggesting hypersensitivity reactions. Perform an
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`analysis by dose and duration of exposure until the time of AE development in cases
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`identified by MedDRA SMQ for hypersensitivity and angioedema.
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`4.
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`In addition to updating the analysis of exposure by total daily dose, perform an analysis
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`of exposure to APL-130277 for Studies 300 and 301 using self-reported daily frequency
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`of administration by patients.
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`5. For open-label Study CTH-301, submit the complete report or an interim report, if the
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`study is still ongoing at the time of resubmission.
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`6.
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`In the 120-Day Safety Update, the EXDOSFRQ (Dosing Frequency per Interval) column
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`in the ADEX dataset is blank. Please provide this information in the amended datasets,
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`using the information from the patient dosing diaries prior to each visit. List the doses
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`Reference ID: 4383056
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` NDA 210875
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` Page 6
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` taken per day as 0 through 5. Add a DOSEON column to show the dose prescribed for
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`OTHER
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`Within one year after the date of this letter, you are required to resubmit or take other actions
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`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
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`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
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`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
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`marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter
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`of the submission. The cover letter should clearly state that you consider this resubmission a
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`complete response to the deficiencies outlined in this letter. A partial response to this letter will
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`not be processed as a resubmission and will not start a new review cycle.
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`You may request a meeting or teleconference with us to discuss what steps you need to take
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`before the application may be approved. If you wish to have such a meeting, submit your
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`meeting request as described in the draft FDA Guidance for Industry, “Formal Meetings
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`Between the FDA and Sponsors or Applicants of PDUFA Products,” December 2017 at
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`https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM59054
`7
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`The drug product may not be legally marketed until you have been notified in writing that this
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`application is approved.
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`If you have any questions, call Jack Dan, Regulatory Project Manager, at (240) 402-6940.
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`Sincerely,
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`{See appended electronic signature page}
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`Eric Bastings, MD
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`Deputy Director
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`Division of Neurology Products
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`Office of Drug Evaluation I
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`Center for Drug Evaluation and Research
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`Reference ID: 4383056
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`

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`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`ERIC P BASTINGS
`01/29/2019 09:33:29 PM
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`Reference ID: 4383056
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`