CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`022567Orig1s000
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`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
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`Date:
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`To:
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`Through:
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`From:
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`Subject:
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`Drug Name(s):
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`Application
`Type/Number:
`Applicant/sponsor:
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`OSE RCM #:
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`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
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`December 03, 2010
`
`
`Thomas Laughren, MD, Director
`Division of Psychiatry Products (DPP)
`
`Claudia Karwoski PharmD, Director
`Division of Risk Management (DRISK)
`
`Shawna Hutchins, MPH, BSN RN
`Patient Labeling Reviewer
`Division of Risk Management (DRISK)
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`DRISK Review of Proposed Risk Evaluation and Mitigation
`Strategy (REMS)
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`vilazodone HCL tablets
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`NDA 22-567
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`PGxHealth, LLC
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`2010-784
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`Reference ID: 2871971
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`1. INTRODUCTION
`This review is written in response to a request by the Division of Psychiatry Products
`(DPP) for the Division of Risk Management (DRISK) to review the Applicant’s
`proposed Risk Evaluation and Mitigation Strategy (REMS) and REMS Supporting
`Document for vilazodone hydrochloride (HCL) tablets. The trade name for this
`NDA is currently under review.
`Please send these comments to the Applicant and request a response within two
`weeks of receipt. Let us know if you would like a meeting to discuss these comments
`before sending to the Applicant.
`The DRISK review of the Medication Guide will be provided under a separate cover.
`The DRISK review of the methodology and survey instruments to be submitted by
`the Applicant to evaluate the REMS will be provided under separate cover.
`2. BACKGROUND
`On March 22, 2010 PGxHealth, LLC, submitted a New Drug Application (NDA)
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for vilazodone (HCL) 10 mg, 20 mg, and 40 mg tablets for the treatment of major
`depressive disorder (MDD).
`Section 505-1 of the FDCA authorizes FDA to require the submission of a risk
`evaluation and mitigation strategy (REMS), if FDA determines that such a strategy is
`necessary to ensure that the benefits of the drug outweigh the risks [section 505-1(a)].
`In accordance with section 505-1 of FDCA, the FDA determined that a REMS is
`necessary for vilazodone HCL tablets to ensure the benefits of the drug outweigh the
`increased risk of suicidality in children, adolescents, and young adults as observed in
`short-term studies of major depressive disorder (MDD) and other psychiatric
`disorders. The components of the REMS include a Medication Guide (MG) and a
`timetable for submission of assessments.
`3. MATERIAL REVIEWED
`
`(cid:131) vilazodone HCL tablets Risk Evaluation and Mitigation Strategy (REMS)
`Notification Letter dated November 01, 2010.
`
`(cid:131) Proposed vilazodone HCL tablets Risk Evaluation and Mitigation Strategy
`(REMS) and REMS Supporting Document, submitted on March 22, 2010, and
`received by DRISK on November 23, 2010.
`4. RESULTS OF REVIEW
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`In our review of the proposed REMS, we have:
`• Ensured it includes the elements outlined in the REMS Notification Letter.
`• Ensured it meets the statutory requirements under the Food and Drug
`Administration Amendments Act (FDAAA) of 2007.
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`Reference ID: 2871971
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`5. CONCLUSIONS AND RECOMMENDATIONS
`DRISK concurs with the elements of the proposed REMS.
`Please note, the timetable for submission of the assessment is required to be
`approved as part of the REMS, but not the Applicant’s proposed information about
`the details of the REMS evaluation (methodology/instruments). The methodology
`and instruments do not need to be reviewed or approved prior to approval of the
`REMS.
`We have the following comments and recommendations for the Applicant with
`regard to the proposed REMS.
`Comments to PGxHealth, LLC:
`See the appended vilazodone HCL tablets REMS proposal (Appendix A of this
`memo) for track changes corresponding to comments in this review.
`a. GOAL
`Revise your goal as follows:
`The goal of this REMS is to inform patients about the serious risk associated with
`the use of vilazodone HCL tablets.
`b. Your Medication Guide distribution plan appears to be acceptable. Your detailed
`plan for how you plan to distribute the Medication Guide in accordance with 21
`CFR 208.24 is more appropriate for the REMS Supporting Document.
`• We remind you that under 21 CFR 208.24, you are responsible for ensuring
`that sufficient numbers of Medication Guides are provided with the product
`such that a dispenser can provide one Medication Guide with each new or
`refilled prescription.
`• We remind you that under 21 CFR 208.24, you are responsible for ensuring
`that the vilazodone HCL tablets carton or container label contains a
`prominent statement that the Medication Guide should be dispensed to each
`patient. We recommend one of the following statements, depending upon
`whether the Medication Guide accompanies the product or is enclosed in the
`carton (for example, unit of use):
`o “Dispense the enclosed Medication Guide to each patient.” Or
`o “Dispense the accompanying Medication Guide to each patient.”
`See our editorial comments on this section of the proposed REMS (see
`Appendix A).
`c. Your proposed timetable for submission of assessments (18 months, 3 years and 7
`years) is acceptable.
`We have some editorial comments in this section of the REMS.
`d. Regarding your REMS Assessment Plan
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`
`•
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`Reference ID: 2871971
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`We acknowledge that you provided a brief description of the REMS Assessment
`Plan. We recommend that you submit for review the detailed plan you propose to
`use to evaluate patients’ understanding about the safe use of vilazodone HCL
`tablets. You may submit the proposed plan after approval of the REMS, however
`submit it at least 90 days before you conduct the evaluation. Code the submission
`“REMS Correspondence.” Make sure the submission includes all methodology
`and instruments used to evaluate the knowledge about the risks associated with
`and safe use of vilazodone HCL tablets.
`If you plan to use a survey to conduct the assessment, we offer the following
`guidance as you develop your proposal.
`1. Recruit respondents using a multi-modal approach. For example, you might
`recruit respondents through physicians’ offices, pharmacies, managed care
`providers, consumer panels, or on-line.
`Explain how often you perform non-respondent follow-up or reminders.
`If you use an incentive or honorarium, provide details on what is offered and
`the estimated dollar value.
`Explain how you select recruitment sites.
`Submit for review any recruitment advertisements.
`2. Describe the rationale for your sample size. Report the 95% confidence
`interval around the expected level(s) of patient knowledge for each key
`risk(s).
`3. Define the expected number of people to be contacted to obtain the proposed
`sample size, and how the sample is determined (selection criteria).
`4. Ensure the sample is demographically representative of the population who
`use the drug (patients).
`5. When possible and appropriate, ensure the sample is diverse in terms of age,
`race, ethnicity, sex, socio-economic status, education level, and
`geographically.
`6. List the inclusion criteria. For example, eligible patient respondents must be:
`(cid:31) Age 18 or older
`(cid:31) Currently taking vilazodone HCL tablets or have taken the drug in the past
`3 months
`(cid:31) Not currently participating in a clinical trial involving vilazodone HCL
`tablets
`(cid:31) Not a healthcare provider
`Submit any screener instruments, and describe any quotas of sub-populations
`used.
`7. Explain how you administer surveys and the intended frequency.
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`Offer respondents multiple options for completing the survey. Be sure to
`include an option for the lower literacy population. For example, respondents
`might complete surveys online or through email, in writing or by mail, over
`the phone, and in person.
`Explain how you train surveyors.
`8. Explain how you control for limitations or bias associated with the
`methodology and survey instrument(s).
`9. Submit for review the introductory text used to inform respondents about the
`purpose of the survey.
`Tell potential respondents that their answers will not affect their ability to
`receive or take (patients) the drug, and that their answers and personal
`information will be kept confidential and anonymous.
`10. Clarify in your methodology that respondents are eligible for one wave of the
`survey only.
`11. The assessment evaluates the effectiveness of the REMS in achieving the goal
`by evaluating patients’ knowledge of the serious risks associated with use of
`the drug. The assessment does not evaluate consumer comprehension of the
`Medication Guide.
`According to regulation (21 CFR 208.24), patients receive the Medication
`Guide at the time the prescription is filled/dispensed. Do not offer respondents
`an opportunity to read or see the Medication Guide, Package Insert, or any
`other related educational materials again prior to taking the survey.
`12. Submit for review the survey instruments (questionnaires and/or moderator’s
`guide), including any background information on testing survey questions and
`correlation to the messages in the Medication Guide.
`13. Ensure the patient knowledge survey includes questions that ask about the
`specific risks or safety information conveyed in the Medication Guide to
`determine if the patient understands the information and knows what to do if
`they experience an adverse event.
`Derive the risk-specific questions from information located in the “What is the
`Most Important Information I should know about vilazodone HCL?” section
`of the Medication Guide.
`Ensure the risk-specific questions are not biased or leading, and that multiple
`choice questions include an instruction to “select all that apply.” Ensure that
`each question has an “I don’t know” answer option.
`Randomize the order of the multiple choice responses on each survey.
`14. Order questions so the risk-specific questions are asked first, followed by
`questions about receipt of the Medication Guide. Collect demographic
`questions last or as part of any screener questions.
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`Do not allow respondents the opportunity or ability to go back to previous
`questions in the survey.
`Explain if and when any education will be offered for incorrect responses.
`15. Include questions about receipt of the Medication Guide in the patient survey
`as a way to fulfill the obligation to report on the distribution of the Medication
`Guide.
`16. Prior to the questions about receipt of the Medication Guide, include text that
`describes a Medication Guide. For example,
`Now we are going to ask you some questions about the Medication Guide you
`may have received with vilazodone HCL tablets. The Medication Guide is a
`paper handout that contains important information about the risks associated
`with use of vilazodone HCL tablets and how to use vilazodone HCL tablets
`safely. Medication Guides always include the title “Medication Guide”
`followed by the word vilazodone HCL and its pronunciation. The Medication
`Guide usually has sections titled “What is the most important information I
`should know about vilazodone HCL,” “What is vilazodone HCL,” and “Who
`should not take vilazodone HCL.”
`17. Use the following (or similar) questions to assess receipt and use of the
`Medication Guide.
`(cid:31) Who gave you the Medication Guide for vilazodone HCL tablets? (Select
`all that apply)
`a) My doctor or someone in my doctor’s office
`b) My pharmacist or someone at the pharmacy
`c) Someone else - please explain: ________________________
`d) I did not get a Medication Guide for vilazodone HCL tablets
`(cid:31) Did you read the Medication Guide?
`a) All,
`b) Most,
`c) Some,
`d) None
`(cid:31) Did you understand what you read in the Medication Guide?
`a) All,
`b) Most,
`c) Some,
`d) None
`(cid:31) Did someone offer to explain to you the information in the Medication
`Guide?
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`Reference ID: 2871971
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`a) Yes, my doctor or someone in my doctor’s office
`b) Yes, my pharmacist or someone at the pharmacy
`c) Yes, someone else – please explain: _____________________
`d) No
`(cid:31) Did you accept the offer? Yes or No
`(cid:31) Did you understand the explanation that was given to you?
`a) All,
`b) Most,
`c) Some,
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`d) None
`(cid:31) Did or do you have any questions about the Medication Guide? Yes or No
`(If Yes, list your question(s) below) Note: Group/code this open text field
`prior to submitting to FDA
`18. Analyze results on an item-by-item or variable-by-variable basis. You may
`present the date using descriptive statistics, such as sample size, mean,
`standard deviation, median, minimum and maximum (for continuous
`variables), and frequency distributions (for categorical variables).
`You may stratify the data by any relevant demographic variable, and
`presented in aggregate. Submit with your assessments all methodology and
`instruments utilized.
`Please let us know if you have any questions.
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`Reference ID: 2871971
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`9 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately
`following this page.
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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.
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`/s/
`----------------------------------------------------
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`SHAWNA L HUTCHINS
`12/03/2010
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`CLAUDIA B KARWOSKI
`12/03/2010
`concur
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`Reference ID: 2871971
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`

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`REMS MEMO – NEW APPROVAL TEMPLATE
`May 18, 2009
`
`Risk Evaluation and Mitigation Strategy (REMS) Memorandum
`
`U.S. FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`Office of Drug Evaluation I
` Division of Psychiatry Products
`
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`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`NDA 22-567
`vilazodone HCl 10 mg, 20 mg, and 40 mg tablets
`PGx Health, LLC
`Ellis Unger, M.D., Office of Drug Evaluation I Deputy Director
`October 15, 2010
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`NDA/BLA #s:
`Products:
`SPONSOR:
`FROM:
`DATE:
`
`
`
`Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to
`require the submission of a risk evaluation and mitigation strategy (REMS) if FDA
`determines that such a strategy is necessary to ensure that the benefits of the drug
`outweigh the risks [section 505-1(a)]. Section 505-1(a)(1) provides the following factors:
`
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`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
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`(A) The estimated size of the population likely to use the drug involved;
`(B) The seriousness of the disease or condition that is to be treated with the drug;
`(C) The expected benefit of the drug with respect to such disease or condition;
`(D) The expected or actual duration of treatment with the drug;
`(E) The seriousness of any known or potential adverse events that may be related to
`the drug and the background incidence of such events in the population likely to
`use the drug;
`(F) Whether the drug is a new molecular entity (NME).
`
`
`After consultations between the Office of New Drugs and the Office of Surveillance and
`Epidemiology, we have determined that a REMS is necessary for vilazodone HCl to
`ensure that the benefits of the drug outweigh the increased risk of suicidality in children,
`adolescents, and young adults as observed in short-term studies of major depressive
`disorder (MDD) and other psychiatric disorders. In reaching this determination, we
`considered the following:
`
`A. The estimated size of the population likely to use the drug involved:
` While it is not possible to estimate the size of the population likely to use vilazodone
`HCl tablets for the indication of major depressive disorder (MDD), the life-time
`prevalence of MDD was 16.2% (32.6-35.1 million U.S. adults), and the prevalence
`for a 12-month period was 6.6% (13.1-14.2 million U.S. adults) in a survey of U.S.
`adults 18 years and older (Kessler et. al. 2003). 1
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`B. The seriousness of the disease or condition that is to be treated with the drug:
`
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`1 Kessler RC et al: The epidemiology of Major Depressive Disorder. JAMA 2003; 289:3095-3105
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`Reference ID: 2883057
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`Vilazodone HCl will be approved for the indication of treatment of MDD. MDD is a
`common disorder, widely distributed in the population, and usually associated with
`substantial symptom severity and role impairment. Patients with MDD have an
`increased risk of suicidality. MDD is associated with marital, parental, social and
`vocational difficulties. MDD may also complicate recovery from other medical
`illnesses.
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`C. The expected benefit of the drug with respect to such disease or condition:
`Vilazodone HCl has demonstrated efficacy in the treatment of MDD in clinical
`studies. Treatment has resulted in significant reduction across the range of depressive
`symptoms. Presumably, effective treatment can also lead to improvement in various
`spheres of functioning in patients with MDD.
`
`D. The expected or actual duration of treatment with the drug:
`The expected duration of therapy with vilazodone HCl in patients who obtain a
`clinical response will range from 6 months to many years, since MDD is considered a
`life-long disease, although the severity of symptoms may vary over time.
`
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`E. The seriousness of any known or potential adverse events that may be related to the
`drug and the background incidence of such events in the population likely to use the
`drug: Known serious risks associated with use of SSRI and SNRI antidepressants
`include clinical worsening and suicidality in children, adolescents, and young adults,
`serotonin syndrome, precipitation of a manic/hypomanic episode, abnormal bleeding,
`interaction with MAOIs, hyponatremia, potential for cognitive and motor impairment,
`and discontinuation symptoms. Because vilazodone has SSRI properties, these are
`potential risks associated with the use of vilazodone HCl.
`
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`F. Vilazodone HCl is a new molecular entity.
`
`In accordance with section 505-1 of FDCA and under 21 CFR 208, the FDA has
`determined that a Medication Guide is required for Vilazodone HCl tablets. FDA has
`determined that vilazodone HCl poses a serious and significant public health concern
`requiring the distribution of a Medication Guide. The Medication Guide is necessary for
`patients’ safe and effective use of vilazodone. FDA has determined that vilazodone HCL
`tablets is a product for which patient labeling could help prevent serious adverse effects
`and that the Medication Guide is important to health and patient adherence to directions
`for use is crucial to the drug’s effectiveness.
`
`The elements of the REMS will be a Medication Guide and a timetable for submission of
`assessments of the REMS.
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`
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`Reference ID: 2883057
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`2
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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.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILLIAM H BENDER
`01/04/2011
`
`ELLIS F UNGER
`01/04/2011
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`Reference ID: 2883057
`
`