CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`202788Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`
`
`
`
`

`

`
`Date
`December 13, 201 1
`
`From
`NDA/BLA #
`
`Su lement#
`
`IS—haronHertz, M.D.
`
`I20-2788
`
`_eview
`
`Date of Submission
`
`March 14, 2011
`
`4, 2012
`Jan .
`PDUFA Goal Date
`_—
`Proprietary Name /
`Subsys/ Fentanyl Sublingual Spray
`Established
`S .
`
`names
`
`Dosage forms / Strength
`
`Proposed Indication(s)
`
`Single dose sublingual spray/ 100 meg, 200 meg, 400 meg,
`600 meg, 800 meg
`Management of breakthrough pain in patients with cancer,
`18 years of age and older, who are already receiving and
`who are tolerant to regular opioid therapy for their
`underlying persistent cancer pain
`
`
`
`0ND Action Paeka - e, includin :
`
`CMC Review
`
`,
`
`Product Quality Microbiology
`Review
`
`Bryan Riley, Ph.D.
`
`OPDP/DDTCP
`
`Sharon Mills, BSN, RN, L. Shenee’ Toombs, Barbara
`
`Fuller, RN, MSN, LaShawn Griffiths, MSHS—PH, BSN,
`RN
`
`CSS Review
`
`'
`
`'
`
`, Ph.D., Silvia Calderon, Ph.D.
`
`Kathleen Davies, Sara Stradle
`
`NDA 202-788 CDTL Memo.doc
`
`Page 1 of 39
`
`Reference ID: 3064807
`
`

`

`
`
`1. Introduction
`
`
`This is a 505(b)(2) application for Subsys, a sublingual, transmucosal, immediate-release
`formulation of fentanyl packaged in a single-dose spray device. During development, the
`product was referred to as fentanyl sublingual spray and is referred to as FSS throughout this
`review. The listed drug referenced by this application is Actiq (NDA 20-747). For this
`reformulation of fentanyl, one efficacy study, several pharmacokinetic studies and two open-
`label safety studies were submitted in support of this application.
`
`
`2. Background
`
`
`This application represents the sixth NDA for a transmucosal immediate-release fentanyl
`(TIRF) product indicated for the management of breakthrough pain in patients with cancer, 18
`years of age and older, who are already receiving and who are tolerant to regular opioid
`therapy for their underlying persistent cancer pain. Actiq was the first oral transmucosal
`fentanyl product approved and is a lozenge on a stick that is moved between the gum and the
`buccal mucosa. Actiq was approved under Subpart H, in large part because of the risk for
`accidental pediatric exposure due the similarity in appearance to a lollipop. A RiskMAP was
`created to attempt to manage the risks associated with this product. In addition to providing
`some methods to try and minimize the risk for accidental pediatric exposure, other goals
`described in the RiskMAP included preventing use in opioid non-tolerant patients and other
`unsafe off-label use. Fentora (NDA 21-947) was the second oral transmucosal fentanyl
`formulation approved and is a tablet that is placed between the buccal mucosa and gum where
`it dissolves with an element of effervescence. Fentora was approved with a RiskMAP
`comparable to Actiq.
`
`Onsolis (NDA 22-266), Abstral (NDA 22-510) and Lazanda (NDA 22-569) followed Actiq
`and Fentora. Onsolis is formulated as a bioerodible membrane that adheres to the buccal
`mucosa. Abstral is a sublingual tablet formulation. Lazanda is formulated as a nasal spray.
`These three products were approved with risk evaluation and mitigation strategies (REMS).
`The reason for the switch to a REMS is described below.
`
`The indication for this group of products, the management of breakthrough cancer pain in
`adult patients who are already receiving, and who are tolerant to, opioid therapy for their
`underlying persistent cancer pain is narrow for two reasons. First, the population identified
`has a specific need for a treatment to address cancer-associated breakthrough pain, which is
`characterized by a quick onset, often high severity, and relatively short duration. These
`formulations of fentanyl are designed to have a relatively rapid rise to Cmax and a relative
`short duration of effect. Fentanyl is a very potent opioid that can cause respiratory depression
`in microgram quantities. For this reason, the indication also reflects the need for patients to be
`opioid-tolerant, a physiological state in which patients are more tolerant to the CNS depression
`and respiratory depression associated with opioids.
`
`
`NDA 202-788 CDTL Memo.doc
`
`
`
`Page 2 of 39
`
`
`
`Reference ID: 3064807
`
`

`

`Based on the postmarketing history of the approved products, it became clear that prescribers
`have found the TTRFs to be useful in patients without cancer pain, both in the setting of
`chronic pain with episodes of breakthrough pain and other painful conditions. In the Actiq
`RiskMAP quarterly reports, the use of Actiq in noncancer pain has exceeded its use in cancer
`pain, although it is used primarily in opioid-tolerant patients with chronic noncancer pain.
`
`Postmarketing trends have also shown an increasing number of nonopioid—tolerant patients
`being prescribed TIRFs and reports of deaths in opioid nontolerant patients. The TIRFs are
`not bioequivalent with one another, and in spite of warnings in the labeling, have been
`inappropriately substituted in the pharmacy and by prescribers. As a result, the Agency
`determined the risks associated with these products would be better addressed through a
`REMS than the original risk management programs. Abstral, Onsolis and Lazanda were
`approved with REMS. To reduce the burden to the healthcare community, a TIRF class
`REMS has been developed. All five of the previously approved products are being rolled into
`this class REMS including Actiq and Fentora which have yet to stand up their own individual
`REMS. Subsys will be a part of this class REMS as well.
`
`3. CMClDevice
`
`The following is from Dr. Pinto’s review:
`
`The drug substance, fentanyl base, is a narcotic analgesic and a Schedule H controlled
`substance that binds to opioid receptors. The Chemistry, Manufacturing, and Control
`(CMC) information for Fentanyl base is provided in DNIF
`(hm)
`. The API is made by
`(m4) at their
`(m4) facility which is
`recommend as adequate by CC (report attached in the appendix). The API will be
`stored and shipped in
`mm
`and has a retest period of
`m“). The DIVIF has been reviewed and found to be
`adequate (P. Maturu, Rev #4 June 2009 and J. Pinto, Rev #5, Oct 2011).
`
`The drug product is formulated as a sublingual, single-dose spray in concentrations of
`1 mg/ml, 2 mg/ml, 4 mg/ml, 6 mg/ml and 8 mg/ml, with a total fill per vial 01
`“M" The
`dose is
`M“)
`m“) The formulation consists of the
`
`active substance, in dehydrated alcohol, propylene glycol, water, xylitol and menthol. The
`pump consists of an actuator, insert, spray pin, needle, stopper, glass vial and vial holder. (m4)
`
`Three packaging configurations are planned containing 6, 14, or 28 devices in a carton. Each
`carton includes a disposal system to accommodate both used and unused devices. The disposal
`system consists of a plastic container
`(m4) and a sealable pouch. The
`mmcontainer is used for the collection and disposal of fentanyl solution from unused FSS
`units; the pouch is designed for the disposal of used/discharged FSS units. The DP is made by
`DPT at their Lakewood, NJ facility which was inspected has been recommended as adequate.
`
`NDA 202—788 CDTL Memo.doc
`
`Page 3 of 39
`
`Reference ID: 3064807
`
`

`

`m“) bottle, holding 28 units of the
`Dr. Pinto reviewed extraction studies of the
`maximum strength drug product. The studies were intended to evaluate the amount of
`recoverable fentanyl. The results show that there is some recovery of fentanyl with extraction
`using acetone, alcohols (dehydrated, isopropanol), ethyl acetate and 6N HCl. The most
`fentanyl recovered was
`mu) using dehydrated ethanol which is equivalent to about 1.3%.
`Heat, shaking, and pH adjustments, did not result in any additional fentanyl being extracted.
`This is discussed further in Section 11.
`
`The used FSS spray devices are intended to be placed in an unlabeled sealable pouch that is
`disposed in the trash. Unused devices are to be disposed of in the pouch after the contents are
`sprayed into a
`(mu) disposal system. The system consists of a 100 cc plastic (HDPE)
`bottle
`W"
`
`Each individual FSS unit will be enclosed in a child-resistant blister package. As reviewed by
`Dr. Reissig of the Controlled Substances Staff, in a test of 50 children (n=50), aged 42-51
`months, the FSS package was found to be 98% child resistant.
`
`The recommended storage temperature is 25° C (77° F) with excursions permitted from 15° to
`30°C (59°-86°F) and an expiry of 36 months is supported.
`
`Dr. Pinto concluded that there were sufficient CMC data to assure the identity, strength, purity,
`and quality of the drug product, provided in the NDA submission. The drug substance
`manufacture and product attributes were referenced to DMF M“, which was reviewed as
`Adequate (P. Maturu, June 2009 and J. Pinto, Rev #5, Oct 2011). The Office of Compliance
`has issued an “Acceptable” overall recommendation for all facilities involved in production of
`the product.
`
`There were two outstanding deficiencies in the drug product stability protocol and stability
`specifications identified by Dr. Pinto in her initial review. The applicant has responded to
`information requests as noted below:
`
`1. There are insufficient data to support the lack of testing for both weight loss and
`ethanol content for batches made at the
`(m4) (commercialization).
`(m4)
`
`comments have been sent to the sponsor:
`
`. Therefore the following IR
`
`IR (4): There is insufficient commercial scale product history, to support the lack of
`testing for both weight loss and ethanol assay during stability. Maintain both the
`ethanol assay test and the weight loss test during routine stability testing. Further
`propose a release and stability specification for weight loss.
`
`NDA 202—788 CDTL Memo.doc
`
`Page 4 of 39
`
`Reference ID: 3064807
`
`

`

`Response: The applicant agreed to continue to test both weight loss and ethanol assay during
`stability and provided updated specifications and a stability study protocol. Dr. Pinto found
`this response to be adequate.
`
`IR(5): There is insufficient commercial scale product history, to support the
`proposed for stability testing. The first three production scale batches and a
`yearly production batch of the 4mg/ml intermediate strength is to be included in the
`stability study.
`
`m“)
`
`Response: The applicant has committed to testing the first three production scale batches and a
`yearly production batch of the 4mg/ml intermediate strength in the stability study. The annual
`stability batches will include the lmg/ml, 4mg/ml and 8mg/ml batches. Dr. Pinto found this
`response to be adequate.
`
`IR(6).
`
`(b) (4)
`. Update the release
`and stability specifications to include testing for pH with data driven acceptance
`criterion.
`
`Response: The applicant has added the pH testing parameter to the release and stability
`specifications. A pH range was not proposed as a specification, but will be added once
`sufficient data is collected on the full scale batches. Dr. Pinto found this response to be
`adequate.
`
`In addition, she also notes the following deficiencies:
`
`IR (3): The specification proposed for Spray Actuation Content is not in accordance
`with the FDA guidance for Nasal Sprays. Tighten the proposed specification to be in
`agreement with the FDA guidance (e.g., individual sprays to within $15 percent of the
`target weight and their mean weight to within 1:10 percent of the target weight).
`
`Response: The applicant has requested to retain the currently proposed specification until data
`from the full scale batches become available. At that time, they commit to providing an update
`on the specification in the annual report. The current specification is
`“(4)
`
`Dr.
`
`Pinto found this response adequate a this is a single spray and the sponsor does not have
`sufficient data, this parameter can be evaluated once there is sufficient data.
`
`“mmust meet
`The microbiology review by Dr. Riley notes that this product
`microbial limits acceptance criteria at release. The initial acceptance criteria submitted by the
`applicant were
`(mm the acceptance criteria for a liquid oral product suggested by USP,
`but the administered dose is small enough that the
`(m4) acceptance criteria are not of concern
`and are acceptable. Similarly, while aqueous drug products should have controls in place to
`ensure the absence of Burkholderia cepacia, since this product is
`(m4), there is no
`concern for B. cepacia.
`
`NDA 202—788 CDTL Memo.doc
`
`Page 5 of 39
`
`Reference ID: 3064807
`
`

`

`A consultative review was conducted by LCDR Alan Stevens of CDRH. LCDR Stevens
`reviewed the device constituent for this Combination Product and provided an assessment of
`the Failure Modes and Effects Analysis. He found the following deficiencies:
`
`1. You have provided a design failure modes and effects analysis. For each component,
`you have identified potential failure modes and associated causes. You claim to have
`identified design controls for each failure mode and, based on the analysis, conclude
`that no further mitigations are required. However, no design controls are identified.
`Instead, the dFMEA has identified manufacturing controls. Please modify the dFMEA
`to identify design controls and provide evidence that implementation of the design
`controls are effective.
`
`Dr. Ryan reviewed the response from the applicant and found the dFMEA submitted was
`comprehensive and that all of the risk priority numbers fell within an acceptable range. The
`most common failures resulted in under dosing or no doses. The failures have4 a severity
`rating of three or less which Dr. Ryan notes is acceptable. She concludes the device issue is
`adequately resolved.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The following is from Dr. Bolan’s review.
`The pharmacology and toxicology of fentanyl have been well characterized. No nonclinical
`toxicology studies were deemed necessary to characterize the safety of fentanyl for this
`product unless abnormalities arose during monitoring of pulmonary function in the clinical
`studies. No abnormalities in pulmonary function were noted in the clinical studies therefore, no
`nonclinical studies with fentanyl were conducted.
`
`The excipients used in the FSS formulation are all found at higher levels in drugs previously
`approved by FDA and do not pose any toxicologic concerns. Extractable and leachable
`assessments were conducted with the
`(m4) FSS container closure
`system. Drug Master File mwfor the
`W" is referenced by the
`Applicant. The
`M“) are used in over 150 approved drugs, many with similar aqueous
`formulations to F58. The Agency’s previous finding of safety for the
`m4) material will be
`relied on in order to support its safety.
`
`The impurifiesldegradants in the drug substance and drug product are controlled at acceptable
`levels. A structural alert for mutagenicity was identified in the drug product degradant
`W" The Applicant conducted an Ames Assay which showed a negative
`result for mutagenicity, therefore “M" can be regulated as a typical non-genotoxic impurity
`according to ICH Q3B(R2). The drug product specification set for “M" in this NDA is
`acceptable.
`
`There are no unique nonclinical issues associated with this product compared to the
`referenced fentanyl product. There are no outstanding concerns with this NDA that would
`preclude approval. The recommendation from Pharmacology/Toxicology is that NDA 202788
`be approved with no post-marketing requirements.
`
`NDA 202-788 CDTL Memo.doc
`
`Page 6 of 39
`
`Reference ID: 3064807
`
`

`

`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`The applicant submitted four clinical pharmacology studies in support of this application.
`Three studies were in healthy subjects: a pilot, single ascending dose PK study, a single-dose
`relative bioavailability study (BA), and a single-dose, crossover, dose proportionality study
`that included an evaluation of the effects of temperature and pH. One study enrolled cancer
`patients to evaluate the effects of oral mucositis on PK.
`
`As summarized by Dr. Qiu, fentanyl is highly lipophilic. The plasma protein binding is 80-
`85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins
`contribute to some extent. Fentanyl is metabolized in the liver and in the intestinal mucosa to
`norfentanyl by cytochrome P450 3A4. Norfentanyl was not found to be pharmacologically
`active in animal studies. Fentanyl is primarily (more than 90%) eliminated by
`biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the
`dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in feces.
`The metabolites are mainly excreted in the urine.
`
`As described by Dr. Qiu, the mean absolute bioavailability of Fentanyl Sublingual Spray 400
`mcg in comparison to fentanyl citrate intravenous injection 100 mcg was 72.1% or AUClast
`and 75.6% for AUCinf, normalized for dose. One 400 mcg spray of FSS resulted in 34% and
`36% greater Cmax and AUCinf values, respectively, compared to an Actiq dose of 400 mcg,
`under fasting conditions.
`
`The average Tmax ranged between 1.25 hours for the 100 mcg and 200 mcg doses to 0.67
`hours for the 600 mcg dose. The mean half life was 5.25 hours for the 100 mcg dose, 8.45
`hours for the 200 mcg dose, and up to 11.99 hours for the 800 mcg dose. While the half-life
`seems long for a drug intended to treat a breakthrough pain, the shape of the PK profile
`demonstrates a large early peak with a long tail as shown in the figure 1 (p. 8) from Dr. Qiu’s
`review. The shape of the PK profile is compatible with the intended use of the product.
`
`Figure 1 Mean Fentanyl Concentration-Time Profiles after Administration of Single Doses of Fentanyl
`Sublingual Spray 100 mcg (Treatment A), 200 mcg (Treatment B), 400 mcg (Treatment C), 600 mcg
`(Treatment D), and 800 mcg (Treatment E) from Study INS-06-004
`
`
`
`
`
`
`NDA 202-788 CDTL Memo.doc
`
`
`
`Page 7 of 39
`
`
`
`Reference ID: 3064807
`
`

`

`
`
`The systemic exposure of fentanyl increased in an approximately dose proportional manner
`over the 100 mcg to 800 mcg range, under fasting conditions based, on Cmax and AUC,
`except for the lower bound of the 90% confidence interval which was slightly low for the
`Cmax of the 600 mcg dose relative to the 800 mcg dose and for the 100 mcg and 200 mcg
`doses for AUC.
`
`There was no clinically important effect from pre-treating the oral cavity with hot or cold
`water. There were small decreases in fentanyl exposure after pretreatment with a low pH
`beverage and small increases following a high pH beverage, but these were small enough to be
`of no clinical importance.
`
`There were important findings in cancer patients with oral mucositis. In patients with Grade 1
`mucositis, mean fentanyl Cmax and AUClast values were 73% and 52% greater, respectively,
`than with patients without mucositis following the administration of a 100 mcg fentanyl
`sublingual spray.
`
`Two patients with Grade 2 mucositis were studied. Fentanyl Cmax values were 7-fold and 4-
`fold greater than the mean Cmax values obtained in patients without mucositis for the two
`patients. However, the highest Cmax in the Grade 2 mucositis patient was only 3-fold greater
`than the highest Cmax in the group without mucositis. The corresponding fentanyl AUClast
`values were 17-fold and 3-fold higher than the average values in patients without mucositis.
`Figure 2 from Dr. Qiu’s review (p. 10) shows the individual PK profiles of patients without
`mucositis on the right and with mucositis on the left. In the figure on the left, the PK profile
`with the notably high fentanyl concentrations was from one of the patients with Grade 2
`mucositis.
`
`Figure 2. Fentanyl plasma concentration-time profiles in subjects without mucositis (left panel)
`and subjects with mucositis Grade 1 or 2 (right panel) from Study INS-09-011
`
`
`
`Dr. Qiu recommended avoiding the use of fentanyl sublingual spray in patients with Grade 2
`and worse mucositis and dose reduction should be done for the patients with Grade 1
`mucositis. I agree with Dr. Qiu that there is no clinically important effect of temperature or
`
`
`
`
`
`NDA 202-788 CDTL Memo.doc
`
`
`
`Page 8 of 39
`
`
`
`Reference ID: 3064807
`
`

`

`pH. Based on the information submitted with the original NDA, I also concurred that FSS
`should not be used by patients with Grade 2 mucositis or higher and that there should be a
`contraindication for this population. As the starting dose of FSS is 100 mcg, the lowest dose,
`there is no way to reduce the starting dose for patients with Grade 1 mucositis. However, as
`patients using FSS are meant to be opioid-tolerant, increased monitoring for respiratory and
`central nervous system depression when initiating dosing is sufficient to ensure patient safety.
`
`(I!) (4)
`
`the applicant sought additional information about the
`patient with the 17-fold increase in AUC. According to additional information obtained after
`the investigator contacted the patient’s family member, the patient brought Actiq to the study
`site and surreptitiously used the Actiq during the study. An amendment to the NDA was
`submitted December 20, 2011 documenting this. It is hard to understand exactly how a subject
`could use an Actiq dose without detection during a clinical pharmacology study, but the
`sustained fentanyl level over 12 hours does seem more compatible with additional dosing of a
`fentanyl product as an explanation. The mean oral bioavailability of FSS is approximately
`70%. If mucositis resulted in a 100% exposure to the fentanyl, it would not result in a 17-fold
`increase in AUC. However, the fentanyl level was 0 at baseline and without more information,
`it is not possible to know whether the Cmax was influenced by the use of Actiq or not, and the
`Cmax was approximately 3-fold higher than the highest Cmax in the non—mucositis patients in
`the study. Given that the intended population is opioid-tolerant, and given that the patient with
`Grade 2 mucositis in question tolerated the high levels of fentanyl without respiratory
`depression, it seems reasonable not to contraindicate the use of FSS in patients with Grade 2
`mucositis. In place of the recommendation will be a recommendation to avoid use of FSS in
`patients with Grade 2 mucositis or higher unless the benefit is expected to outweigh the
`possible risk of respiratory depression.
`
`6. Clinical Microbiology
`N/A
`
`7. Clinical/Statistical- Efficacy
`
`With five approved products in the TIRF class, there has been a fair amount of experience with
`understanding the efficacy of these products. Fentanyl, a mu opioid agonist, is a known
`analgesic, available as intravenous, transmucosal and transdermal formulations. The current
`application relies on the Agency’s prior findings of efficacy for Actiq, the listed drug
`referenced in the application, and one adequate and well controlled clinical trial. As FSS
`delivers fentanyl with a PK profile similar to Actiq, but not bioequivalent, the clinical trial was
`required to confirm that this new formulation provides efficacy in the intended population.
`
`Drs. Yip and Zhou have reviewed Study 1NS-05-001 in detail. This was a multicenter,
`placebo-controlled, 10—period crossover study in opioid—tolerant cancer patients with
`breakthrough pain. Key inclusion criteria included adult patients with a diagnosis of cancer
`and persistent cancer pain or its treatment of moderate or less intensity, taking at least 25 meg
`
`NDA 202—788 CDTL Memo.doc
`
`Page 9 of 39
`
`Reference ID: 3064807
`
`

`

`
`
`of transdermal fentanyl per hour or 60 mg of oral morphine per day, 30 mg of oxycodone per
`day, 8 mg of oral hydromorphone or equivalent per day, around-the-clock, for at least one
`week, and, on average, one to four episodes of BTCP over the previous week at least partially
`controlled by supplemental medication of at least 5 mg immediate-release morphine or an
`equivalent short-acting opioid (e.g., oxycodone, hydrocodone, or acetaminophen with
`codeine.) Key exclusion criteria included the presence of painful erythema, edema or ulcers
`under the tongue, brain metastases, or clinically relevant abnormalities in vital signs, liver
`enzymes or serum creatinine. Concomitant use of CYP 3A4 inducers or inhibitors was
`prohibited.
`
`Patients not using Actiq or Fentora prior to the study were titrated onto FSS according to the
`following algorithm:
`
`
`(cid:131)
`
`(cid:131)
`
`(cid:131)
`
`(cid:131) Start with the 100 mcg dose of FSS. Treat one episode of breakthrough pain.
`(cid:131)
`If this dose was effective and tolerated, the next episode of was treated with the same
`dose of FSS.
`If pain relief was inadequate after 30 minutes then the patient was to re-dose with one
`additional FSS dose.
`If the pain continued for 30 minutes following the re-dose, patients were instructed to
`take their usual analgesic medication as rescue medication.
`If a patient consistently required an additional 100 mcg of FSS at two subsequent
`breakthrough pain episodes, the patient proceeded to the next higher FSS dose
`strength, 200 mcg.
`
`
`This continued until a successful dose was identified or a maximum dose of 1600 mcg (two
`800 mcg sprays) failed to work and the patient then exited the study. Patients previously using
`Actiq or Fentora were allowed to begin on doses of FSS greater than 100 mcg based on their
`prior TIRF doses and then continued with titration according to the algorithm.
`
`Patients were titrated to a successful dose, defined as a dose of FSS that consistently treated
`two consecutive breakthrough pain episodes and that was tolerated, and were supplied with a
`10-dose drug pack containing 10 separate unit doses, marked 1 to 10. Patients were instructed
`to self-administer each dose, starting at unit dose 1 and working through to unit dose 10, in
`order, for each of 10 individual episodes of target breakthrough cancer pain. Patients were
`instructed to wait at least four hours between treated breakthrough pain episodes, and to treat
`no more than two breakthrough pain episodes with study drug in a given day.
`
`One hundred and sixty-one patients were screened and 131 were enrolled in the study. One
`patient never received study drug. Of the 130 patients that entered titration, 32 (25%)
`withdrew prior to entering the double-blind crossover phase of the study. Dr. Yip explored the
`reasons for discontinuation during titration and the most common reasons were adverse events
`and inability to titrate to a successful dose.
`
` A
`
` total of 45 patients were identified as having protocol violations One patient (Subject
`110003) was discontinued from the study during the titration period for a protocol violation.
`The patient was found to have lied about having cancer and, in fact, did not have cancer. The
`
`NDA 202-788 CDTL Memo.doc
`
`
`
`Page 10 of 39
`
`
`
`Reference ID: 3064807
`
`

`

`
`
`patient was not included in the double-blind period. Two patients (Subject 110-007 and 110-
`006) were noted as not meeting the inclusion criterion of “experience persistent pain related to
`the cancer or its treatment of moderate or lesser intensity in the 24 hours prior to assessment
`by a verbal rating scale at the Screening Visit” and waivers were not granted for their
`participation. The Applicant was asked why the patients were enrolled and included in the
`study and queried the investigator. The response was that both patients had persistent cancer
`pain that was rated as severe at screening, but generally had pain of moderate intensity and so
`were enrolled. Based on this explanation, including these patients appears acceptable. The
`remaining violations were reviewed and were not sufficient to warrant discontinuation from
`the study.
`
`Of the 98 patients who entered the double-blind period, three patients discontinued early, and
`79 completed all 10 doses of blinded study drug. Patient disposition is presented in the
`following table from Dr. Zhou’s review.
`Table 1 Patient Disposition
`
`Source: Table 2 (p. 8) from Dr. Zhou’s review
`
`The demographic characteristics of the study population are presented in the following table
`from Dr. Zhou’s review. As a crossover design, there were no concerns about imbalance
`across treatment groups. The study patients were mostly white and less than 65 years of age.
`
`Table 2
`
`
`
`NDA 202-788 CDTL Memo.doc
`
`
`
`Page 11 of 39
`
`
`
`Reference ID: 3064807
`
`

`

`
`
`Source: Table 3 (p. 8) from Dr. Zhou’s review
`
`The final dose after titration ranged from 100 mcg to 1600 mcg. The distribution of final
`titrated dose is presented in the following table.
`
`
`
`NDA 202-788 CDTL Memo.doc
`
`
`
`Page 12 of 39
`
`
`
`Reference ID: 3064807
`
`

`

`
`
`Table 3 Final titrated dose.
`SUBSYS Dose
`
`Total No. (%)
`n=96
`4 (4%)
`7 (7%)
`14 (15%)
`15(16%)
`23 (24%)
`20 (21%)
`13 (14%)
`
`100 mcg
`200 mcg
`400 mcg
`600 mcg
`800 mcg
`1200 mcg
`1600 mcg
`
`The primary efficacy analysis was the summed pain intensity difference over 30 minutes
`(SPID30), based on the mean of the SPID30 across each episode for each treatment, i.e. the
`seven active-treated episodes were averaged and the three placebo-treated episodes were
`averaged. As noted by Dr. Zhou, her analysis differed from the applicants in that she included
`all 96 patients in the ITT population, regardless of the number of episodes treated and whether
`they were compliant with treatment order. Using the full ITT population, excluding data
`subsequent to the use of rescue mediation, and using last observation carried forward to impute
`missing values, Dr. Zhou was able to replicate the applicant’s primary analysis and
`demonstrate that FSS was statistically superior in reducing pain intensity using the SPID30.
`The following table shows Dr. Zhou’s results from the primary efficacy analysis.
`
`Table 4
`
`
`
`Source: Table 5 (p. 10) from Dr. Zhou’s review
`
`Dr. Zhou conducted subgroup analyses for gender and age. She found no statistically
`significant interaction between gender and treatment, although there was an interaction
`between age and treatment, with a smaller effect size for older patients. Statistically
`significant differences in favor of FSS for the SPID30 analysis remained for both groups,
`patients under the age of 65 and patients 65 years of age and older. These results are shown in
`the following table.
`
`
`
`
`
`
`NDA 202-788 CDTL Memo.doc
`
`
`
`Page 13 of 39
`
`
`
`Reference ID: 3064807
`
`

`

`
`
`Table 5
`
`
`Source: Table 6 (p. 11) from Dr. Zhou’s review
`There were too few non-white patients (13%) for a meaningful subgroup analysis based on
`race.
`
`The secondary efficacy analyses included total pain relief at 30 minutes (TOTPAR30) and
`Patient Global Evaluation of Study Medication at 30 minutes. These analyses found
`statistically significant difference between active and placebo treatments in favor of the active
`drug. Additional analyses of SPID and TOTPAR at 5, 10, 15, 45 and 60 minutes were
`conducted by the applicant on an evaluable population of 92 patients. The applicant claimed
`these were statistically significantly different between treatments and favored active drug,
`however, these evaluations were not corrected for multiplicity and were not repeated with the
`full ITT population as they are not included in labeling.
`
`In addition, the use of rescue medication was examined by the applicant. Among the
`evaluable population, rescue medication was used by patients during 28% of episodes treated
`by placebo compared to 10% of episodes treated by active drug.
`
`Overall, Study INS-05-001 was successful in demonstrating the efficacy of FSS in reducing
`breakthrough pain in opioid-tolerant cancer patients.
`
`
`8. Safety
`
`
`The applicant describes 490 subjects exposed to FSS and making up the safety database,
`however 107 patients from two PK studies were pretreated with naltrexone and so, would not
`have been able to contribute safety data other than local reactions. Study INS-09-011 was a
`single dose study of FSS in cancer patients evaluating the effects of mucositis enrolling 18
`subjects. The primary safety database is based on studies INS-05-001 (Study 001), the
`efficacy study, and INS-06-007 (Study 007), an open-label safety study lasting up to 90 days
`that rolled patients over from Study 001 and enrolled novel patients. There were 359 subjects
`who took a least one dose of FSS from these two studies that contributed to the safety
`database. The 359 patients represent 130 patients who underwent titration and 98 who entered
`the double-blind period of Study 001, 90 who rolled over from Study 001 to Study 007, and
`179 novel patients who enrolled in Study 007.
`
`
`NDA 202-788 CDTL Memo.doc
`
`
`
`Page 14 of 39
`
`
`
`Reference ID: 3064807
`
`

`

`
`
`The extent of exposure from Studies 001 and 007 is presented in the f