V,.—.~\
`
`the 6-month safety data is derived from Study LVBL, wherein all 1169 patients received the
`10 mg dose for one month prior to up-titration to 20 mg.
`
`The total number of medically significant cardiovascular adverse events in the entire
`NDA was so small as to preclude adequate assessment of potential relationship to Cialis.
`These events include syncope, angina pectoris, chest pain, arrythmia, myocardial infarction,
`heart failure, ccrebrovascular accident, and cardiac arrest. There were a few reports of these
`types of events occurring during the immediate post-dosing period. These could be plausibly
`related to Cialis. In order to absolutely rule out Cialis as the cause of these events, very large
`controlled trials might be necessary. Are such trials possible or necessary in the pre-
`marketing period? In the post-marketing period? Would studies of surrogate markers be
`useful? For example, the sponsor has actively ongoing trials assessing the potential effect of
`Cialis on coronary blood flow using PET scanning and on cardiac stress test performance in
`men with stable angina. My final recommendation on this issue at this moment would be to:
`a.
`obtain the results from coronary artery PET scanning (LVBZ).
`b. obtain the results from stress testing in patients with stable coronary artery disease
`(LVCP).
`c. obtain the results from a larger and better controlled QT study.
`d.
`request the sponsor derive QTc data from Study LVBS (using dosage strengths up to
`500 mg).
`request the sponsor submit a detailed analysis of the effect of Cialis on the
`cardiovascular system (from all NDA data sources), and
`review this entire “cardiovascular package” in consultation with the Division of
`Cardio—Renal Drug Products and/or the Cardio—Renal Advisory Committee.
`
`e.
`
`f.
`
`Assessments of the interaction with nitrates were not adequate to fully appreciate and
`manage the risk to those patients who have urgent need for therapy with nitrates after
`taking Cialis. This is particularly relevant to Cialis due to its approximately 17 hour half—1ife
`which is prolonged by 5 hours in the elderly and by perhaps even longer in men with renal
`insufficiency.
`
`Assessments of the QT interval were not adequate to completely assess the potential for
`Cialis 20 mg to prolong the QT interval. Assessments of QT were not conducted at high
`enough doses, nor with enough patients. Assessments of the potential for the metabolite
`methylcatechol glucuronide to prolong QT were not conducted.
`
`Assessment of safety of the 20 mg dose in patients with clinically significant renal
`insufficiency were not adequate to assess risk in that population. Based upon the
`diminished clearance in patients with at least mild renal insufficiency, the resultant increase
`in exposure by two times, the resultant prolongation of exposure to tadalafil metabolites, and
`the limited safety information at those exposures (e.g. following doses of 40 mg and higher),
`it is not possible to predict safety outcomes in this population. This concern is compounded
`by the exclusion of patients with clinically significant renal insufficiency in the clinical trials
`and the increased incidence of unexplained adverse events (e.g. myalgias and back pain) in
`these patients in clinical pharmacology trials.
`
`Assessments of safety in the diabetic population were not adequate to assess risk in that
`population. Only 119 diabetics received 20 mg in all Phase 3 pivotal trials combined and of
`that total, only 47 were not pre-screened for the presence of orthostatic hypotension at
`baseline (as in Study LVBK).
`
`MonoSo1 1018-0001
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`MonoSo1 V. ICOS
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`IPR2017-00412
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`MonoSol 1018-0001
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`MonoSol v. ICOS
`IPR2017-00412
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`8. Assessments in humans to explain the pathophysiology of the adverse event terms
`“myalgia” and “back pain” were not adequate. I believe that there is a need to provide
`reasonable assurance in humans that these symptoms do not reflect medically significant
`underlying pathophysiology. The sponsor has not aggressively sought the etiology of these
`symptoms. This concern is compounded by the fact that the incidence and severity of
`myalgias and back pain appear to increase with higher dose and higher exposure to tadalaiil.
`
`9. The potential for interaction between tadalafil and alcohol as evidenced by findings in
`the 10 mg dosage strength study has not been acknowledged by the sponsor. There are
`no labeled precautions nor warnings for this potential interaction.
`
`10. Interactions between some anti-hypertensive medications and tadalafil have not been
`conducted at the 20 mg dose. In addition, some interactions with the 10 mg dosage
`strength have not been fully acknowledged by the sponsor. The potential for more
`significant and severe drug interactions in the renally and hepatically impaired has not been
`considered.
`
`11. Assessments of interactions with warfarin and with aspirin were not conducted with the
`20 mg dosage strength. This is particularly relevant given the recognized potential for
`phosphodiesterase inhibition to adversely effect platelet function.
`
`12. Assessments of an interaction between Cialis and certain widely used alpha-adrenergic
`antagonists were not conducted. In this respect, potential for interaction was conducted
`using the alpha blocker least likely to show an interaction (tarnsulosin). This is especially
`important since many of the same middle-aged and elderly men who will receive Cialis are
`also candidates for concomitant treatment for symptoms of benign prostatic hypertrophy
`(BPH).
`
`Other deficiencies that are significant in my view but do not rise to the level of a “not
`approvable” deficiency are listed below:
`
`1. The Division of Scientific Investigation’s (DSI) decision not to conduct routine inspections of
`all relevant pivotal trials is considered an outstanding item in the FDA’s review. Given the
`relative paucity of medically significant adverse events in the entire Phase 3 program and
`disparities in adverse event reporting incidences between Canada, Australian, and U.S. trials
`and the others (e.g. Taiwan and Spain), I advocate inspection of each trial that is intended to
`support the approval of Cialis.
`
`2. The sponsor should describe the percentage of patients in the Phase 3 trials who previously
`used sildenafil, who previously responded to sildenafil, and who previously tolerated
`sildenafil. In addition, the sponsor does not make plainly evident that there were no sildenafil
`“failures” included in the Phase 3 clinical program.
`
`3. ,, T
`
`m_ T
`
`4. There is a single manufacturing site in Indiana (Eli Lilly) for which the final recommendation
`from Office of Compliance is pending. At this moment, there appears to be good
`manufacturing practice (GMP) deficiencies.
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`M0nQS0l 1018-0002
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`MonoSol 1018-0002
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`5. Assessments of effects on vision were so flawed as to provide little useful data (as per Dr.
`Chambers). The sponsor should conduct new studies in order to assess the impact of tadalafil
`on vision.
`
`2. Background
`
`Erectile dysfunction (ED) has been defined has the inability of the male partner to attain and
`maintain an erect penis in the context of the overall sexual experience. Over the past decade, our
`understanding of the condition has rapidly advanced. It is well-recognized that many, if not most
`cases of erectile dysfunction have an “organic” component. In fact, we have come to realize that
`vascular smooth muscle dysfunction is a major reason for ED. We now understand ED to be a
`multifaceted disease impacted by numerous systemic forces including atherosclerosis, diabetes,
`renal insufficiency, heart disease, smoking, alcohol use, other endocrinopathies, traumatic injury,
`neurologic dysfimction, psychological disturbances, concomitant medications, among a plethora
`of others conditions and factors.
`
`For years, practitioners have been faced with these patients, often in urgent need of help for this
`condition. For quite some time, the only available modalities of treatment were psychological
`counseling, unapproved and approved herbal therapies, devices such the vacuum erection device
`(VED), and surgical implantation of semi-rigid and (recently) inflatable rods. Over the last few
`years, there has been a rapid advancement in the understanding of pharmacologic modalities to
`help patients.
`
`Intracavemosal phannacotherapy; that is, the use of vasodilating medications injected directly
`into the corpora cavernosa is now an available modality (e.g. injectable alprostadil or Caverject).
`Various mixtures of unapproved and approved vasodilators have been administered directly into
`the penile shafts of such patients. These drugs include papaverine, phentolamine, vasoactive
`intestinal polypeptide, and alprostadil. Unfortunately, drawbacks of such therapy include fear of
`injection, injection pain, drug-related penile pain, and prolonged erection/priapism. Eventually,
`most patients withdraw from injection therapy.
`
`lntraurethral vasodilating medications are also approved for ED (e.g. alprostadil or MUSE).
`These suppositories “melt” upon insertion into the urethra and “seep” through the penile tunics
`into the corpus spongiosum and cavemosa and are supposed to act similarly to the direct injection
`of such substances. The advantage of an intraurethral suppository is clear: insertion of a pellet
`into the meatus is associated with less fear and discomfort than a direct injection. This modality
`is also limited by its route, by direct penile pain, by occasional systemic blood-pressure lowering
`effect, and by modest efficacy.
`
`Of greatest prominence has been the addition of Viagra (sildenafil citrate) to the ED
`annormentarium. Sildenafil is an selective inhibitor of Type S cyclic guanosine monophospate
`(cGMP) specific phosphodiesterase (PDE). By inhibiting the action of this phosphodiesterase,
`sildenafil enhances the vasodilating effect of endogenous nitric oxide (NO) in the penile corpora.
`This allows for the enhanced influx of arterial blood to the corpora following the neurologic
`signal for release of NO and ultimately, prolongation and intensification of the hardness of the
`erection. It is administered orally as “on-demand” therapy approximately 1 hour prior to sex. Its
`use has been limited by several factors including: the lack of spontaneity, cormnonly reported
`adverse reactions such as dyspepsia, rhinitis, headache, flushing and blue vision. Of greatest
`concern has been its potentially (and actual) life-threatening interaction with nitrates, a modest
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`MonoSol 1018-0003
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`7.... .-
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`interaction with other anti-hypertensives, and of course, the fairly large number of reports of
`myocardial infarction and sudden death among users during the last 3 years. While there is
`clearly a linkage between adverse outcomes and the nitrate/sildenafil interaction, it has been
`impossible to “dissect out” an actual sildenafil-related effect in the infrequent cardiovascular
`events. This is due to confounding factors in middle-aged and elderly men including chronic
`diseases, concomitant medications, concomitant sexual activity afier long periods of abstinence,
`and a huge number of users. Limited clinical pharmacology experiments (both in human trials,
`in-vivo and in-vitro experiments), data from controlled trials, and data from international
`observational cohorts has not revealed a direct role for sildenafil in these events. And, in fact, the
`
`number of such cases did drop after a November 1998 labeling change which may have
`encouraged more judicious usage in men with advanced heart disease. The event number has
`declined continuously since then.
`
`Cialis (or tadalafil or IC351) is a novel Type 5 PDE inhibitor. It was pursued by the ICOS
`Corporation initially because of its potential to improve upon Viagra. It has a prolonged half-life
`(17 hours) and therefore would allow for a longer period of potential responsiveness. It was
`originally thought to be more selective for the “penile” of Type 5 PDE. However, early results
`still demonstrated a significant systemic interaction with nitrates, implying a less than selective
`effect on the systemic vasculature. In addition, it was also notable that such adverse events as
`dyspepsia, rhinitis and vasodilation were not uncommon, again implying a lack of clinically
`improved selectivity for PDE5 over sildenafil. Evidence of effect on the ‘retinal” PDE (or Type
`6) was thought to be less of a problem than with Viagra, and that still may ultimately prove to be
`a benefit (although it is not yet supported as one). Of concern, however, even from the earliest
`IND stages, the occurrence of vague complaints of “back pain” and diffuse “myalgias” were
`reported when lC35l was given in high doses to volunteers. Also of concern were the findings
`of “arteritis” in beagle dogs. While these findings were qualitatively similar to those in dogs
`given sildenafil, the exposures at these doses were similar to or below those being given to man in
`the early tadalafil trials. In fact, studies for tadalafil were on IND “Clinical Hold” until the
`sponsor agreed to lower the doses by upwards of 10-fold and follow patients for clinical evidence
`of arteritis.
`
`At the time of the presumed End-of-Phase 2 (EOP2) meeting, it become clear that a similar toxic
`effect on animal testes was happening. Therefore, the sponsor was told at the EOP2 meeting that
`the FDA recommended that they refrain from initiating Phase 3 U.S. trials until the testes-
`damaging effect was disproved in humans. The sponsor planned and conducted two U.S. “semen
`safety” trials. Nevertheless, while these trials were in progress, the sponsor planned, designed
`and conducted an entire Phase 3 controlled and open-label, efficacy and safety development
`program overseas (e. g. South America, Mexico, Canada, Taiwan, Australia and Europe). This
`was carried out with no specific agreement from FDA. However, the Division had previously
`provided the sponsor with some guidance on the “general elements” of Phase 3 trials in ED (e. g.
`endpoints, designs, durations, eligibility criteria. among other issues). After finishing this
`international program, the sponsor requested and we held a pre-NDA meeting.
`
`Therefore, the critical times in this IND were:
`1. Submission of the IND (November 6, 1997) and subsequent Clinical Hold (December 9,
`1997)
`2. Lifting of the Clinical Hold (July 29, 1998).
`3. Meeting with the sponsor for purposes of providing “general comments” and “general
`guidance" (June 9, 1999).
`4. Meeting with the sponsor at the “would-be” EOP2 meeting (August 30, 1999)
`5. The Pre-NDA meeting.(February 21, 2001)
`
`h4onoSoll0l8-0004
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`3. Design of the program and clinical trials to support the indication
`3.1. Overall program
`
`In support of the clinical efficacy and safety of Cialis for the treatment of erectile dysfunction
`(ED), -the sponsor submitted the results from the following sixteen (16) clinical efficacy and
`safety trials in males with ED:
`
`1. Six (6) Phase 3 trials (herein referred to as the “Phase 3" or “pivotal” trials)
`2. Three (3) active—con1Iolled trials (the “active-comparator” trials)
`3 Three (3) placebo—controlled trials designed to assess time-to-onset of action and duration of
`responsiveness (the “supplementary” trials)
`4. Four (4) Phase 2 dose-ranging trials (the “Phase 2” trials).
`
`In support of the safety of chronic administration of Cialis, the sponsor also submitted results
`from the following eight (8) clinical safety trials:
`
`1. Four (4) open-label safety studies (LVBL, LVBD, LVDR, and DSD07 [LVBE]).
`2. Two (2) placebo—controlled studies investigating the effect of Cialis on serfien characteristics
`(LVCD and LVCZ).
`3. Two (2) controlled studies investigating of the effect of Cialis on vision (LVAN and LVCN).
`
`There were approximately forty additional studies conducted as part of the Clinical Pharmacology
`and Human Pharrnacokinetics evaluation. These are discussed separately in Dr. Roy’s review
`and the relevant section of this memo.
`
`3.2. The “pivotals” (N=6)
`
`The burden for supporting efficacy and safety for Cialis falls predominantly on the six Phase 3 (or
`“pivotal” trials). These were:
`
`LVBN — conducted at 19 investigative sites in Canada, Mexico and Argentina from
`December 1999 to May 2000 (placebo, 5 mg and 10 mg, N=2l5).
`
`LVBK — conducted at 18 investigative sites in Spain from December 1999 to August
`2000 (placebo, 10 mg, and 20 mg, N=216).
`
`LVCE — conducted at 18 investigative sites in Canada from March 2000 to August 2000
`(placebo, 2.5 mg, 5.0 mg, and 10 mg, N=31 1).
`
`LVCQ — conducted at 4 investigative sites in Australia from September 2000 to February
`2001 (placebo and 20 mg, N=140).
`
`LVCO — conducted at 8 investigative sites in Taiwan from October 2000 to February
`2001 (placebo, 10 mg, 20 mg, N=l96).
`'
`
`L_V_fl —— conducted at 25 investigative sites in Canada from October 2000 to April 2001
`(placebo, 10 mg and 20 mg, N=253).
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`M0n0S01 1018-0005
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`All of these six trials were designed similarly. These were randomized, double-blinded, placebo-
`controlled, parallel-arm design trials with the objective of evaluating the safety and efficacy of
`intermittent (or “on~demand”) dosing of different doses of Cialis compared to placebo in men
`with ED. All trials consisted of two phases; first, a four-week no-treatrnent baseline period
`followed by a 12-week, double—blind treatment period. Patients were evaluated at the following
`timepoints: a screening visit (prior to the baseline period), a baseline visit (after the baseline
`period) and monthly visits during the treatment period.
`
`The primary timepoints of interest were at Visit 2 (baseline) and Visit 5 (Week 12 or endpoint).
`The primary efficacy endpoint was the same in all three trials. In that regard, the primary
`endpoint was actually tripartite and included the following items:
`
`1.
`
`the 30-point Erectile Function (EF) domain of the International Index of Erectile Function
`(IIEF).
`2. Question #2 of the Sexual Encounter Profile (SEP), a per-event diary, that asks specifically
`“Were you able to insert your penis into the partner’s vagina?”, and
`3. Question #3 of the SEP, that asks specifically “Did your erection last long enough for you to
`have successful intercourse‘?”.
`
`Each of these three endpoints was calculated as a mean change-from-baseline. For the two SEP
`endpoints, the assessments reflect mean per-patient change-from-baseline event rates. The
`Division’s goal in advising this three-part primary endpoint is to allow straightforward clinical
`interpretation of small changes in EF domain score. The HEF is a fully validated patient-reported
`outcome instrument; however, the Division has occasionally struggled with the “clinical
`relevance” of small changes from baseline or small differences between drug and placebo.
`Secondary endpoints were numerous and included among others, all other domains from the IIEF,
`individual questions fi'om the HEF, results of the total patient SEP, results from the partner SEP,
`results from the Global Assessment Question, etc. The statistical analysis plan called for the
`comparison of change-from—baseline for each endpoint between each drug group and placebo at
`an alpha level of 0.05 for each endpoint.
`
`The patient eligibility criteria were virtually identical between trials. The inclusion criteria called
`simply for men aged 18 and older with “erectile dysfunction” of at least 3 months duration, a
`monogomous, stable, heterosexual relationship, and at least 4 attempts made during the baseline
`period. ED was defined as “a consistent change in the quality of erections that adversely affected
`the patient’s satisfaction with sexual intercourse”. Exclusion criteria were numerous and included
`the following relevant items:
`
`1.
`
`Impotence caused by other primary sexual disorders including premature ejaculation or
`impotence caused by untreated endocrine disease.
`2. History of radical prostatectomy or other pelvic surgery with subsequent failure to achieve
`erection.
`
`
`
`>'.°‘."‘."‘P"
`
`History of penile implant or evidence of clinically significant penile deformity.
`Evidence of clinically significant renal insufficiency within 6 months prior to Visit 1.
`Evidence of clinically significant hepatobiliary disease as evidenced by,AST/SGOT or
`ALT/SGPT >3 times ULN at Visit 1.
`
`Hemoglobin Alc >l3% at Visit 1.
`Patients with chronic stable angina treated with long-acting nitrates, or patients with chronic
`stable angina who required short acting nitrates within the last 90 days.
`8. Angina occurring during sexual intercourse in the last 6 months.
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`10.
`
`ll.
`
`12.
`
`13.
`14.
`15.
`I6.
`17.
`
`18.
`
`19.
`20.
`21.
`22.
`23.
`
`Patients with unstable angina, specifically, those meeting the criteria for Class I, H, or 111 of
`the Braunwald Classification of Unstable Angina.
`History of myocardial infarction or coronary artery bypass graft surgery within 90 days prior
`to Visit 1, or percutaneous coronary intervention within 90 days of Visit 1.
`Any supraventricular arrythrnia with an uncontrolled ventricular response (mean heart rate
`>100 bpm) at rest despite medical or device therapy.
`History of spontaneous or induced sustained ventricular tachycardia response (mean heart
`rate >100 bpm for at least 30 seconds) despite medical or device therapy.
`Presence of an internal cardioverter-difrbrillator.
`
`History of cardiac arrest despite medical or device therapy.
`Any evidence of congestive heart failure, specifically, NYHA Class 2 or above.
`Significant conduction defect within 90 days prior to Visit 1.
`Systolic blood pressure >170 or <90 mm Hg, or diastolic BP >100 or <50 mm Hg at
`screeening; or patients with malignant hypertension.
`History of significant central nervous system injury within the last 6 months, including stroke
`or trauma.
`
`History of HIV infection.
`Current treatment with nitrates, cancer chemotherapy, or anti—androgens.
`History of drug, alcohol, or substance abuse within the last 6 months.
`Prior ineffective treatment with sildenafil citrate.
`
`Any condition that would interfere with the patient’s ability to provide informed consent or
`comply with study instructions, would place patients at increased risk, or might confound the '
`interpretation of the study results.
`
`There were _rr_u_'r_ior design differences between the six pivotals. These include: the following:
`
`1. Only four of the six pivotal trials studied the 20 mg dosage strength (LVBK, LVCQ,
`LVCO and LVDJ).
`2. LVBK (Spain) enrolled only diabetics, although well-controlled diabetics were not
`excluded from other trials.
`
`3.
`
`In LVBK (Spain, diabetic-only), patients who met criteria for “orthostatic hypotension”
`at screening were excluded.
`4. LVCQ (Australia) was submitted in interim study report format at Week 12 of the
`treatment period, but was actually continued as a placebo-controlled study for a total of
`24 weeks and was submitted in its entirety as an amendment to the NDA.
`5. LVCQ (Australia) was the only study to compare only 20 mg to placebo and not to any
`other dosage strength.
`6. All studies randomized patients evenly between treatment groups except for the two trials
`conducted last: LVDJ (placebo: 10 mg: 20 mg = l:2:2) and LVCQ (placebo: 20 mg =
`1:2)
`
`Reviewer’s comments:
`
`1.
`
`In general, these pivotals were adequately designed to assess efficacy. However, I have
`concerns regarding the overall assessment of safety:
`a. The number of patients per treatment group per study was small and this serves
`to limit optimal assessment of drug safety in any individual trial.
`b. The total number of diabetic patients who received the 20 mg; dose was 119. Of
`those, 72 were pre-screened for the absence of baseline orthostatic hypotension.
`c. Data from Taiwan and Spain revealed lower incidences of the most frequent
`adverse events for both the 10 mg and 20 mg dose compared to the other trials.
`The reason for this difference is unclear.
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`2.
`
`It is concerning that all patients with “clinically significant” renal insufficiency were
`excluded in light of the increased exposure to drug and metabolite in patients with
`mild and moderate renal insufficiency and the increased incidence of the
`unexplained adverse events “back pain” and “myalgia” in that population.
`
`3. While there were no “sildenafil failures” in these trials (and that is acceptable), it was not
`made clear how many patients were’ actually former “sildenafil responders”. A high
`percentage of sildenafil responders would enrich these trials for both efficacy and for
`safety.
`
`3.3. The “active-comparator trials” (N=3)
`
`The three active comparator trials were identified and designed as follows:
`
`LVBO - was a placebo and active-controlled, double-blinded, double-dummy, parallel
`arm-design trial comparing Cialis to placebo and to Viagra as “on—demand” therapy for
`men with ED
`
`Four hundred twelve (412) patients were randomized to three arms (placebo, Cialis and
`Viagra). A 12-week active treatment period was preceded by a 4-week baseline period.
`The study compared a dose-titration regimen of 5 mg and 10 mg of Cialis to 50 mg
`and 100 mg of Viagra and to a similarly titrated placebo. The primary endpoints were
`the EF domain of the HEF, SEP Question #2, and SEP Question #3. Secondary endpoints
`included other IIEF and SEP data
`*
`
`The study was conducted at 34 investigative centers in the Belgium, France, Germany
`and The Netherlands from November 1999 to May 2000.
`
`Reviewer’s comment:
`
`1. A dose-titration regimen of Cialis using 5 mg to 10 mg was clearly superior to
`placebo.
`2. Cialis (5 mg to 10 mg) was not shown to be statistically non-inferior to Viagra
`(50 mg to 100 mg) in this trial. After this study, all pivotal trials were designed
`to study Cialis 20 mg.
`
`LVCF - was a double-blinded, double-dummy, two-period, two-sequence, active-
`control, crossover design-trial comparing Cialis 10 mg to Viagra 50 mg as “on—demand”
`therapy for ED. Fifty-seven (57) men with ED were randomized. The duration of each
`treatment period was 4 weeks separated by a 2-week washout and preceded by a 2-week
`no-treatment baseline. The primary endpoint was “patient preference” but quantitative
`indices of erectile function were also assessed (e.g. IIEF and SEP data).
`
`The study was conducted in 5 investigative centers in the United States from May 2000
`to September 2000.
`
`Reviewer’s comment: Cialis 10 mg was statistically non-inferior to "Viagra 50 mg in
`both the EF domain score of the HEF and the primary endpoint, patient preference.
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`M0n0S01 1018-0008
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`LVCY — was a double-blinded, double-dumrny, active-control, two-period, four-
`sequence, crossover-design trial comparing Cialis 20 mg to Viagra 50 mg and comparing
`Cialis 20 mg to Viagra 100 mg. Ninety-one (91) men with ED were randomized. The
`duration of each treatment period was 4 weeks separated by a 2-week washout and
`preceded by a 4-week no-treatrnent baseline. The primary endpoint was the EF domain of
`the IIEF. Secondary endpoints included SEP data and other quantitative indices of
`erectile function.
`
`The study was conducted in 6 investigative centers in the United States from January
`2001 to April 2001.
`
`Reviewer’s comment: Cialis 20 mg was statistically non-inferior to Viagra 100 mg in
`the EF domain score of the IEEF.
`
`3.4. The three “supplementary” trials (N-3)
`
`
`Three (3) placebo-controlled trials were conducted with the objective of assessing
`of action and
`of responsiveness. These were:
`
`LVBJ — was a randomized, double-blind, double-dummy, placebo-controlled, two-
`
`period, crossover study comparing a single dose of 10 mg
`formulation to a
`
`single dose of the 10 mg
`' formulation in terms ofpercentage ofpatients
`with T ofa “Rigiscan-confirmed” adequate erection within 30 minutes of
`dosing. This study was conducted in 61 male patients at 4 U.S. investigative sites.
`
`LVCK — was a randomized, double-blind, double—dummy, placebo-controlled parallel
`
`arm study comparing 10 mg, 20 mg and placebo in terms of the
`-
`ofan adequate erection within thefirst 30 minutes after dosing. In this trial, patients
`
`were tested for
`’ after each of 4 attempts. The study was conducted in 223
`male patients at 10 U.S. investigative sites.
`
`LVDG — was a randomized, double-blind, placebo-controlled parallel arm study
`comparing 20 mg and placebo in terms of the eflicacy ofsingle doses at 24 hours and at
`36 hours after dosing. The total number of attempts made by a given patient was four
`(two at each timepoint). The study was conducted in 348 male patients at 34
`investigative sites in the U.S., France, Spain, Germany, Sweden and Denmark.
`
`Reviewer’s comments:
`
`1. The Rigiscan ‘Tr ‘study (LVBJ) is considered exploratory due to its
`dependence on Rigiscan and its censoring of data at 30 minutes.
`
`2. The clinical
`study (LVCK) is also considered exploratory due to its
`censoring of data at 30 minutes.
`3. The t ‘-\ of responsiveness study (LVBG) was not appropriately designed to
`actually test
`-;__.___—-T but rather efficacy at a. given time point It
`does appear that Cialis is statistically more effective than placebo in some patients at
`24 hours and 36 hours after dosing.
`
`0
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`MonoSo1 1018-0009
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`MonoSol 1018-0009
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`3.5. The “Phase 2” trials (N=4)
`
`The four Phase 2 trials were originally identified as DSD01, DSDO4, DSD06, and DSD08. These
`were renamed LVBI, LVBG, LVBF, and LVAC, respectively. These studies were conducted
`
`using a precursor formulation --——~'———-—-—
`of the to-be-marketed _,
`formulation.
`They also studied doses as high as 100 mg. Given the increased Cmax with the _———/~
`formulation when compared with the 1....‘ formulation and the higher doses used in Phase 2,
`these studies provide relevant data for potential safety risks and for exploration of the relationship
`between pharmacokinetics and pharmacodynamics.
`
`DSD01 QLVBI1 was a randomized, double—blind, placebo-controlled, two period, two-
`sequence, crossover study comparing placebo to 100 mg. The endpoint of interest was
`cumulative duration of erection as measured by Rigisican-study afier a single dose. Forty
`(40) men with ED were randomized at three sites in The Netherlands. This first lC35l
`clinical study was conducted from November 1997 to March 1998.
`
`DSD04 (LVBG) was a randomized, placebo-controlled, parallel-arm design study
`comparing placebo to doses of 10 mg, 25 mg, 50 mg and 100 mg. Patients received daily
`dosing for 21 days. The primary endpoints of interest were Questions #3 and #4 of the
`IIEF. Two hundred ninety-four patients (294) were randomized at 19 investigative sites
`in Belgium, France, Germany, and the Netherlands. The study was conducted from May
`1998 to October 1998.
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`DSD06 gLVBF) was a randomized, placebo-controlled parallel-arm design study .
`comparing placebo to doses of 2 mg, 5 mg, 10 mg and 25 mg. Patients received 14 “on-
`demand” doses over a treatment period of 21 days. The primary endpoints of interest
`were Questions #3 and #4 of the IIEF. One hundred seventy-nine patients (179) were
`randomized at 13 investigative sites in the United States. This was the first human study
`conducted under IND# 54,553. The study was conducted from September 4, 1998 to
`December 7, 1998.
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`Reviewer’s comment: It is notable that even doses as low as 2 mg -,-—
`
`.
`‘ were found to be effective in this U.S. trial. The sponsor believes
`77
`that a therapeutic effect “plateau” was reached at doses “between 10 mg and 25
`
`mg
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`DSD08 (LVAC1 was a randomized, placebo-controlled parallel-arm design study
`comparing placebo to doses of 2 mg, 5 mg, 10 mg and 25 mg. Patients received “on-
`demand” doses (no more than once daily) over a treatment period of 21 days. The
`primary endpoints of interest were Questions #3 and #4 of the IIEF. Two hundred twelve
`patients (212) were randomized at 10 investigative sites in the Canada. The study was
`conducted from April 1999 to August 1999.
`
`Reviewer’s comment: It is again notable that 2 mg was found effective in terms
`of attaining an erection (Question #3) but not in maintaining an erection
`(Question #4). The sponsor concluded that 5 mg was the lowest effective dose in
`this Canadian study.
`
`Reviewer’s comment: The results from these Phase 2 studies must be analyzed
`
`in light of the higher doses of
`formulation compared to the to-be-
`marketed formulation.
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`MonoSol 1018-0010
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`MonoSol 1018-0010
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`3.6. The “open-label safety” studies (N=4)
`
`The sponsor conducted 4 open-label, dose-titration type, safety studies. Two of these provide a
`limited amount of information. They are:
`
`DSDO7 (LVBE) - was a 10-week, open—label, dose-titration safety extension of Phase 2
`trials.
`
`LVDR - was an open-label, safety extension of pivotal studies LVDJ (Canada) and LVCQ
`(Australia). It includes 331 patients enrolled at 23 investigative sites. It was initiated on
`February 2001 and therefore ha