Guidance for Industry
`
`Allergic Rhinitis: Clinical Development
`Programs for Drug Products
`
`DRAFT GUIDANCE
`
`This guidance document is being distributed for comment purposes only.
`
`Comments and suggestions regarding this draft document should be submitted within 90 days of
`publication of the Federal Register notice announcing the availability of the draft guidance. Submit
`comments to Dockets Management Branch (HF A-305), Food and Drug Administration, 5630 Fishers
`Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number
`listed in the notice of availability that publishes in the Federal Register.
`
`Additional copies of this draft guidance document are available from the Drug Information Branch,
`Division of Communications Management, HFD-210, 5600 Fishers Lane, Rockville, MD 20857, (Tel)
`301-827-4573, or from the Internet at http://www.fda.gov/cder/guidance/index.htm.
`
`For questions on the content of the draft document contact Martin H. Himme~ 301-827-1050.
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`April2000
`Clin.
`
`J: \!GU/DANC\2 718dft. doc
`06/14/00
`
`PLAINTIFFS'
`TRIAL EXHIBIT
`PTX0025
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`MEDA_APTX03502727
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`CIP2129
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
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`

`

`Guidance for Industry
`
`Allergic Rhinitis: Clinical Development
`Programs for Drug Products
`
`Additional copies are available from:
`
`Office of Training and Communications
`Division ofCommunications Management
`Drug Information Branch, HFD-21 0
`Center for Drug Evaluation and Research (CDER)
`5600 Fishers Lane
`Rockville, Maryland 20857
`(Tel) 301-827-4573
`(Internet) http:/ /www.fda.gov/cder/guidance/index. htm
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Apri12000
`Clin.
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`Table of Contents
`
`1
`
`INTRODUCTION .................................................................................................................................................. l
`
`ll BACKGROUND .................................................................................................................................................... l
`
`llL OVERALL CONSIDERATIONS- ADULT PROGRAM ............................................................................. 2
`
`A . NEW MOLECULAR ENTITY ............................................................................................................................ 2
`1.
`Number of Trials ......................................................................................................................................... 2
`Dose .............................................................................................................................................................. 2
`2.
`3.
`Safety Monitoring ...................................................................................................................................... 2
`4.
`Corticosteriod Issues ................................................................................................................................. 3
`O!ANGE IN FORMULATION AND/OR DEVICE .............................................................................................. 4
`Oral Formulations ..................................................................................................................................... 4
`Topical Nasal Formulations .................................................................................................................... 4
`Safety Monitoring ...................................................................................................................................... 5
`Corticosteriod Issues ................................................................................................................................. 6
`
`1.
`2.
`3.
`4.
`
`B.
`
`IV. OVERALL CONSIDERATIONS- PEDIATRIC PROGRAM ..................................................................... 6
`
`A. NEW MOLECULAR ENTITY OR NEW PEDIATRIC INDICATION ............................................................... 6
`Drugs Not Previously Studied in Adults ................................................................................................ 7
`I.
`Drugs Already Studied in Adults ............................................................................................................. 7
`2.
`3.
`Safety Data .................................................................................................................................................. 7
`4.
`Corticosteriod Issues ................................................................................................................................. 7
`O!ANGE IN FORMULATION AND/OR DEVICE .............................................................................................. 8
`
`B.
`
`V.
`
`PROTOCOL ISSUES AND ELEMENTS .......................................................................................................... 8
`
`A .
`B.
`C.
`D.
`E.
`F.
`
`I.
`2.
`3.
`4.
`
`TRIAL DESIGN ................................................................................................................................................... 8
`INCLUSION CRITERIA ...................................................................................................................................... 9
`EXCLUSION CRITERIA ................................................................................................................................... 10
`BLINDING ......................................................................................................................................................... 11
`FORMULATIONS AND DOSAGE REGIMENS ................................................................................................. 11
`EVALUATION .................................................................................................................................................. 11
`Assessment of Patient Compliance ........................................................................................................ 11
`Assessment of Rescue Medication Use .................................................................................................. l2
`RatingSystem ........................................................................................................................................... l2
`Recording Scores ..................................................................................................................................... 12
`
`V1 DATAANALYSISISSUES ............................................................................................................................... 13
`
`A.
`B.
`C.
`D.
`
`COLLECTION OF DATA ................................................................................................................................. 13
`TIME TO MAXIMAL EFFECT ........................................................................................................................ 14
`DURATION OF EFFECT (END-OF-DOSING INTERVAL ANALYSIS) ........................................................... 14
`ONSET OF ACTION ......................................................................................................................................... 14
`
`Vll
`
`SAR PROPHYLAXIS TRIALS ................................................................................................................... 15
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`Draft- Not for Implementation
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`GUIDANCE FOR INDUSTRY1
`
`(Due to the complexity of this draft document, please identify specific comments by line number.
`Use the pdf version of the document whenever possible.)
`
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`6 Allergic Rhinitis: Clinical Development Programs for Drug Products
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`30 When finalized, this document will replace the previous Points to Consider: Clinical
`Development Programs for New Nasal Spray Formulations (January 1996). Sponsors are
`31
`encouraged to discuss details of study design and specific issues relating to individual drug
`3 2
`products with division review staff prior to conducting clinical trials.
`3 3
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`35 Allergic rhinitis includes both nasal and non-nasal symptoms. The main nasal symptoms of
`3 6
`allergic rhinitis are nasal itching (i.e., nasal pruritus), sneezing, rhinorrhea, and nasal congestion.
`37 Nasal pruritus and sneezing are induced by sensory nerve stimulation, whereas congestion
`
`I.
`
`INTRODUCTION
`
`This guidance is intended to assist sponsors of new drug applications (NDAs) in designing
`development programs for oral and intranasal drug products for the treatment of allergic rhinitis
`in children and adults. The guidance addresses issues of study design, effectiveness, and safety
`for new drugs being developed for the treatment of seasonal allergic rhinitis (SAR) and perennial
`allergic rhinitis (PAR).
`
`II.
`
`BACKGROUND
`
`Information about the pathophysiology and treatment of allergic rhinitis and its subtypes, SAR
`and PAR, has grown markedly in the past decade. The recommendations in this guidance are
`based on a careful assessment of important issues raised in the review of both adult and
`pediatric allergic rhinitis clinical trials and the Agency's current understanding of the mechanism
`of the two related disorders of SAR and PAR. The pathophysiology of SAR and PAR are very
`similar in terms of the chemical mediators produced and end-organ manifestations, with
`differences between the two entities primarily based on the causes and duration of disease. The
`study design issues pertaining to SAR and PAR trials are also very similar. Thus, these two
`categories are treated collectively in this guidance as allergic rhinitis, with differences in
`recommendations for the design of SAR and PAR trials indicated.
`
`1 This guidance has been prepared by the Division of Pulmonary and Allergy Drug Products in the
`Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. This guidance
`document represents the Agency's current thinking on clinical trial design of seasonal and perennial allergic
`rhinitis studies in adults and children. It does not create or confer any rights for or on any person and does
`not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the
`requirements of the applicable statutes, regulations, or both.
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`results from vasodilation with resultant engorgement of cavernous sinusoids. Rhinorrhea can be
`induced by increased vascular permeability as well as direct glandular secretion. Important non-
`nasal symptoms commonly associated with allergic rhinitis include eye itching, eye tearing,
`itching of ears and/or palate, and eye redness.
`
`III. OVERALL CONSIDERATIONS- ADULT PROGRAM
`
`A New Molecular Entity
`
`1. Number ofTrials
`
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`43 A growing number of chemical mediators are believed to contribute to allergic rhinitis. They
`include histamine, leukotrienes (L TC4, L 1D4, and L 1E4), kinins, prostaglandins, chemotactic
`44
`45
`factors, neuropeptides (e.g., substance P, CGRP, VIP), interleukins -1, -5, -6, -8, and tumor
`necrosis factor-a. Additional mediators with a potential role in allergic rhinitis will likely be
`46
`identified in the future. Despite different causes and temporal patterns of disease, the same
`4 7
`groups of chemical mediators appear to be regulators of the responses in seasonal and perennial
`48
`allergic rhinitis. It is for this reason that distinctions between SAR and PAR in terms of clinical
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`trial design will be made only in clinically relevant areas.
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`For approval of a new molecular entity in adult and adolescent patients (age 12
`years and older), at least two adequate and well-controlled phase 3 clinical trials are
`recommended to support either the SAR or PAR indication. Alternatively, a
`sponsor can submit one SAR and one PAR trial in support ofboth the indications, if
`both trials are adequate and well-controlled phase 3 trials and both trials
`demonstrate the safety and effectiveness of the drug for the indications.
`
`2. Dose
`
`The dose-response relationship for the new drug should be evaluated in these trials.
`These trials, or other supporting trials, should identify a lowest effective dose for
`the drug (i.e., the lowest dose that demonstrates a statistically significant difference
`between the to-be-marketed drug and the placebo). This recommendation is
`particularly important for intranasal corticosteroids.
`
`3. Safety Monitoring
`
`These trials should also address safety concerns, such as monitoring for adverse
`events, performing routine laboratory tests (i.e., blood chemistry, liver fimction tests,
`complete blood count with differential), urinalyses, and electrocardiograms, as
`appropriate. For SAR and PAR phase 3 trials, routine laboratory tests should be
`obtained in study patients at least at the initial screening and at the last visit.
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`For some allergic rhinitis drugs (particularly drugs in the antihistamine class), part of
`the safety program should include a thorough cardiac safety evaluation, with studies
`performed in both men and women. A suggested approach would include:
`
`• Screening and end-of-treatment ECGs, including a careful assessment of the
`QTc interval and any T wave abnormalities, as read by a ECG reviewer blinded
`to study treatment.
`
`• Human dose escalation studies that evaluate serial ECGs at drug exposures up
`to dose-limiting toxicity of any organ system.
`
`• For drugs metabolized by the cytochrome P450 3A4 system, drug interaction
`studies performed with both a macrolide and azole antibiotic.
`
`• 24-hour Holter monitoring performed before, during, and, as appropriate, on
`completion of the efficacy trials for allergic rhinitis drugs suspected to have an
`effect on QTc intervals from previous studies.
`
`In addition to the studies described above, case report forms and study reports
`should include a detailed description of all serious cardiac adverse events and
`pertinent ECGs.
`
`Sponsors are encouraged to contact the review division regarding appropriate
`cardiac safety monitoring for their respective drug development programs.
`
`For many allergic rhinitis drugs, some assessment of the degree of sedation
`compared to the placebo should be provided in the safety database. This should
`primarily be based on individual patient adverse event reports of sedation and/or
`drowsiness (or similar terminology, as defined by the sponsor's adverse event
`dictionary).
`
`Generally, long-term safety data should include at least 300 patients evaluated for 6
`months and 100 patients evaluated for 1 year. The overall patient database should
`include at least 1500 patients. (See the International Conference on Harmonisation
`guidance on the Extent of Population Exposure Required to Assess Clinical
`Safety for Drugs Intended for Long-term Treatment of Non-Life Threatening
`Conditions (March 1995).)
`
`4. Corticosteroid Issues
`
`Important safety issues for intranasal corticosteroids that would ordinarily be
`addressed in the adult clinical program include:
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`• Assessment of adrenal function using either timed urinary free cortisol level
`measurements (i.e., 12-hour or 24-hour), or 24-hour plasma cortisol AUC
`levels pretreatment and after at least 6 weeks post-treatment with study
`medication. A placebo and an active control (e.g., oral prednisone) should be
`included in these studies.
`
`• Evaluation for possible cataract formation by slit-lamp examination, pre- and
`post-treatment.
`
`• Evaluation for glaucoma, using intra-ocular pressures monitored pre- and post(cid:173)
`treatment.
`
`B. Change in Formulation and/or Device
`
`1. Oral Formulations
`
`For a change in an oral dosage form from an approved oral formulation to a new
`oral formulation of the same drug substance, an alternative to conducting the new
`molecular entity program described above is to demonstrate bioequivalence
`between the two formulations. This is based on pharmacokinetic comparisons (e.g.,
`AUC, Cmax, Cmin) between the approved and to-be-marketed formulations. This
`equivalence approach allows the indications and patient populations for the new
`formulation to be the same as those described in the labeling of the approved
`product. If a significant new excipient, not previously administered at comparable
`levels to humans, is present in the new formulation, or if the tolerability of the new
`formulation is otherwise in question, short- and possibly long-term safety data may
`still be important for patients receiving the new formulation, even if bioequivalence is
`demonstrated. Additional safety and efficacy trials may be necessary to support a
`new formulation ifbioequivalence is not demonstrated.
`
`2. Topical Nasal Formulations
`
`For changes in formulation and/or device for a topical nasal product (e.g., aqueous
`pump, spray), one of two approaches can be used to demonstrate the safety and
`effectiveness of the new drug product: (1) establishment of comparability between
`the new and previously approved (reference) formulation, or (2) development of the
`new formulation and/or device by a usual program for a new drug product (i.e.,
`stand-alone approach).
`
`• Comparability Approach
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`To demonstrate clinical comparability between the new and reference formulations,
`comparison of the dose-response curves of these two formulations in a single
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`efficacy and safety trial is recommended. Two doses of each formulation, in
`addition to placebo, are desirable for dose-ranging determination. The dose(cid:173)
`ranging study should be designed to permit determination of how doses of the new
`formulation compare to the approved doses of the reference formulation with regard
`to onset of action and effectiveness. Comparative pharmacokinetic (PK)
`measurements (Cmax, Tmax, and AUC) should be included in this trial, as appropriate
`and technically feasible. If the reference formulation is indicated for both SAR and
`PAR, the dose-ranging trial can be performed in patients with either SAR or PAR
`(see section V of this guidance, Protocol Issues and Elements, for recommended
`trial durations). If the reference formulation is approved for indications in addition
`to SAR and/or PAR (e.g. , nasal polyps or nonallergic rhinitis) no additional studies
`are needed to support the same indications for the new product, if comparability, as
`described above, is well established between the new and reference formulation.
`
`• Stand-Alone Approach
`
`An alternative approach or stand-alone approach for evaluating a topical nasal
`drug product with a formulation change could be a single, dose-ranging, placebo(cid:173)
`controlled efficacy and safety trial of the new formulation in patients with either SAR
`or PAR. A single dose of the reference formulation as a positive control is
`recommended. Demonstration of effectiveness for either of these two clinical
`indications would allow labeling to include efficacy for both, if the reference
`formulation already had labeling for both. If additional indications (e.g., nasal
`polyps and nonallergic rhinitis) previously approved for the reference formulation
`are sought for the new formulation, a single clinical trial for each additional indication
`is recommended. Furthermore, as with the comparability approach,
`determination of the pharmacokinetics of the drug is recommended during the
`stand-alone approach and can be performed during the efficacy trial, if feasible.
`
`3. Safety Monitoring
`
`For both oral and topical nasal formulation programs described above, safety
`monitoring should be included for the duration of the trials. This would include
`evaluation of adverse clinical events, routine laboratory tests (i.e., blood chemistry,
`liver fi.mction, complete blood count with differential), urinalysis, and ECGs, as
`appropriate.
`
`In either of these formulation programs, demonstration of long-term safety may still
`be important, if new inactive ingredients have been added that could affect safety, or
`if the new formulation and/or device results in higher systemic exposure to active
`ingredients compared to the approved product. In addition, if pharmacokinetic data
`for the formulations are not feasible, long-term safety data for the new formulation
`may be recommended. If necessary, long-term safety may be established by
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`documenting exposure of at least 200 patients to the new formulation for 6 months
`at the dosage proposed for marketing. Due to the duration, these studies are
`generally conducted in patients with PAR. An active control arm, consisting of a
`single dosage level of the reference formulation, is recommended. Symptom-guided
`dosage adjustment by study patients during the long-term open label study should
`be avoided, as this complicates analysis of the safety data To minimize dropouts
`and to address ethical considerations, stratification of patients and dosage according
`to symptom severity is acceptable at the start of the open label study. However, a
`sufficient number of patients who receive the highest dose proposed for marketing
`should be included. Rescue medication should not include other intranasal drugs or
`intranasal products.
`
`4. Corticosteroid Issues
`
`For corticosteroids, if the new formulation causes higher systemic exposure to the
`drug substance than other formulations (either intranasally or orally inhaled) already
`marketed or under development for which an adequate assessment of HP A axis
`effects has been conducted, or if pharmacokinetic data on these other formulations
`is unavailable, an evaluation of the effect of the new formulation on the HP A axis is
`strongly recommended. For HPA axis evaluation, measurement oftimed (12- or
`24-hour) urinary free cortisol levels or serum cortisol AUC before and after 6
`weeks of treatment are the preferable methods of assessment. If the sponsor plans
`to claim comparability between the reference and new formulations, and a
`pharmacokinetic comparison of the two products is not available, comparison with
`the highest marketed dose of the reference formulation is recommended.
`
`For a change in a device, data on the performance and reliability of the new device
`over the period of intended use may need to be provided.
`
`IV.
`
`OVERALL CONSIDERATIONS- PEDIATRIC PROGRAM
`
`A New Molecular Entity or New Pediatric Indication
`
`The pediatric age ranges proposed for a drug product, particularly for very young
`patients, should be justified by the sponsor based on the presence of disease and the
`need for treatment in that age group. Drugs indicated for the treatment of allergic rhinitis
`are used in children below the age of 2 years; therefore, a complete pediatric program
`should evaluate the safety of antihistamines in children down to age 6 months. Similarly,
`based on clinical use experience, the safety of intranasal corticosteroids, cromolyn-like
`drugs, and anticholinergics should be evaluated in children down to age 2. Sponsors
`are encouraged to discuss the specifics of pediatric programs with the division on a
`case-by-case basis.
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`1. Drugs Not Previously Studied in Adults
`
`For approval of a new molecular entity in pediatric patients (patients younger than
`12 years), the number of studies recommended depends on whether the drug is
`already approved in adult patients. For a new molecular entity (NME) not
`previously approved or adequately studied in adults, the clinical program would be
`the same as that described for adults. This would include two adequate and well(cid:173)
`controlled safety and efficacy trials along with appropriate long- and short-term
`safety data. For an NME intranasal corticosteroid, the performance of a growth
`study (possibly postapproval) is recommended in order to assess the potential of
`the corticosteroid to suppress growth in children
`
`2. Drugs Already Studied in Adults
`
`For drugs already approved and/or adequately studied in adults but not yet studied
`in children, an appropriate pediatric dose should be determined. In addition,
`adequate short- and long-term safety information for the proposed pediatric age
`group should be provided. For oral formulations where a reasonable
`pharmacokinetic/pharmacodynamic (PK/PD) link for effectiveness has been
`established, PK data from children can be used to determine comparable exposure
`to adult patients, and therefore the appropriate pediatric dose.
`
`For intranasal formulations, the performance of efficacy studies in pediatric patients
`is recommended, since plasma drug levels are not consistently detectable or reliable
`as measures of local bioavailability and topical efficacy.
`
`3. Safety Data
`
`Typically, 3 months of additional specific pediatric safety data for intranasal
`products and 1 month of additional safety data for oral products are recommended.
`These data should be collected in placebo controlled trials. However, the duration
`and number of pediatric patients exposed to the study drug for safety monitoring
`should be determined on an individual basis for each drug, based on anticipated side
`effects, pediatric PK data, and safety concerns.
`
`4. Corticosteroid Issues
`
`For intranasal corticosteroids, performance of a 6-week HPA axis study is
`recommended. Because of ethical concerns about the use of oral prednisone as an
`active comparator in adrenal response studies in children, inclusion of an oral
`prednisone arm in pediatric adrenal assessment studies is not typically
`recommended. However, inclusion of an active comparator arm (e.g., an intranasal
`corticosteroid approved in the pediatric population) is encouraged.
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`Based on recent information that intranasal corticosteroids have the potential to
`decrease growth velocity in children, a growth study is recommended for
`prepubertal children as a phase 4 commitment, if not before. If the studies are to be
`performed postapproval, it may be useful for a sponsor to include a knemometry
`study in the NDA submission to provide some PO growth data for consideration
`during the initial review. Growth studies should evaluate growth before and after
`treatment with the intranasal corticosteroid, using stadiometry to assess growth.
`Such a growth study should enroll patients with allergic rhinitis, incorporate a run-in
`period, and be placebo controlled. Sponsors should ensure that an adequate
`sample size is studied and that there is a reasonable duration of treatment (ordinarily
`1 year). These recommendations allow for a better estimate of the decrease in
`growth velocity seen in association with intranasal corticosteroid use. Information
`on a clinically significant change in growth derived from knemometry studies should
`not be used to determine the expected change in growth velocity for longer-term
`studies that use stadiometry to measure growth. This is because of the nonlinearity
`of growth and differences in study durations for these two techniques. Sponsors are
`encouraged to discuss the details of their pediatric growth study design with the
`review division
`
`B. Change in Formulation and/or Device
`
`In situations where a sponsor has conducted a change in the formulation and/or device
`comparability program in adults, as described above, additional pediatric efficacy
`studies may not be required if:
`
`• The safety, efficacy, and PK of the new formulation are comparable to that of the
`reference formulation in adults, and
`
`• The reference formulation has been approved for use in an appropriate pediatric
`age range.
`
`However, depending on the specific changes that were made in the formulation and/or
`device, additional safety and/or use studies in children may be needed.
`
`v.
`
`PROTOCOL ISSUES AND ELEMENTS
`
`A. Trial Design
`
`In the development programs of allergic rhinitis drugs, otherwise well-designed and
`well-conducted studies may occasionally fail to show effectiveness. This is due in part
`to the subjective nature of the assessments and spontaneous variability in the disease.
`This observation makes the use of a placebo control of paramount importance, since a
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`Draft- Not for Implementation
`
`positive-control equivalence trial cannot be interpreted in such a situation. If the intent is
`to show that the new product is significantly more effective than an approved active
`control, a positive-control study may be sufficient.
`
`The following are general recommendations on trial design for phase 3 allergic rhinitis
`(SAR and PAR) trials in adults and adolescents (older than 12 years) and children
`(younger than 12 years).
`
`• These studies should be double-blind, placebo-controlled, and parallel group,
`preferably with a placebo run-in period.
`
`•
`
`Inclusion of an active control arm is recommended for both reformulation programs
`(as described above) and for new drug development programs. For the new drug
`development program, the positive-control study is helpful in intetpreting trials in
`which there is not a demonstrable difference between the test drug and the placebo.
`
`• The duration of the double-blind treatment period should be at least 2 weeks for
`SAR trials and 4 weeks for PAR trials.
`
`• For SAR trials, the study protocol should discuss plans for measuring pollen counts
`at the different study centers. The study report should document the exposure of
`patients to the relevant allergens during the study period. It may also be helpful to
`collect data on the number of rainy days during the trial and the extent of patient
`exposure to outdoor air.
`
`• For SAR trials, randomization of patients within each center into the double-blind
`portion over a short time period (e.g., 3-4 days) is encouraged, as this generally
`reduces variability in allergen exposure.
`
`• Many patients with PAR may have concomitant SAR. Therefore, PAR trials should
`be conducted during a time when relevant seasonal allergens are less abundant and
`therefore less likely to influence results of the trial (i.e., late fall and winter).
`
`B. Inclusion Criteria
`
`• For SAR effectiveness trials, patients should have a history of SAR for a minimum
`of 2 years before study entry. Documentation of sensitivity by positive skin testing
`(by prick or intradermal methods) or by adequately validated in vitro tests for
`specific IgE (e.g., RAST, PRIST) to the relevant seasonal allergen for the
`geographic area of the study within 12 months prior to enrollment is recommended.
`A positive skin test is generally defined as a wheal ~ 3 mm larger than the diluent
`control