2. 1.0 REGULATORY GOALS AND ASSUMPTIONS
1.1 GOALS
PRIMARY GOAL: Approval of Drug (Product #ABX154) by United States Food & Drug
Administration (US-FDA), which paves the way for marketing of the drug in the United States,
providing topical treatment to patients of onychomycosis in fingernails and toenails without
lunula involvement due to Trichophyton rubrum.
SECONDARY GOALS:
a) Decide proper dosage to be given at the pre clinical study, so that it can be standardized
for the human use.
b) Planning of the requisite steps to be taken for Chemistry, Manufacturing and Control
(CMC) of the product, and to effectively display the physiochemical properties of the
drug.
c) Displaying the adequate information for the pre clinical testing, and their route of
conduction.
d) To lay down a specific timeline and format of the conduction of clinical trials, and
minimize the timeline for the drug approval
e) Provide an insight about the core labeling and risk assessment of the drug.
f) Carry out the human clinical trials at par with the protocols, and guidance documents
provided by the FDA.
1.2 ASSUMPTIONS
1.2.1 GENERAL ASSUMPTIONS:
a) The drug manufacturing for clinical trials shall be as per laboratory standards and
specifications specified by the Research and Development Department.
b) The most suitable indication is based upon corporate mission, and the status of development,
and shall be directed towards a generalized skin treatment.
3. c) The role of the company employees will be pivotal, and thus the drafting shall be a result of
the coordinated efforts of the departments, specifically department of Regulatory Affairs.
d) Two pre submission meetings to be held on 2nd
November, 2015 and 12th
November 2015 to
gain regulator understanding of and/or agreement with significant preclinical or clinical testing
plans and the regulatory strategy as a whole and Identification milestones for preparing for,
requesting and conducting these meetings.
e) Development and marketing teams are onboard with the regulatory context and implications
for all the markets where an approval will be sought for the product, and equally important, an
effective line of communication has to be in place with the regulatory bodies. When discussing
any research and development or regulatory project with the competent authorities, it is essential
to set up meetings and/or discussions appropriately.
f) Identification of the key features of our product and the markets where to sell it and conduct
all the necessary studies, avoiding duplication of local studies in different regions wherever
possible by the regulatory authority. Proper selection of registration procedure and assembling
data dossier upon your submission. Throughout the whole process regular communication with
the regulatory authorities is necessary, so the company has a good idea of the procedural steps
still to be completed.
1.2.2 FILING ASSUMPTIONS
a) Submission of Pre IND request letter to FDA, to be in effect latest after 13 months of the
regulatory plan approval by the Director Regulatory Affairs of the company.
b) The IND submission that includes the results of the preclinical work, the candidate drug’s
molecular structure, details on how the investigational medicine is thought to work in the body, a
listing of any potential side effects as indicated by the preclinical studies, manufacturing
information and a detailed clinical trial plan that outlines how, where and by whom the studies
will be conducted, should be submitted after the pre IND doubts and guidance are cleared from
the FDA.
4. c) The filings and relevant data of the clinical and pre clinical testing to be done by the
regulatory writing department, and must be executed within 15 days of the result verification of
the Research and Development Department.
d) Describe specific approaches planned for regulatory submissions, such as filing a Request for
Designation for a combination product, requests for expedited review, modular PMA review,
paper vs. electronic submission, STED format, etc.
1.2.3 EFFICACY ASSUMPTIONS
a) The drug efficacy is assumed to be constant with the laboratory testing, and is solely
dependent on the response of the animals and the conduction of clinical trials.
b) Development of tolerance or absence of tolerance
c) Study of disease state progression, and presence or absence of active metabolites and their
contribution to clinical effects.
1.2.4 SAFETY ASSUMPTIONS
a) The drug is assumed to be safe over the topical use over the finger and toe nails.
b) The clinical trials will be conducted under the surveillance of the operations manager.
c) The effects of the drug over other components of the body is not known.
1.2.5 NON CLINICAL ASSUMPTIONS
a) Intended route of therapeutic administration is topical.
b) Frequency of drug administration will be decided after the pre clinical trials.
c) Purity of drug substance used in non clinical studies is not intended to be greater than clinical
programme, in order that impurities become qualified as studies progress.
d) Stability of both the drug substance (API) and the drug product (API and its excipients) under
appropriate storage conditions and in anticipated animal dosing formulation must be
demonstrated.
e) GLP compliant bioanalytical must be developed and validated to verify the purity of the
substance, concentrations of the drug in dosing solutions, and detect drug substance and
5. metabolite in blood or other matrices, whose validation is the rate limiting step of the non
clinical programme, and thus should be completed prior to the initiation of toxicology studies.
1.2.6 CMC ASSUMPTIONS
a) The drug structure and product is verified by the Research and Development Department, and
has passed the laboratory tests, which makes it valid to be used under manufacturing for the
clinical trials, and toxicology tests.
1.0 RISK MANAGEMENT ASSESSMENT
RISK ASSOCIATED ASSESSMENT
Individuals likely to show hypersensitivity,
such as mild and transient irritation (redness).
Addition of another chemical compound in the
solution which is antagonistic to the
hypersensitivity causing agent.
Could be administered by opthalmic, oral or
vaginal routes by ignorant patients.
Use of any polar solvent, like water, could help
to wash down the solution substance easily.
Periungual erythema and erythema of the
proximal nail fold
Conduction of studies on the human clinical
trials over the nails, and assessment of the
allergic reagents due to the IgE reactions over
the fingernails and toes.
Treatment-emergent adverse events (TEAE),
that cause Mild rash in the form of periungual
erythema and nail disorders.
Removal of the unattached, infected nail, as
frequently as monthly, trimming of
onycholytic nail, and filing of excess horny
material should be performed by professionals
trained in treatment of nail disorders.
Application site reactions and/or burning of the
skin occurred
Patients should file away (with emery board)
loose nail material and trim nails, as required,
6. every seven days after Topical Solution, 8%, is
removed with alcohol. Topical Solution, 8%,
should be applied once daily (preferably at
bedtime or eight hours before washing) to all
affected nails with the applicator brush
provided and should be applied evenly over the
entire nail plate. It should be applied to the nail
bed, hyponychium, and the under surface of
the nail plate when it is free of the nail bed
(e.g., onycholysis).
2.0 REGULATORY ACTIVITES
2.1 CURRENT STAGE ACTIVITIES
a) Review of Investigational Medicinal Product Dossier
b) Collection, evaluation and compilation of the scientific data and information on the
product
c) Market review by the Regulatory Affairs department, and assessment of the other
already present drugs which deal with the topical application against Trichophytum
rubrum.
d) Decisions to be rendered on outsourcing strategy to some partners, nature of tasks to be
transferred, and also the structure and organization of that pharmaceutical company.
e) Decisions on the funding, risk benefits, and the reimbursement of the investments over
the product clinical trials and the rendering of the non clinical trials.
f) Discussions of the operational systems, staff and methodologies over the procurement of
the approval from FDA, and the proper use of animals in the trials.
g) Conduction of pre hand survey of population for easy conduction of the clinical trials, if
approved by FDA on first chance.
7. 3.2 TIMELINE
CHEMISTRY, MANUFACTURING AND CONTROL (CMC).
DRUG SUBSTANCE
PROPERTIES AND POINTS TO BE
CONSIDERED ABOUT DRUG
SUBSTANCE (TEST)
SOP NUMBER TEST METHOD
(IF ANY)
NOMENCLATURE, STRUCTURE AND
GENERAL PROPERTIES SOP #11 NA
MANUFACTURE
a) Manufacturers
b) Description of manufacturing processes
and process controls
i) Flow diagram
ii) Process narrative
iii) Process controls
c) Control of materials
i) Starting materials
ii) Reagents, Solvents, Auxiliary materials
d) Control of critical steps and
intermediates
e) Manufacturing process development
SOP #334 Company handbook
(Sections 2.3, 4.5)
8. CHARACTERIZATION
a) Elucidation of structure
b) Other characteristics
i) Physiochemical properties
ii) Solid state forms
c) Impurities
i) Types (Organic, inorganic, residual
solvents, heavy metals)
ii) Classification
(specified/unspecified/identified/unidentifi
ed)
iii) Reporting, Identification and
Qualification thresholds
iv) Acceptance criteria
v) Qualification
Visual, Near Infrared (NIR)
ICH Q3B qualification
threshold (QT) and
identification threshold
(IT). Genotoxic and
carcinogenic risk to be
evaluated via structure
activity relationship (SAR)
assessment.
CONTROL OF DRUG SUBSTANCE
a) Specifications
i) Water Determination (Karl Fischer)
ii) Residue on ignition
iii) Specific rotation
b) Analytical Procedures
i) Assays (HPLC) – evaluate strength of
dosage forms.
SOP #122
SOP #154
SOP #343
SOP #114
Test method 022
Test method 334
Test method 014
Titrimetry
SOP #1224
SOP #678
SOP #T26
9. DRUG PRODUCT
PROPERTIES AND
POINTS TO BE
CONSIDERED ABOUT
DRUG PRODUCT (TEST)
SOP NUMBER TEST METHOD
Appearance SOP #122 Visual (TM 046)
Odour SOP #228 TM 144
Viscosity of the topical
solution
SOP #111 TM 089
Moisture content USP TM 9900
Identification (NIR) SOP #1122 TM 567
Antimicrobial Preservative
Content
SOP #009 TM 8876
Antioxidant content SOP #2234 Use same method as impurity
testing for oxidative
degradation.
pH SOP #212 TM 897
Sterility (Container closure
systems) – sealed foil of
transdermal patch
SOP #121 TM 656
Peel adhesion test (Container
closure systems)
SOP #213 TM 777
11. PRE CLINICAL TESTING
Assumptions:
a) Candidate selected – Mice
b) Monetary Support – 4.5 million USD
c) Sufficient test article
d) New chemical entity
e) As required under 21 CFR 312.23(a)(8)(iii), it is declared that each study subject to good
laboratory practices (GLP) regulations was performed in full compliance with GLPs
TOXICOLOGY STUDY PLAN OUTLINE
GENOTOXIC STUDY PLAN
TEST SUBJECT USED PROPOSED PROTOCOL
(DESCRIPTION)
In vitro genotoxicity test
to be conducted with
ciclopirox
Salmonella
E.coli
V79 Chinese hamster lung
fibroblast
A549 cells
CT3T cells
Rat Hepatocyte cells
Evaluation of gene mutation
Evaluation of gene mutation
Chromosome aberration assay and gene
mutation assay (HGPRT)
Unscheduled DNA synthesis
Cell Transformation assay
Mouse lymphoma forward mutation assay
and unscheduled DNA sysnthesis.
12. REPRODUCTIVE / FERTILITY STUDY PLAN
TEST SUBJECT USED PROPOSED PROTOCOL
(DESCRIPTION)
Oral reproduction studies Rats Doses upto 2300 mg ciplopirox
olamine/kg/day
TERATOGENETIC STUDY PLAN
TEST SUBJECT USED PROPOSED PROTOCOL
(DESCRIPTION)
Teratogenetic effects:
Pregnancy category B
Mice
Rats
Rabbits
Monkeys
Doses upto 1200 mg ciplopirox
olamine/kg/day in mice, rats and rabbits,
and monkeys to receive upto 1900 - 2100
mg ciplopirox olamine/kg/day.
SYSTEMIC TOXICITY STUDY PLAN
TEST SUBJECT USED PROPOSED PROTOCOL
(DESCRIPTION)
Multiple dose topics study Rabbits
Dogs
Dose level of 500 mg/kg/day (6.0 g/m2
),
for 4 weeks.
To be followed by 3 month study in
rabbits and 6 month study in dogs by
daily topical application of free acid at
10% concentration.
13. CARDIOVASCULAR (ECG) STUDY PLAN
TEST SUBJECT USED PROPOSED PROTOCOL
(DESCRIPTION)
Oral doses Rats
Dogs
Dose level of 10 mg ciplopirox
olamine/kg/day for 3 months.
TOXICOKINETIC STUDY PLAN
TEST SUBJECT USED PROPOSED PROTOCOL
(DESCRIPTION)
Toxicokinetic study plan
(oral) at NOEL
Rats
Dogs
Serum drug level to be maintained
between 2750-3350 mg/mL.
4 week rabbit dermal study, which will be
done by dosing upto 1000 mg/kg/day
CARCINOGENETIC STUDY PLAN
TEST SUBJECT USED PROPOSED PROTOCOL
(DESCRIPTION)
Cutaneous doses Female mice Proposal of 1% and 5% topical solutions
in PEG 400, twice per week for 50 weeks,
followed by 6 month drug free
observation period.
14. DOSAGE PLAN OUTLINE (SINGLE DOSE)
GROUP
ID
DOSE LEVEL ANIMALS /
GROUP
TOTAL DOSE TIMELINE BUDGET
Control 0 mg/kg 50 00 1 months 60 K
Low-
dose
1500 mg/kg 50 1500 2 months 100 K
Mid-
Dose
2400 mg/kg 50 2400 3 months 180 K
High-
Dose
3300 mg/kg 50 3300 6 months 320 K
TOTAL 200 7200 12 months 660 K
SUSCEPTIBILITY TESTING PLAN
TEST SUBJECT USED PROPOSED PROTOCOL
(DESCRIPTION)
Determine ciclopirox MIC
values against the
dermatophytic molds
Trichophyton rubrum Susceptibility method will depend upon
composition and pH of media and the
utilization of nutritional supplements.
15. NON GLP ANIMAL TESTING PLAN OUTLINE
PARAMETERS PROPOSED TESTS
Pharmacology Studies Broth and solid media to be utilized with/without
additional nutrients to determine ciclopirox
Minimum Inhibitory Concentration (MIC) for
dermatophytic molds.
Efficacy studies and mechanism of action Proposed use of in vivo and in vitro infection
models against Trichophyton mentagrophytes
and Trichophyton rubrum in ovine hoof material.
ADME Testing
Absorption
Distribution
Metabolism
Excretion
Oral administration of 14
C to mice and detection
of excreta after 12 hours of intake.
Determination of systemic absorption for 5 mm
of skin once daily for 6 months.
Determination of random serum concentrations
and 24 hour urinary excretion at 2 weeks, and at
1, 2, 4 and 6 months after initiation of treatment,
and 4 weeks post treatment.
16. PRECLINICAL TESTING BUDGET AND TIMELINE
STUDY TIME TO GET FINAL
REPORT
ESTIMATED COST
(US DOLLARS)
In Vitro Studies
Pharmacology Studies 3 months 45K
Efficacy studies and
mechanism of action
5 months 33K
ADME Studies
(Pharmacokinetics)
4 months 12K
Susceptibility studies 3 months 77K
Antifungal drug reactions and
resistance studies
2 months 12K
Safety Studies 5 months 50K
Toxicology studies
Toxicokinetic studies 06 months 18K
Carcinogenic studies 08 months 200K
Cardiovascular ECG studies 04 months 29K
Systemic toxicity studies 10 months 123K
Reproductive / Fertility
studies
6-9 months 34K
Teratogenic studies 17 months 100K
Genotoxic studies 17-19 months 200K
Animal based specifications
dependent on species
Rat 3 months 3K
Mice 3 months 3K
Rabbit 5 months 10K
Dog 2 months 12K
Monkeys 3-5 months 20K
TOTAL 113 months 981K
17. CLINICAL TESTING OUTLINE
PHASE 1
OBJECTIVES:
To assess a safe & tolerated dose
To see if pharmacokinetics differ much from animal to man
To see if kinetics show proper absorption, bioavailability
To detect effects unrelated to the expected action
To detect any predictable toxicity
PROPOSED STRATEGY TIMELINE BUDGET (US DOLLARS)
Number of volunteers: 70+
i) Application of the topical
solution daily to fingernails
ii) Removal of the solution
from fingernails each week
iii) Sampling of distal portions
of the nail after 7, 14, 30 and
45 days of treatment.
iv) Determination of the
penetration of ciclopirox
(main component) into the nail
by examining the 4 layers of
equal volume of transverse
section of the nails.
v) Use of 10% aqueous
solution of Polyehylene glycol
for ciclopirox extraction.
Approximately 4-6 months 5.5K
18. PHASE 2
PROPOSED STRATEGY TIMELINE BUDGET (US DOLLARS)
Determination of systemic
absorption, efficacy and safety
of the product with patients
with dermatophytic
onychomycoses of the
fingernails.
Number of patients: 30 – 200
Number of late phase patients:
450-500
i) Application of topical
solution once at bedtime for 6
months (24-26 weeks) to all
onychomycotic fingernails and
toes.
ii) Application over the entire
nail plate, and proximal and
lateral nail folds,
approximately 5 mm into the
folds. Removal of old coat
with soap.
iii) Measurement of serum and
24 hour urine concentration,
and their collection at Day 1
(Baseline), Month 2, 4 and 6,
and after 4 weeks post
treatment.
iv) Collection of blood
7 Months – 12 Months 23K
19. samples to be done 16-20
hours after application of the
product.
PHASE 3
PROPOSED STRATEGY TIMELINE BUDGET (US DOLLARS)
Double blinded study of the
safety and efficacy of our
product versus its vehicle in
patients with distal subungual
tinea unguium of the toenails
Number of patients: 250-1000
ii) In addition to phase 2
protocol, the product shall also
be applied to nail bed,
hyponchium and ventral
surface.
12-18 Months 50K
For any further queries, and suggestions about the nature, protocol, and use of the terms, the
reader is advised to contact the regulatory affairs department of GEN Biotech.
RENESHA SRIVASTAVA
Associate, Regulatory Affairs.
