Transcript Regulatory Considerations in the development of Topical

Regulatory Considerations in
the Development of Topical
Microbicides
Prof.S.D.Seth
Advisor
Indian Council of Medical Research
New Delhi
The Need for Vaginal
Microbicides
• Safe, effective, acceptable and affordable vaginal
microbicides to reduce the risk of STD transmission,
particularly HIV, are urgently needed as an alternative
or adjunct to condom use.
• Access to a safe and effective microbicide would
benefit both women and men. However, women’s
need for a protective method that
they can control is particularly great.
Topical Microbicide
A range of drug/ biologic product
formulation.
Application device/ dosage form variable
Vaginal or rectal route.
Microbiological activity against HIV
and/or STDs.
Action on sperm
The ideal Microbicide
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Would be active against a range of STD-causing pathogens,
Not irritate mucosal surfaces
Be available in spermicidal and nonspermicidal formulations
Be acceptable, easy to use and affordable
Coat and stick to mucosal surface
Not be absorbed systemically
Have long duration
Be effective immediately
Be stable at high temperatures and
Maintain or even enhance normal vaginal ecology
Regulatory Guidelines
Investigational new drugs have to follow the
guidelines under the Govt. of India Drugs
and Cosmetic Acts Schedule ‘Y’- Notification
Jan 2005 (GSR.294(E)).
Regulatory Requirements
Chemical and Pharmaceutical
Information
Chemistry
Data on Formulation
Quality control
Stability Studies
Regulatory RequirementsSpecial considerations
Microbiological evaluation
Proof of concept studies should
be conducted in vitro.
In vitro activity should be
assessed against the strains of
HIV and specially against
HIV-1c prevalent in India.
Regulatory RequirementsSpecial considerations
Other Microbiological Consideration
pH sensitivity
Effect of biological load-mucus,
semen or blood
Effect on the normal flora.
Effect on cell lining of vagina.
Effect on vaginal secretions.
Regulatory Requirements
Pharmacology/ toxicological Studies
Pharmacology Studies - Animal studies
for Specific and General
pharmacological actions.Follow-up and
Supplemental Safety studies.
Pharmacokinetics: absorption,
distribution; metabolism; excretion.
For further details refer to Schedule ‘Y’
Regulatory Requirements
Already marketed Spermicides –
No additional non clinical pharmacology
/ toxicology studies are needed.
For further details refer to Schedule ‘Y’
Regulatory Requirements
Animal Toxicology
General Aspects
Systemic Toxicity Studies
Special Studies
Male Fertility Study
Female Reproduction
Teratogenicity Studies
Perinatal Toxicity
Toxicology Studies
To support the safety of the individual phases of
clinical development, studies in at least two animal
species (one being a non-redent)
Used to assess acute, subchronic and chronic toxicity
at the proposed site of exposure.
Potential sites of exposure to topical microbicides for
the prevention of STDs include vaginal, cervical,
penile, oral and
rectal mucosal areas
Toxicology Studies (continues…)
Studies should use at least three dose levels of the drug
and an appropriate control, with the high dose showing
frank toxicity
Low dose showing little or no toxicity
To be applied should be in its final formulation and the
study duration should be equal to, or longer than, the
proposed duration of treatment in the clinical trial.
An early trial, the duration of treatment is for less than two
weeks, a nonclinical study duration of
two weeks should generally be used.
Pharmacokinetic/Toxicokinetic Studies
Concurrent pharmacokinetic/toxicokinetic analyses should be
performed to evaluate the drug’s ADME (absorption, disposition,
metabolism and excretion) profile and to determine if the drug is
systemically absorbed.
Major pharmacokinetic endpoints such as maximum plasma
concentration, time to maximum plasma concentration, area
under the concentration, time curve, volume of distribution,
bioavailability and clearance should be
determined.
To better assess margins of safety, the animal
pharmacokinetic data should be compared
with data in humans.
Regulatory RequirementsSpecial considerations
New Formulation or Combination of
Already Marketed Drugs
Vaginal Toxicity tests
Mucosal and dermal irritation tests
Dermal hypersensitivity test
Photosensitivity
Pharmacokinetic studies to
determine the systemic absorption
Regulatory RequirementsSpecial considerations
Vaginal Toxicity Tests
Rabbit or dog (6 to 10 animals-each group).
Test substance applied topically.
Higher concentrations or several daily applications
to achieve multiples of daily human dose.
Applied for minimum 7 days (more according to
clinical use),maximum 30 days.
Observations- swelling,closure of
introitus & histopathology of
vaginal wall.
Toxicity Studies (contd….)
Safety of a drug should be performed according to GLP
Microbicides are intended for intermittent use during periods in
which the individual will be at risk of contracting a STD and
contraceptives are intended for intermittent use over long periods
of reproductive competence, they are, for regulatory purposes
considered to be chronically administered drugs
Latter stages of clinical development, six month studies in a rodent
and one year toxicity studies in a non-rodent (rabbit or dog)
Carcinogenicity and Genotoxicity studies in rats and mice should
be performed during the late stages of the drug development
program
Irritation
Drug-induced irritation should be evaluated in animals at
both the macroscopic and microscopic levels
Vaginal irritation tests should be carried out in rabbits with
daily applications for ten days.
Rabbits are adequately tested by the vaginal route for
adverse effects in toxicity studies, no separate vaginal
irritation study is required
Drug is found to be irritating to mucosal tissues additional
pharmacokinetics should be carried out to compare the
extent of penetration of the drug across the inflamed tissue
with that occurring in intact tissue
The absorption kinetics of the drug is facilitated when the
mucosa is compromised
Hypersensitivity and Photosensitivity
The potential to produce hypersensitivity and
photosensitivity of the drug should be evaluated
Genotoxicity
Tests should be carried out to evaluate all new
molecular entities for the potential to induce genotoxic
effects
A gene mutation test in bacteria
An in vitro mouse lymphoma tk assay or a mammalian
cell in vitro
An in vivo test for chromosomal damage
The three tests chosen indicate that the drug is devoid
of genetic toxicity, no additional studies need to be
carried out.
More if the battery is positive, the sponsor will be
expected to carry out additional genotoxicity test in
Reproductive Toxicology
Should be carried out to explore the possible
effects of the drug on fertility and reproductive
performance.
Additional studies should be performed to examine
whether the drug is teratogenic or has an affect on
perinatal/postnatal development.
Studies designed to assess the teratogenic
potential should be carried out in two species,
usually in rats and rabbits.
Reproductive toxicology studies should be
completed prior to phase 2/3 trials.
Carcinogenicity
Carcinogenicity information is usually obtained
during the final phase of the clinical development
program.
For a vaginal contraceptive, carcinogenicity tests
in rats and mice should be submitted with the NDA
for a microbicide.
Carcinogencity studies are also required, but the
expected date of completion of the studies in
relation to the filing of the NDA may vary.
The drug should be administered for two years
First-Generation Products
Developed in the 1990s, the earliest microbicide
products are expected to provide partial protection
against HIV infection. First generation microbicides
include products that work by forming physical
barriers to the virus and by changing the chemistry
woman’s vagina to make infection less likely.
Next-Generation Products
Next-Generation microbicides – those
specifically designed to be active against
HIV – as well as combination therapies hold
promise of even greater protection against
HIV transmission than earlier formulations.