Drug utilisation guidelines from FDA for children with eye disease
In an article sponsored by ISOPT Clinical, Wiley Chambers MD of the US FDA talks to Ron Neumann of ISOPT Clinical about increasiing pharmacologic knowledge in children suffering from eye diseases.
[caption id="attachment_6148" align="alignnone" width="350"]
Wiley Chambers, MD[/caption]
Q: How does the FDA exert its influence in order to increase pharmacologic knowledge in children suffering from eye diseases?
A (WC): The Food, Drug and Cosmetic Act was amended with the passage of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). In essence, BPCA provides a carrot, an incentive to study and label a product for use in children (in the form of a six-month extension of sales exclusivity).
PREA is a stick for the regulatory agency, the ability to require that a product be studied in all relevant populations. Ultimately, PREA and BPCA have a shared goal of providing new paediatric information, drug labelling, and encouraging the appropriate use of medication to treat these patients. FDA is responsible for carrying out the intent of both laws simultaneously and effectively. Drugs and biologics are both covered by PREA and BPCA.
There are differences and similarities between PREA and BPCA, including:
*PREA studies are mandatory; BPCA studies are voluntary.
* PREA requires studies only on indication(s) under review; BPCA studies relate to an entire moiety and may include unapproved and different indications.
*Studies for orphan indications are exempt from PREA; however, written requests may be issued for orphan indications under BPCA.
*Studies conducted for either PREA/BPCA must be included in the labelling after review by the FDA.
Within ophthalmology, we expect every drug product to be studied in all age groups unless a specific reason is provided.
Q: Taking PREA and BPCA in mind, can you tell us briefly some examples where either were utilised to provide more data in ocular paediatric diseases?
A (WC): Over the past 30 years, well before PREA and BPCA, ophthalmic anti-infective and anti-allergic studies have routinely included kids, as those diseases are highly prevalent in paediatric populations. Studies in these
areas have continued under PREA and BPCA. Intraocular pressure (IOP)-lowering agents were often not studied in children until the FDA requested studies. For example, brimonidine paediatric information was
added post-approval after receiving
a BPCA request by the agency.
Timolol happened to be studied along with other IOP-lowering products in paediatric patients. The unanswered question for paediatric patients taking prostaglandin analogues is: what will happen after 20 years of melanosome stimulation. Melanosome stimulation has been shown to be safe in studies of up to five years. However, BPCA is not well set up to
answer such long-term questions.
Q: Children are less prone to ocular diseases - how does
the agency deal with scarcity of some indications in
younger populations?
A (WC): Within ophthalmology, we expect every drug product to be studied in all age groups unless a specific reason is provided. For many ophthalmic diseases, there is little if any difference between the eyes of children and adults, and most ophthalmic drug products for these conditions are approved for use in both adults and paediatric patients. Enrolment in clinical trials is generally opened to paediatric patients as soon as there is some expectation of benefit from the drug product.
Drug products for pupillary dilation, cycloplegia and topical anaesthetics are approved for use in children. However, some ocular diseases, for example age-related macular degeneration, does not exist in children (or generally adults under 50 years of age) and therefore paediatric studies are not required. Glaucoma rarely occurs in patients under 18 years of age, and when it does, it is often treated with surgical procedures. Dry eye conditions rarely occur in individuals less than 18 years of age.
Q: Is there guidance for specific child conditions such as retinopathy of prematurity (ROP), children's herpetic and bacterial keratitis, anti-myopic drugs and anti-inflammatory drugs for paediatric uveitis?
A (WC): The agency does not have any formal guidance documents for any of the indications listed above. ROP studies are done today with great caution due to concern of the potential systemic effects of vascular endothelial growth factor (VEGF) inhibitors. Herpetic keratoconjunctivitis tends to be very rare before the age of three years. At that age the cornea has completed its development, and thus there are only minimal differences in drug effect from the adult disease. However, there have been very few new drug products studied in this area for years. Uveitis is often studied in patients of all ages, although the prevalence of uveitis in children is low.
Q: Do you have any insights to share regarding reporting of adverse events in children and utilisation of drugs in children, with much information derived from adults and extended to children?
A (WC): The agency strongly encourages the reporting of all adverse events, from all sources and all age groups. Since many of the drugs utilised in paediatric ophthalmology have been on the market for a long time, the adverse event profile is fairly well known. With the exception of ROP, it is common for ophthalmic drug products utilised in children to have obtained sufficient knowledge during initial development to support approval in children at the time of initial approval.
Dr Wiley Chambers is Deputy Director, Division of Transplant & Ophthalmology Products, Center for Drug Evaluation & Research, at the US FDA
Wiley Chambers: wiley.chambers@fda.hhs.gov
Wiley Chambers, MD[/caption]
Q: How does the FDA exert its influence in order to increase pharmacologic knowledge in children suffering from eye diseases?
A (WC): The Food, Drug and Cosmetic Act was amended with the passage of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). In essence, BPCA provides a carrot, an incentive to study and label a product for use in children (in the form of a six-month extension of sales exclusivity).
PREA is a stick for the regulatory agency, the ability to require that a product be studied in all relevant populations. Ultimately, PREA and BPCA have a shared goal of providing new paediatric information, drug labelling, and encouraging the appropriate use of medication to treat these patients. FDA is responsible for carrying out the intent of both laws simultaneously and effectively. Drugs and biologics are both covered by PREA and BPCA.
There are differences and similarities between PREA and BPCA, including:
*PREA studies are mandatory; BPCA studies are voluntary.
* PREA requires studies only on indication(s) under review; BPCA studies relate to an entire moiety and may include unapproved and different indications.
*Studies for orphan indications are exempt from PREA; however, written requests may be issued for orphan indications under BPCA.
*Studies conducted for either PREA/BPCA must be included in the labelling after review by the FDA.
Within ophthalmology, we expect every drug product to be studied in all age groups unless a specific reason is provided.
Q: Taking PREA and BPCA in mind, can you tell us briefly some examples where either were utilised to provide more data in ocular paediatric diseases?
A (WC): Over the past 30 years, well before PREA and BPCA, ophthalmic anti-infective and anti-allergic studies have routinely included kids, as those diseases are highly prevalent in paediatric populations. Studies in these
areas have continued under PREA and BPCA. Intraocular pressure (IOP)-lowering agents were often not studied in children until the FDA requested studies. For example, brimonidine paediatric information was
added post-approval after receiving
a BPCA request by the agency.
Timolol happened to be studied along with other IOP-lowering products in paediatric patients. The unanswered question for paediatric patients taking prostaglandin analogues is: what will happen after 20 years of melanosome stimulation. Melanosome stimulation has been shown to be safe in studies of up to five years. However, BPCA is not well set up to
answer such long-term questions.
Q: Children are less prone to ocular diseases - how does
the agency deal with scarcity of some indications in
younger populations?
A (WC): Within ophthalmology, we expect every drug product to be studied in all age groups unless a specific reason is provided. For many ophthalmic diseases, there is little if any difference between the eyes of children and adults, and most ophthalmic drug products for these conditions are approved for use in both adults and paediatric patients. Enrolment in clinical trials is generally opened to paediatric patients as soon as there is some expectation of benefit from the drug product.
Drug products for pupillary dilation, cycloplegia and topical anaesthetics are approved for use in children. However, some ocular diseases, for example age-related macular degeneration, does not exist in children (or generally adults under 50 years of age) and therefore paediatric studies are not required. Glaucoma rarely occurs in patients under 18 years of age, and when it does, it is often treated with surgical procedures. Dry eye conditions rarely occur in individuals less than 18 years of age.
Q: Is there guidance for specific child conditions such as retinopathy of prematurity (ROP), children's herpetic and bacterial keratitis, anti-myopic drugs and anti-inflammatory drugs for paediatric uveitis?
A (WC): The agency does not have any formal guidance documents for any of the indications listed above. ROP studies are done today with great caution due to concern of the potential systemic effects of vascular endothelial growth factor (VEGF) inhibitors. Herpetic keratoconjunctivitis tends to be very rare before the age of three years. At that age the cornea has completed its development, and thus there are only minimal differences in drug effect from the adult disease. However, there have been very few new drug products studied in this area for years. Uveitis is often studied in patients of all ages, although the prevalence of uveitis in children is low.
Q: Do you have any insights to share regarding reporting of adverse events in children and utilisation of drugs in children, with much information derived from adults and extended to children?
A (WC): The agency strongly encourages the reporting of all adverse events, from all sources and all age groups. Since many of the drugs utilised in paediatric ophthalmology have been on the market for a long time, the adverse event profile is fairly well known. With the exception of ROP, it is common for ophthalmic drug products utilised in children to have obtained sufficient knowledge during initial development to support approval in children at the time of initial approval.
Dr Wiley Chambers is Deputy Director, Division of Transplant & Ophthalmology Products, Center for Drug Evaluation & Research, at the US FDA
Wiley Chambers: wiley.chambers@fda.hhs.gov
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