- Email: [email protected]
Successful development of an orphan drug for the pediatric population
350
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
status epilepticus in childhood: prospective population-based study. Lancet 368, 222–229. Conroy, S., Morton, R., Dixon, H., Porter, A., Choonara, I.A., 2000. prospective study of intranasal midazolam for children with acute seizures. Paediatr. Perinat. Drug Ther. 4, 52–57. McIntyre, J., Robertson, S., Norris, E., et al., 2005. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet 366, 205–210. Mpimbaza, A., Ndeezi, G., Staedke, S., Rosenthal, P.J., Byarugaba, J., 2008. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: a randomized clinical trial. Pediatrics 121, e58–e64. Scott, R.C., Besag, F.M.C., Boyd, S.G., et al., 1998. Buccal absorption of midazolam: pharmacokinetics and EEG pharmacodynamics. Epilepsia 39, 290–294. Scott, R.C., Besag, F.M.C., Neville, B.G.R., 1999. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet 353, 623–626.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.065 Successful development of an orphan drug for the pediatric population P. Mambrini, Y. Kibleur ∗ Lucane Pharma, 172 rue de Charonne, 75011 Paris, France E-mail address: [email protected] (Y. Kibleur). The title of this presentation includes several aspects: Pediatric population. By definition, the pediatric population is a small and fragile population compared to the general population. Consequently, to develop a medicinal product for such a population is of poor interest for the Pharma industry, for various reasons among which economical reasons and the difficulty to handle clinical trials. Orphan drugs is a legal terminology which appeared in the European legislation in 2000. Such legislation was implemented to mimic the Orphan Drug Act in place in the US since 1983. An Orphan Drug is a medicinal product which is indicated for a rare disorder. The disorder must affect not more than 5/10000 inhabitants (prevalence). Such a disease must be debilitating or life threatening for which no treatment is available. In case a treatment is already available for such a disease, a new medicinal product must bring a significant benefit over the existing (in most cases, a clinical significant benefit). The main incentives in EU brought by this legislation are: 10 years of commercial exclusivity, the free access to scientific advice at EMA, the access to the centralized procedure whatever the product is. To illustrate what this means in term of number of patients the definition of an Orphan Drug, here are some examples: France: 32000 patients, Italy: 28000 patients, Germany: 45000 patients, Spain: 20000 patients, Portugal: 5000 patients, and European Union: 250000 patients. For those of you approaching their retirement, this level of prevalence was considered 30 years ago as being attractive enough to stimulate the development of medicinal products without any incentives. The key achievement of this Orphan Drug legislation has been to stimulate the development of much lower prevalence which was not considered at all in the past. The classical process involves to (1) generate some initial date which can support the potential claim, (2) apply for an ODD at EMA (COMP), and (3) to develop, implement and submit your Marketing Authorization Application to EMA as any MAA). Granting of an ODD is a great achievement, but worth nothing until MA is granted. Granting of a MA for a medicinal product which benefits of an ODD is worth something as it gives instantly access to market exclusivity of 10 years throughout the EU.
Rare disorders. Quite a lot of those disorders are of genetic origin, which means most often a pediatric population and a lifelong treatment. The translation is: a very small population of patients, and a rather secured market from financial stand point. A successful development. This is a difficult area as it should be considered from various angles: a/Market need, b/Technical achievement, c/Regulatory, and d/Economics Taking as an example Sodium Phenylbutyrate a product we have developed at Lucane Pharma over the last 3 years, as an adjunctive treatment for long term management of Urea Cycle disorders (UCD) involving deficit in CPS, OTC or ASS. UCD is a group of genetic disorders, extremely rare (about 600 patients in the EU) characterized by a dysfunction of the urea cycle. Without entering into biochemistry, the main consequence is the accumulation of waste nitrogen (main source: protein intake) as ammonia, which is a very toxic compound for the brain. Symptoms may occur at a very early stage or at a later stage. When symptoms occur, ammonia levels can increase dramatically, consequence being irreversible neurological damage or death. It is therefore critical to assess the diagnostic as quickly as possible. The aim of the therapy is to decrease the ammonia level as quickly as possible, using nitrogen scavengers (sodium phenylbutyrate, sodium benzoate). Phenylbutyrate and benzoate get rid of the waste nitrogen through 2 different biochemical pathways, which are complementary. They have to be used 3–4 times a day, lifelong, by infants, children or adults. Therefore, the product developed has to fit several needs, on top of being effective, among which palatability, convenience of the route of administration, easy conditions for storage. Since the mid 1990s, a product is available worldwide, registered in the EU since 1999. However phenylbutyrate is characterized by a very bad taste jeopardizing the compliance and making life of both patients and parents very difficult. Taste is so awful that children may need the use of a nasogastric tube to get the product. Dieticians have used all possible tricks to mask the taste of this molecule, without any success. It was therefore critical to assess in an objective way the bad taste of this active substance. Some experiments were conducted using the e-tongue technology in experiments carried out at University of Düsseldorf. Results clearly demonstrate the strong taste of this compound as NaPB stimulates all sensors. It is therefore useful to try to mask such an awful taste, to expect a good compliance to the treatment. This being done, the next challenge was to develop a formulation which can fit the patient population at any age, as the very small number of patients forbid to develop several formulations. Two major constraints influenced the selection of the formulation: the age (children under 6 years of age cannot swallow standard tablets or capsules) and the high daily dose (related to the bodyweight and the protein diet). Due to various characteristics of the molecule and the need of the patient population, we ended up to a specific formulation which includes a two-step coating sugar sphere. It is coated successively with API and with a taste masking agent. With such a size of particles, it is rather difficult to succeed on a laboratory scale, and even much more difficult to upscale. The outcome is a very small granule (250 m, Fig. 1) which flows very well, stable at room temperature and more importantly tasteless. The e-tongue technology does not allow demonstrating the taste masking as the API has to be put in solution and is such a strong e-tongue sensors stimulant. A continuous dissolution profile study was the way to demonstrate that no API is released at the beginning, and then very progressively released (Guffon et al., 2012). This demonstrates the taste masking effectiveness as such small granules can easily be swallowed followed by a glass of water, or sprinkled on food, before the starting of the release of the API.
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
351
in parallel with the small size of the patient population on an EU basis, even more on a national basis. The batch being by definition small, packaging in 25 different languages becomes immediately a nightmare. It is therefore of the utmost importance to rationalize the packaging and a specific box has been developed which allows having all different languages on the same box. This will allow having only one pack for the whole EU, making it manageable from batch release and logistic point of view. The final hurdle will be the negotiation of an acceptable price from the various social systems to make the whole project viable. The current financial environment is not the most favorable but we are hoping to be able to give you next year the conclusion of this presentation that this was a successful development. Fig. 1. Structure of the NaPB two-step coated granule.
Reference To be able to take the right dose prescribed, a specific CE-labeled dosing spoon was developed and validated (Fig. 2) to allow a wide flexibility in the dose ranging; fitting the needs of all patients. The bioequivalence of this formulation with the reference powder was a prerequisite to the whole development and the curves between the reference and the new formulation can hardly be distinguished (Guffon et al., 2012). Moreover the taste characteristics were evaluated in healthy volunteers and confirmed the statistical differences in palatability in favor of this new formulation vs. the reference on bitterness, saltiness and general acceptability. Eventually, the adverse events reported showed 5 ageusia and 1 dropout for severe vomiting after the reference product, and none with ours, all these results confirming the previous in vitro results. Going towards success. An ODD was granted in February 2012 to this new formulation, even though a reference product was registered in the EU since 1999. This ODD was based on a significant clinical benefit over the reference product. A Marketing Authorization Application was introduced in March 2012, and responses to D120 questions are under preparation. Still some hurdles before talking about a successful development, among which the packaging. There are more than 24 different languages in the EU and soon 25 (+Croatian). This has to be put
Guffon, N., Kibleur, Y., Copalu, W., et al., 2012. Developing a new formulation of sodium phenylbutyrate. Arch. Dis. Child. 97, 1081–1085, http://dx.doi.org/10.1136/archdischild-2012-302398.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.066 Microparticulates as drug carriers for pediatric use Norbert Pöllinger Glatt GmbH, Pharmaceutical Services Europe, Binzen, Germany
1. Background “An appropriate drug formulation is the basis of an efficient drug therapy for children. It should allow administering medicines to children accurately and safely. If children refuse to take their medicine or if the formulation concept fails due to a pediatric particularity, the efficacy of the therapy is at risk and medication errors are possible.” (Tuleu et al., 2010). Therefore, the goal is to develop relevant and acceptable pediatric formulations with convenient and precise dosing characteristics in an industrial scale suitable for marketing at affordable cost. The oral administration is the preferred route of administration. It is well accepted in all age groups if administered in a suitable form and allows accurate and flexible dosing. When the taste is acceptable, oral liquids are favored by children. Ideally, medicines should be available in both liquid and solid oral dosage forms. Palatability has become an integral part of formulation development to ensure acceptability of medicines by children (quality part of PIP). While adults can overcome the innate reluctance to swallow a bitter pill, small children cannot make that educated decision. In particular bitter taste lingers longer than other tastes and cannot be simply overcome by adding other taste like a flavor. Therefore, a bad taste must be encapsulated to render the taste imperceptible. Micropellets are considered to be an interesting concept to realize a broad spectrum of pediatric drug products. 2. Considerations on pediatric drug products
Fig. 2. CE-labeled NaPB specific spoon.
When oral pediatric drug products shall be developed a number of important aspects such as the dosage form, the topic of fixed or individualized doses, the potential combination of APIs, the excipients to be used and the taste must be considered in depth. In addition, the specific age of the pediatric patients, the specific conditions to be treated and the specific cultural and treatment settings must be taken into account.
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
status epilepticus in childhood: prospective population-based study. Lancet 368, 222–229. Conroy, S., Morton, R., Dixon, H., Porter, A., Choonara, I.A., 2000. prospective study of intranasal midazolam for children with acute seizures. Paediatr. Perinat. Drug Ther. 4, 52–57. McIntyre, J., Robertson, S., Norris, E., et al., 2005. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet 366, 205–210. Mpimbaza, A., Ndeezi, G., Staedke, S., Rosenthal, P.J., Byarugaba, J., 2008. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: a randomized clinical trial. Pediatrics 121, e58–e64. Scott, R.C., Besag, F.M.C., Boyd, S.G., et al., 1998. Buccal absorption of midazolam: pharmacokinetics and EEG pharmacodynamics. Epilepsia 39, 290–294. Scott, R.C., Besag, F.M.C., Neville, B.G.R., 1999. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet 353, 623–626.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.065 Successful development of an orphan drug for the pediatric population P. Mambrini, Y. Kibleur ∗ Lucane Pharma, 172 rue de Charonne, 75011 Paris, France E-mail address: [email protected] (Y. Kibleur). The title of this presentation includes several aspects: Pediatric population. By definition, the pediatric population is a small and fragile population compared to the general population. Consequently, to develop a medicinal product for such a population is of poor interest for the Pharma industry, for various reasons among which economical reasons and the difficulty to handle clinical trials. Orphan drugs is a legal terminology which appeared in the European legislation in 2000. Such legislation was implemented to mimic the Orphan Drug Act in place in the US since 1983. An Orphan Drug is a medicinal product which is indicated for a rare disorder. The disorder must affect not more than 5/10000 inhabitants (prevalence). Such a disease must be debilitating or life threatening for which no treatment is available. In case a treatment is already available for such a disease, a new medicinal product must bring a significant benefit over the existing (in most cases, a clinical significant benefit). The main incentives in EU brought by this legislation are: 10 years of commercial exclusivity, the free access to scientific advice at EMA, the access to the centralized procedure whatever the product is. To illustrate what this means in term of number of patients the definition of an Orphan Drug, here are some examples: France: 32000 patients, Italy: 28000 patients, Germany: 45000 patients, Spain: 20000 patients, Portugal: 5000 patients, and European Union: 250000 patients. For those of you approaching their retirement, this level of prevalence was considered 30 years ago as being attractive enough to stimulate the development of medicinal products without any incentives. The key achievement of this Orphan Drug legislation has been to stimulate the development of much lower prevalence which was not considered at all in the past. The classical process involves to (1) generate some initial date which can support the potential claim, (2) apply for an ODD at EMA (COMP), and (3) to develop, implement and submit your Marketing Authorization Application to EMA as any MAA). Granting of an ODD is a great achievement, but worth nothing until MA is granted. Granting of a MA for a medicinal product which benefits of an ODD is worth something as it gives instantly access to market exclusivity of 10 years throughout the EU.
Rare disorders. Quite a lot of those disorders are of genetic origin, which means most often a pediatric population and a lifelong treatment. The translation is: a very small population of patients, and a rather secured market from financial stand point. A successful development. This is a difficult area as it should be considered from various angles: a/Market need, b/Technical achievement, c/Regulatory, and d/Economics Taking as an example Sodium Phenylbutyrate a product we have developed at Lucane Pharma over the last 3 years, as an adjunctive treatment for long term management of Urea Cycle disorders (UCD) involving deficit in CPS, OTC or ASS. UCD is a group of genetic disorders, extremely rare (about 600 patients in the EU) characterized by a dysfunction of the urea cycle. Without entering into biochemistry, the main consequence is the accumulation of waste nitrogen (main source: protein intake) as ammonia, which is a very toxic compound for the brain. Symptoms may occur at a very early stage or at a later stage. When symptoms occur, ammonia levels can increase dramatically, consequence being irreversible neurological damage or death. It is therefore critical to assess the diagnostic as quickly as possible. The aim of the therapy is to decrease the ammonia level as quickly as possible, using nitrogen scavengers (sodium phenylbutyrate, sodium benzoate). Phenylbutyrate and benzoate get rid of the waste nitrogen through 2 different biochemical pathways, which are complementary. They have to be used 3–4 times a day, lifelong, by infants, children or adults. Therefore, the product developed has to fit several needs, on top of being effective, among which palatability, convenience of the route of administration, easy conditions for storage. Since the mid 1990s, a product is available worldwide, registered in the EU since 1999. However phenylbutyrate is characterized by a very bad taste jeopardizing the compliance and making life of both patients and parents very difficult. Taste is so awful that children may need the use of a nasogastric tube to get the product. Dieticians have used all possible tricks to mask the taste of this molecule, without any success. It was therefore critical to assess in an objective way the bad taste of this active substance. Some experiments were conducted using the e-tongue technology in experiments carried out at University of Düsseldorf. Results clearly demonstrate the strong taste of this compound as NaPB stimulates all sensors. It is therefore useful to try to mask such an awful taste, to expect a good compliance to the treatment. This being done, the next challenge was to develop a formulation which can fit the patient population at any age, as the very small number of patients forbid to develop several formulations. Two major constraints influenced the selection of the formulation: the age (children under 6 years of age cannot swallow standard tablets or capsules) and the high daily dose (related to the bodyweight and the protein diet). Due to various characteristics of the molecule and the need of the patient population, we ended up to a specific formulation which includes a two-step coating sugar sphere. It is coated successively with API and with a taste masking agent. With such a size of particles, it is rather difficult to succeed on a laboratory scale, and even much more difficult to upscale. The outcome is a very small granule (250 m, Fig. 1) which flows very well, stable at room temperature and more importantly tasteless. The e-tongue technology does not allow demonstrating the taste masking as the API has to be put in solution and is such a strong e-tongue sensors stimulant. A continuous dissolution profile study was the way to demonstrate that no API is released at the beginning, and then very progressively released (Guffon et al., 2012). This demonstrates the taste masking effectiveness as such small granules can easily be swallowed followed by a glass of water, or sprinkled on food, before the starting of the release of the API.
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
351
in parallel with the small size of the patient population on an EU basis, even more on a national basis. The batch being by definition small, packaging in 25 different languages becomes immediately a nightmare. It is therefore of the utmost importance to rationalize the packaging and a specific box has been developed which allows having all different languages on the same box. This will allow having only one pack for the whole EU, making it manageable from batch release and logistic point of view. The final hurdle will be the negotiation of an acceptable price from the various social systems to make the whole project viable. The current financial environment is not the most favorable but we are hoping to be able to give you next year the conclusion of this presentation that this was a successful development. Fig. 1. Structure of the NaPB two-step coated granule.
Reference To be able to take the right dose prescribed, a specific CE-labeled dosing spoon was developed and validated (Fig. 2) to allow a wide flexibility in the dose ranging; fitting the needs of all patients. The bioequivalence of this formulation with the reference powder was a prerequisite to the whole development and the curves between the reference and the new formulation can hardly be distinguished (Guffon et al., 2012). Moreover the taste characteristics were evaluated in healthy volunteers and confirmed the statistical differences in palatability in favor of this new formulation vs. the reference on bitterness, saltiness and general acceptability. Eventually, the adverse events reported showed 5 ageusia and 1 dropout for severe vomiting after the reference product, and none with ours, all these results confirming the previous in vitro results. Going towards success. An ODD was granted in February 2012 to this new formulation, even though a reference product was registered in the EU since 1999. This ODD was based on a significant clinical benefit over the reference product. A Marketing Authorization Application was introduced in March 2012, and responses to D120 questions are under preparation. Still some hurdles before talking about a successful development, among which the packaging. There are more than 24 different languages in the EU and soon 25 (+Croatian). This has to be put
Guffon, N., Kibleur, Y., Copalu, W., et al., 2012. Developing a new formulation of sodium phenylbutyrate. Arch. Dis. Child. 97, 1081–1085, http://dx.doi.org/10.1136/archdischild-2012-302398.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.066 Microparticulates as drug carriers for pediatric use Norbert Pöllinger Glatt GmbH, Pharmaceutical Services Europe, Binzen, Germany
1. Background “An appropriate drug formulation is the basis of an efficient drug therapy for children. It should allow administering medicines to children accurately and safely. If children refuse to take their medicine or if the formulation concept fails due to a pediatric particularity, the efficacy of the therapy is at risk and medication errors are possible.” (Tuleu et al., 2010). Therefore, the goal is to develop relevant and acceptable pediatric formulations with convenient and precise dosing characteristics in an industrial scale suitable for marketing at affordable cost. The oral administration is the preferred route of administration. It is well accepted in all age groups if administered in a suitable form and allows accurate and flexible dosing. When the taste is acceptable, oral liquids are favored by children. Ideally, medicines should be available in both liquid and solid oral dosage forms. Palatability has become an integral part of formulation development to ensure acceptability of medicines by children (quality part of PIP). While adults can overcome the innate reluctance to swallow a bitter pill, small children cannot make that educated decision. In particular bitter taste lingers longer than other tastes and cannot be simply overcome by adding other taste like a flavor. Therefore, a bad taste must be encapsulated to render the taste imperceptible. Micropellets are considered to be an interesting concept to realize a broad spectrum of pediatric drug products. 2. Considerations on pediatric drug products
Fig. 2. CE-labeled NaPB specific spoon.
When oral pediatric drug products shall be developed a number of important aspects such as the dosage form, the topic of fixed or individualized doses, the potential combination of APIs, the excipients to be used and the taste must be considered in depth. In addition, the specific age of the pediatric patients, the specific conditions to be treated and the specific cultural and treatment settings must be taken into account.