Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Wa

1. Regulatory requirements for the development of medicinal products for pediatric use Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007

2. Regulatory requirements for the development of medicinal products for pediatric use Presenter: Dr Tom Sam Industrial Pharmacy Section International Pharmaceutical Federation (FIP) The significant contributions to this presentation of the following persons is gratefully acknowledged: - Nicole Herijgers - NV Organon - Lisette Vromans - NV Organon

3. Outline • Regulatory environment • Timing of pediatric studies during development • Type of development studies needed • Addressing pediatric information in the labelling • Need for special drug formulations

4. Introduction • Use of unlicensed and off-label medicines in children is wide-spread • > 60% of all medicines used in children have never been tested and are not authorised in the peadiatric population ([i]) • These products have only been tested in adults, not necessarily in the same indication or same disease. • Lack of information and appropriate pharmaceutical formulations may expose children to unwanted side effects or underdosing without the expected efficacy. [i]Le Cam, Y. Medicines for children: better, more and faster. Regulatory Rapporteur. May 2005: 8.

5. Requirements (1) • Canada - Registration of pediatric drug follows normal procedure. • Australia - Market authorisation may be denied / delayed, if clinical pediatric data is not included but is deemed appropriate. • India - If new drug is intended to treat both adults and pediatric patients, the pediatric population should be included in the clinical trials from an early point onwards. If pediatric data is not included, this needs to be justified in detail. • China - Registration of pediatric drug follows normal procedure. Clinical trials on children are discouraged unless the drug-use is limited to only the pediatric population.

6. Requirements (2) • Japan - No mandatory pediatric clinical trials. There are however, ongoing projects organized by the MHLW (Ministry of Health, Labour and Welfare), which aim to facilitate an accelerated review of off-label pediatric drugs. • South Korea - Non-established legislation for pediatric drugs. • Switzerland - Pediatric studies are not mandatory for drug registration, unless the drug has potential pediatric use.

7. US legislation on pediatric medicines • Pediatric Rule issued by FDA in December 1998 ([i]).Required the conduct of pediatric studies and development of pediatric formulationsThe Pediatric Rule suspended in October 2002. • Pediatric Research Equity Act (PREA) law in 2003 ([ii],[iii]). • Pediatric Exclusivity Provision - complementary to the PREA,which provides an incentive for companies who perform clinical trials in the pediatric population ([iv]). [i] Pediatric Rule was codified at 21 CFR 314.55 and 601.27 with additional amendments to 21 CFR 201, 312, 314 and 601. [ii] Pediatric Research Equity Act of 2003 (http://www.fda.gov.cder.pediatric/index.htm accessed on 27 March 2006) [iii] Draft Guidance for Industry – How to comply with the Pediatric Research Equity Act. September 2005((http://www.fda.gov.cder.pediatric/index.htm accessed on 27 March 2006). [iv] This provision was originally included in the FDA Modernisation Act 1997(http://www.fda.gov.cder.pediatric/index.htm accessed on 27 March 2006), but after its sunset it has been retained in the Best Pharmaceuticals for Children Act 2002 (http://www.fda.gov.cder.pediatric/index.htm accessed on 27 March 2006).

8. Items to be addressed in a proposed pediatric study request Type and objective of studies to be performed Indications to be studied Number of patients to be studied Age groups in which the studies will be performed Study endpoints Timing of assessments (if appropriate) Entry criteria Drug information Dosage form Regimens Route of administration Drug-specific safety concerns to be monitored or assessed Statistical information, including power of study and statistical analyses of the data Labeling that may result from the studies Format of report to be submitted to the FDA Timeframe for submitting reports of the studies Template for a proposed pediatric study request is available at www.fda.gov/cder/pediatric/wr_template.htm

9. EU legislation on pediatric medicines (1) • 26 January 2007European pediatric medicines legislation into force • Objectives: • Increasing high quality research in medicines for children • Promoting development and authorisation • Improving information on medicines for children • To be achieved without doing unnecessary studies in children and without delaying development in adults

10. EU legislation on pediatric medicines (2)Key elements (1) • Pediatric development mandatory for • all new products • all new indications, pharmaceutical forms and routes of administration of existing products that are still protected by patent • Pediatric development encouraged for off-patent medicines (PUMA)

11. EU legislation on pediatric medicines (3)Key elements (2) • First contact with Regulatory Authorities about pediatric development to take place ‘not later than upon completion of the human pharmacokinetic studies in adults’ • Regulatory authority translation: contact us after completion of phase I !

12. EU legislation on pediatric medicines (4)Timelines Registration dossier First PIP Regular updates Phase1 Phase 2 Phase 3

13. EU legislation on pediatric medicines (6)What is at stake? • An application …shall be regarded as valid only if it includes…. • The results of all studies performed and details of all information collected in compliance with an agreed pediatric Investigation Plan (PIP) • Unless there is… • A decision of the Agency granting aproduct-specific waiver • A decision of the Agency granting aclass-waiver… • A decision of the Agency granting adeferral The documents in the application shall cumulatively cover all subsetsof the pediatric population

14. Pediatric Investigation Plan (PIP) • A research and development programme aimed at ensuring that the necessary data are generated determining the conditions in which a medicinal product may be authorised to treat the pediatric population

15. Principles of the PIP • Covers all subsets of the pediatric population • Covers existing and new indications, forms and routes of administration • Focuses on trials that allow labelling the product for appropriate use in all relevant subsets • Focuses on development of appropriate formulations if applicable • Contains all relevant information: favourable or unfavourable, incomplete or discontinued pharmaco-tox or clinical trials, results form trials in other indications

16. Contents of PIP (1) • Sections A to E plus Annexes (section F) • A. Administrative and product information • B. Overall development of the product • Similarities/differences of disease/condition between populations (adult/pediatric) • Anticipated similarities/differences effect of product on disease/condition • Prevalence and incidence in the pediatric population • Current methods diagnosis, prevention or treatment in pediatric population • Significant therapeutic benefit/fullfillment therapeutic need (in pediatric population)

17. Contents of PIP (2) • C. Applications for product specific waivers • D 1-4. Strategic evaluation and choices: • D1. Overall proposed strategy • D2. Strategy in relation to quality aspects • D3. Strategy in relation to non-clinical aspects • D4. Strategy in relation to clinical aspects

18. Contents of PIP (3) • D5. Planned measures for the pediatric development • Overall summary table non-clinical and clinical section • Outline of each of the planned or performed studies • Synopsis of the protocol (non-clinical or clinical) • D6 Timeline of measures in the plan

19. Contents of PIP (4) • E. Application for deferrals • F. Annexes as appropriate • References • Investigator’s brochure • Opinions and decisions by Competent authorities • Scientific advice by Competent Authorities • Latest approved Product Information (for authorised product)

20. Approval needed

21. Comparison of pediatric drug regulation * The Best Pharmaceuticals for Children Act provides a mechanism for public funding (via National Institutes of Health) of pediatric studies of certain drugs if the manufacturers of those drugs decline to conduct the requested studies

22. Outline • Regulatory environment • Timing of pediatric studies • Type of development studies needed • Addressing pediatric information in the labelling • Need for special drug formulations

23. 2. Timing of pediatric studies • US and EU legislation requires that the marketing authorisation for a new drug contains a pediatric assessment (i.e. data from pediatric studies) • unless the applicant has obtained a waiver or deferral • All subsets of the pediatric population should be addressed

24. Waivers • Waiver for medicines that are unlikely to benefit children. • Waiver according to US PREA:- the product does not represent a meaningful therapeutic benefit therapy over existing therapies([1])- the product is not likely to be used by a substantial number of pediatric patients([2]), - the studies would be impractical or impossible in the specified population (e.g. neonates), or there is already existing evidence of ineffective or unsafe use • Waiver according to EU:- the pediatric Committee intends to publish lists of waivers of specific medicinal products and classes of medicinal product [1]Meaningful therapeutic benefit over existing therapies: i.e. if drug would represent a significant improvement in the treatment, diagnosis, or prevention of a disease, compared with marketed products adequately labeled for that use in the relevant pediatric population or the drug is in a class of products or for an indication for which there is a need for additional options (5). [2]Substantial: i.e. in general 50,000 patients, but nature and severity of the condition should be taken into account (5).

25. Deferrals A deferral until a specified date after approval of the drug can be only be obtained: • when studies in children will be more appropriate when there exists some initial experience on use of a products in adults or studies in children might take longer than studies in adults. • In addition, pediatric studies may be delayed when development of a pediatric formulation is not complete

26. Pediatric lists FDA: • List of approved drugs for which additional pediatric information is expected to be beneficial ([i])) • May help companies to identify important issues and pediatric needs in a particular therapeutic area EMEA: • Pediatric Committee will make an inventory of therapeutic needs for children before end 2009 • Pediatric Working Party is working on lists (lists already published on cardiovascular products and pain ([ii],[iii]) [i] FDA’s “Pediatric list” is available on http://www.fda.gov/cder/pediatric/peddrugsfinal.htm (accessed 6 March 2006). [ii] EMEA assessment of pediatric needs - cardiovascular products. October 2005. EMEA/CHMP/327847/2005. http://www.emea.int (6 march 2006). [iii] EMEA assessment of pediatric needs - pain. June 2005. EMEA/CHMP/189220/2005. (http://www.emea.int, accessed on 6 march 2006).

27. Non-clinical safety studies (1) • Safety data from previous adult human exposure should be available before pediatric clinical trials start • Appropriate repeated dose toxicity studies, all reproduction studies and the standard battery of genotoxicity tests should be available prior to the initiation of trials in pediatric populations ([i]) • Juvenile animal studies should be considered on an individual basis when previous animal data and human safety data are insufficient. [i] ICH M3 Non-clinical safety studies for the conduct of clinical trials. November 2000. (http://www.ich.org accessed on 6 March 2006). [ii] FDA Guidance for Industry – nonclinical safety evaluation of pediatric drug products. February 2006. Obtained from www.fda.gov/cder/guidance/index.htm (19 march 2006).

28. Non-clinical safety studies (2) • Need for non-clinical testing in juvenile animals for pediatric indications - detailed recommendations in a specific FDA guideline ([ii])- draft CPMP guideline ([iii]) • Need for carcinogenicity testing should be addressed prior to longterm exposure in pediatric clinical trials considering the length of treatment or cause for concern [iii] CPMP Draft Guideline on the need for non-clinical testing in juvenile animals on human pharmaceuticals for pediatric indications. September 2005. EMEA/CPMP/SWP/169215/2005. http://www.emea.eu.int (obtained on 23 May 2006).

29. Outline • Regulatory environment • Timing of pediatric studies • Type of development studies needed • Addressing pediatric information in the labelling • Need for special drug formulations

30. Pediatric clinical studiesAge classification of pediatric patients • pediatric patients cannot be considered as one homogenous group • considerable differences in development (e.g. physical, cognitive and psychosocial) • the identification of which ages to study should be medicinal product-specific and be justified • dividing the pediatric population into many age groups might needlessly increase the number of patients required.

31. Pediatric clinical studiesAge classification of pediatric patients • Preterm newborn infants; unique spectrum of diseases, rapid development and differences in their body functions, unique response to treatment, requirements for forms of medications that can be safely administered given their especially small size.) • Term newborn infants (0 to 27 days); volumes of distribution may be different than those in older pediatric patients, blood-brain barrier is not fully mature. Oral absorption may be less predictable, hepatic and renal clearance mechanisms are immature and rapidly changing. • Infants and toddlers (28 days to 23 months); rapid mental, physical and immune development. Elimination of drugs from the body may exceed that in adults. Considerable variability in response to medication, because the development does not occur at the same rate in all children. • Children (2 to 11 years); large variation and variability in development. Onset of puberty is highly variable and heralds a time of accelerated growth and marked changes which may alter response to medications and doses required. • Adolescents (12 to 16-18 years (dependent on region)); sexual maturation: medicinal products may intervene with the actions of sex hormones and impede development. Rapid growth and continued neurocognitive development. Increasing independance and responsibility; willingness to take medication may become a problem

32. Pediatric clinical studiesSafety studies in children • always necessary to support an indication in this population • age-appropriate, normal laboratory values and clinical measurements should be used in such studies. • long-term studies or surveillance data (chronic therapy or during the posttherapy period) may be needed to determine possible effects on skeletal, behavioral, cognitive, sexual and immune maturation and development. • postmarketing data are also important because at time of approval the pediatric database is limited • the company should submit a risk management plan to identify the risks and a set of activities and interventions designed to prevent or minimise risks • pharmacovigilance for medicines used by the pediatric population, because under-reporting (i.e. children may be unable to communicate adverse events) and off-label use may increase the occurrence of adverse drug reactions ([i]). [i] Guideline on conduct of pharmacovigilance for medicines used by the pediatric population, EMEA, August 2005 (http://www.emea.int.pdfs/human/phvwp/23591005en.pdf, accessed on 6 March 2006).

33. Pediatric clinical studiesEfficacy – PK approach (1) • If 1) the product is to be used in the pediatric population for the same indication as studied and approved in adults 2) the disease process is similar in adults and pediatric population and outcome of therapy is likely to be comparable • then extrapolation from adults efficacy data may be appropriate. • if a drug’s effect is well characterised with regard to important PK parameters and these parameters have been correlated well with activity in adults, PK studies in the pediatric population will reveal which dose will produce blood levels similar to those observed in adults. • In this way, adults efficacy data can be extrapolated to the pediatric population and no special pediatric clinical efficacy will be necessary (PK approach). • A similar approach can be used for extrapolation of efficacy from older to younger pediatric patients.

34. Pediatric clinical studiesEfficacy – PK approach (2) • Both EMEA and FDA have recently drafted detailed guidance for pediatric PK studies ([i],[ii],[iii]). • In addition, EMEA has published discussion papers on the impact of renal, liver, heart and lung immaturity when investigating medicinal products for children ([iv],[v],[vi]). • [i] CHMP Draft Guideline on the role of pharmacokinetics in the development of medicinal products in the pediatric population. EMEA/CHMP/EWP/147013/2004. February 2005. (www.emea.int) • [ii] EMEA concept paper on the development of a committee for proprietary medicianl products (CPMP) points to consider document on the evaluation of the pharmacokinetics of medicinal products in the pediatric population (EMEA/18939/03) (http://www.emea.eu.int). • [iii] Draft Guidance for Industry – General considerations for pediatric pharmacokinetic studies for drugs and biological products. November 1998 ((http://www.fda.gov.cder.pediatric/index.htm) • [iv] EMEA Discussion paper on the impact of renal immaturity when investigating medicinal products intended for pediatric use. CPMP/PEG/35132/03 December 2004 www.emea.eu.int. • [v] EMEA Draft Discussion paper on the impact of liver immaturity when investigating medicinal products intended for neonatal use. EMEA/CHMP/PEG/194605/2005. July 2005. • [vi] EMEA Draft concept paper on the impact of lung and heart immaturity when investigating medicinal products intended for neonatal use. November 2005. EMEA/CHMP/114218/2006. http://www.emea.eu.int.

35. Pediatric clinical studiesEfficacy – PK/PD approach / clinical efficacy • If comparability of disease course or outcome of therapy in pediatric studies is expected to be similar to adults, but the appropropriate blood levels are not clear then it may be possible to use measurements of a pharmacodynamic (PD) effect related to clinical effectiveness to confirm the expectations of effectiveness and to define the dose and concentration needed to attain that PD effect (PK/PD approach). • In all other cases, clinical efficacy studies are needed. It may be necessary to develop, validate and employ different endpoints for specific age and developmental subgroups. Measurement of subjective symptoms such as pain requires different assessment instruments for patients of different ages.

36. Pediatric clinical studiesDecision tree for evaluation of clinical efficacy in pediatric population Similar disease process? Appropriate blood levels are clear? no yes Same indication studied? no Clinical efficacy studies yes Outcome of therapy is likely to be comparable? no yes no yes PK/PD approach Linear PK no yes PK approach

37. Pediatric clinical studies • It is highly recommended that the pediatric clinical program is discussed with regulatory authorities already at an early stage of development. - The EU regulation proposes a system of free EMEA scientific advice for issues related to the pediatric development plan. - In the US, scientific advice can be obtained during the ‘formal’ meetings with the FDA, like pre-IND meeting and end-of-phase I or II meeting ([i]). • There are serious ethical and legal constraints that impact the performance of research in children ([ii],[iii]). Special measures are needed to protect the rights of pediatric study participants and to shield them from undue risk. [i] FDA Guidance for industry. Formal meetings with Sponsors and Applicants for PDUFA products. February 2000. (http://www.fda.gov/cder). [ii]V. Isitt, Legal and ethical problems peculiar to pediatric clinical trials. Part 1: Legal issues. The Regulatory Review, June 2002 Volume 5 Issue 4; 12-16. [iii] EU Directive 2001/20/EC on the implementation of good clinical practice in the conduct of clinical tirals on medicinal products for human use. Official Journal of the European Communities, 2001, L121/34-44.

38. Pediatric clinical studies • In the EU it is proposed that an EU network of investigators and trial centres will conduct research and development in children in order to ensure high-quality research. A database of pediatric studies is proposed to be build onto the EU Community database for clinical trials (EudraCT).

39. Outline • Regulatory environment • Timing of pediatric studies • Type of development studies needed • Addressing pediatric information in the labelling • Need for special drug formulations

40. Pediatric clinical studiesLabeling (1) • Information about the use of a drug in the pediatric population should be included in the labeling. • The US Pediatric Rule prescribes that a special “Pediatric use” subsection should be included in the labeling ([i]). This subsection must summarise any limitations on the pediatric indications, need for specific monitoring, specific hazards of the drug, differences between pediatric and adult responses to the drug, and other information related to the safe and effective use of the drug in pediatric patients. If appropriate, details should be further discussed under the “Clinical Pharmacology”, “Clinical Studies”, “Contraindications” and/or “Warnings” section of the labeling. More detailed recommendations on the inclusion of pediatric PK/PD data in the labeling is provided in a draft guidance document. [i] FDA 21 CFR Part 201.23 Specific requirements on content and format of labeling for human prescription drugs. Revision of “Pediatric Use” subsection in the labeling (http://wwww.fda.gov.cder/pediatric/pediatric_rule1994.htm)

41. pediatric clinical studiesLabeling (2) • The EU guideline on summary of product characteristics ([i]) provides guidance on how to include pediatric information in the EU labeling. Relevant information should be included in section 4.2 “Posology and method of administration”, with crossreferences to sections 4.1 “Therapeutic information”, 4.3 “Contraindications”, 4.4 “ Special warnings and precautions for use, 4.5 “Interaction with other medicinal products and other forms of interaction”, 4.8 “Undesirable effects”, 4.9 “Overdose”, 5.1 “Pharmacodynamic effects”, 5.3 “Pharmacokinetic properties”, and 6.6 “Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product” if applicable. • [i] EU Notice to Applicants. A guideline on summary of product characteristics. October 2005. (www.pharmacos.eudra.org/F2/eudralex/ vol-2/C/SPCGuidRev1-Oct2005.pdf (obtained on 20 May 2006))

42. pediatric clinical studiesLabeling (3) • The draft EU regulation proposes that not only the information regarding the results of studies in children (whether positive or negative), but also information on the status of the pediatric Investigation Plan, waivers and deferrals will be included in the product information. • The EMEA Working Group on Quality Review of Documents has issued a guidance document which addresses the pediatric patient in the package leaflet ([ii]). It provides suggestions on how to addresss situations in which the pediatric patient is in the care of a parent or a carer who is not a health professional. [ii] EMEA Working Group on Quality Review of Documents. Addressing the pediatric or incapacitated patient in the package leaflet. 2000. http://www.eudra.org/emea.html).

43. Outline • Regulatory environment • Timing of pediatric studies • Type of development studies needed • Addressing pediatric information in the labelling • Need for special drug formulations

44. Pediatric drug formulation (1) Many medicines are currently not available in formulations suitable for administration to children. Children vary greatly in their ability to use different dosage forms. This is related to their age, physical development and ability to coordinate, but also to psychological development and understanding. As a result younger patients that cannot take the adult formulation may be denied important new therapies, or they may have to take formulations that may be poorly or inconsistently bioavailable ([i]). [i] EMEA Reflection paper: formulations of choice for the pediatric population. EMEA/CHMP/PEG/194810/2005. June 2005.

45. Pediatric drug formulation (2) Both US and EU regulation require that an appropriate formulation for the pediatric population (i.e. appropriate for each age category to be studied) is used (5,7). In the pediatric drug develop plan (US) and Pediatric Investigation Plan (EU) any measures to adapt the formulation of the medicinal product to make its use more acceptable, easier, safer or more effective for different subsets of the pediatric populations should be described. Since development of pediatric formulations can be difficult and time-consuming, the development of these formulations should be considered early in development (2). The EMEA has recently published a Reflection Paper with some general guidance for the development of pediatric formulations. Taste, smell and texture are important factors for orally administered medicines. Rate of dissolution and ability to keep medication at site of absorption will be important for buccal or sublingual administration. In general, administration should be as comfortable, painless or stressless as possible, in order that a child will tolerated repeated administration of medicines. See next slide. Pharmacokinetic studies are generally needed to support the development of pediatric formulations ([i]). Such bioequivalence studies are normally carried out in adults.

46. Pediatric drug formulation (3) Issues to be considered when developing a pediatric formulation* • What is minimal dosage frequency? • One dosage form fits all or a full range • Minimal impact on life style (esp for adolescents) • Minimum, non-toxic excipients • Convenient, easy and reliable administration • Easily produced, elegant and stable • Cost and commercial viability * EMEA Reflection paper: formulations of choice for the pediatric population. EMEA/CHMP/PEG/194810/2005. June 2005.

47. Pediatric drug formulation (4) • FDA and EMEA can waive the requirement to develop an appropriate formulation for the treatment of children if the applicant can demonstrate that reasonable attempt to produce a pediatric formulation necessary for that age group has failed. • In that case the manufacturer should provide information to improve the quality, safety and efficacy of such manipulations during the time that they are necessary and unavoidable; e.g. information on issues surrounding cutting tablets into smaller segments, on suitability of tablets for crushing and on suitable powder diluents (plus compatibility and stability of crushed tablets with common foods and drinks).

48. Conclusions (1) • EU and US marketing authorisations for a new drug should contain a pediatric assessment (i.e. data from pediatric studies). • Consider the following issues when developing a new drug for a pediatric indication: 1) Can a waiver or deferral for studies in pediatric population or subgroups be obtained? 2) Are non-clinical safety studies required for conduct of pediatric clinical studies? 3) Is the formulation of the drug appropriate for each age category to be studied? • Outline the pediatric studies in a pediatric Investigational Plan (EU) or a Pediatric Drug Development Plan (US). Submit these plans to regulatory authorities at end-of-phase II (or end-of-phase I in case of serious and life-threatening diseases that lack adequate therapy).

49. Conclusions (2) • In both EU and US there is an incentive for studying medicines for children. In order to qualify for such a reward, the pediatric study should be agreed upon with regulatory authorities via an agreed pediatric Investigation Plan (EU) or Written Request (US) prior to carrying out the study. For global development, it is important that the timing of requesting a pediatric incentive should be harmonised in both EU and US, in order to qualify for both the EU and US pediatric incentive. • Clinical efficacy in the pediatric population can be assessed via different approaches, depending on the characteristics of the drug (i.e. PK approach, PK/PD approach, clinical efficacy studies).

50. Conclusions (3) • The specific timing of pediatric clinical studies depends on - product- type of disease- safety considerations and - efficacy and safety of alternative treatments. • Safety studies are always necessary in the pediatric population. • Specific guidance is available on how to include pediatric information in the labeling.