Chin Koerner Executive Director US Regulatory and Development Policy

Chin Koerner Executive Director US Regulatory and Development Policy Novartis Pharmaceuticals Corporation 1700 Rockville Pike Suite 510 Rockville, MD 20852 Tel 301.468.5607 Fax 301.468.5614 Email: Chin.Koerner@novartis.com Comments on FDA Draft Guidance for Industry Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans Docket number: FDA-2013-D-0814 Date: September 10, 2013 Dear Sir/Madam: Novartis appreciates the opportunity to comment on this important Guidance document. We commend FDA for issuing guidance to help the pharmaceutical development industry navigate today s more complex diseases and needs of pediatric patients. This is an excellent overview of the legislation intended to facilitate better understanding of the use of pharmaceutical and biological therapies in pediatric populations. We submit the following comments for FDA s consideration and look forward to further opportunities to discuss these issues with the Agency. General Comments With the passage of FDASIA PREA there is now permanent legislation for mandatory pediatric research. Moving forward, it will be important for FDA and Industry to work together to ensure the intent of FDASIA PREA is preserved. In this regard, Novartis has three overarching recommendations: global harmonization, resource conservation, and scope and intent of FDASIA PREA. Global Harmonization In the interests of optimizing the ability to gather meaningful information from pediatric studies we request that FDA and EMA harmonize on submission templates, process for interactions with Health Authorities, and elements of required paediatric programs. Novartis recommends the FDA and EMA consider, to the extent possible, a common core document for the US Pediatric Study Plan (PSP) and the EU Paediatric Investigation Plan (PIP). Novartis also recommends the FDA and EMA convene stakeholders to bring consensus to the types of non-clinical and clinical studies that are needed. Resource Conservation Under FDASIA PREA the amount of regulatory process for pediatric research planning has increased significantly. Industry and FDA will require significant increase in dedicated resources to meet these new regulatory obligations. It will be important to be efficient and conserve resources where FDA can exercise regulatory discretion to decrease regulatory burden: for example, the need of a PSP and a 210 day review for minor PSP amendments, the need of a PSP for non new indications such as a formulation

or route of administration change, and the need for a second round of review with the NDA/BLA even after a Letter of Agreement has been issued. We encourage FDA to give these suggestions serious consideration to minimize administrative process while continuing to strive to use PREA as a regulatory tool to serve the greater good of children. Scope and Intent of PREA Novartis commends the FDA for its implementation of PREA related provisions over the last 10 years. Since the passage of PREA 2003, it has been extremely helpful to have clear and concise guidance in the form of Draft Guidance to Industry: How to Comply with the Pediatric Research Equity Act. Pediatric drug development (like adult development) is planned across multiple indications (depending on mechanism of action) over many years. Depending on complex factors such as difficulty of recruitment, competing priorities, the initiation, progression, and completion of these studies will vary across indication. The legislative underpinning of PREA to limit required studies to the adult indication under investigation has proved to be extremely successful. We recommend that FDA continue to be clear in what is required in the PSP under FDASIA PREA i.e. the indication being sought to be studied in the pediatric population. Including requests in the PSP for other uses to be studied under BPCA, or other uses under other INDs or other studies under agreements with other Health Authorities could be confusing for what is actually required to be in the PSP. Because most companies will likely discuss new investigational uses for a drug with FDA at some point during the development of these indications, e.g. EOPII meetings, Novartis recommends that requests for information on other uses than the sought after indication be deleted or moved to a separate guidance from the FDASIA PSP guidance. Specific comments on this Guidance Line Number Comment and Rationale 98-100 A sponsor who is planning to submit a marketing application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration (i.e., that triggers PREA) is required to submit an initial PSP. 101-106 By statute, a biosimilar product that has not been determined to be interchangeable with the reference product is considered to have a new active ingredient for purposes of PREA. The sponsor should submit the initial PSP to the relevant drug s IND for review by the Center for Drug Evaluation and Research (CDER) Proposed change (if applicable) Novartis encourages FDA to use regulatory discretion when requiring PSP submissions and additional pediatric studies for new dosage forms, new dosing regimen or new route of administration. If previous pediatric studies have been conducted with a particular active moiety in a particular indication, the clinical information needed to describe the use of that treatment in children has been established. We encourage the use of Modelling and Simulation and/or extrapolation for additional information that may be needed when PREA is triggered with the same active moiety. Novartis acknowledges that under BPCIA, a biosimilar product which has not been determined to be interchangeable with the reference product is subject to PREA and therefore must submit a PSP. These comments are on an approach for sponsors and the Agency when fulfilling the PSP requirement for a biosimilar. When a reference product for the biosimilar is labelled for both pediatric and adult use, extrapolation from the reference product to the biosimilar product for the adult and pediatric indications would be a valid approach to address biosimilar PREA requirements. In fact, this approach is acknowledged in lines 175-177 of this

or Center for Biologics Evaluation and Research (CBER) review division as appropriate. Sponsors should submit an initial PSP according to the time frame outlined in section IV. Timing of a PSP Submission. guidance. BPCIA authorizes the FDA to license a biosimilar for any indications of the originator using in part abbreviated clinical studies and extrapolation between indications and populations. In short, extrapolation is a well accepted regulatory approach in the realm of biosimilars ICH Q5E, allows for the regulatory presumption that all indications, including pediatric use, of the pre-change product will be apply to the post-change product. And, if analytical differences can be shown, these would be generally accepted to not be clinically relevant. We agree that for biosimilars, the extrapolation from the adult population to the pediatric population should require justification, but we also believe there is scientific basis for being able to extrapolate from the reference product to the biosimilar if the reference product label already includes useful prescribing information for pediatrics. The biosimilar should be able to rely on the reference product for the pediatric information and should not have to submit additional pediatric data that would delay pediatric access to biosimilars while providing little useful information. This science based approach should be used to fulfil PREA requirements for all biosimilars. In conclusion, appropriate extrapolation between indications and populations, from reference product to biosimilars can offer a rigorous scientific and ethical approach consistent with BPCIA that could fulfil PREA obligations for a non-interchangeable biosimilar. 111-126 A sponsor must submit the initial PSP before the date on which the sponsor submits the required assessments and not later than 60 calendar days after the date of the EOP II meeting. The July 2012 European Medicines Agency Report to the European Commission on the experience acquired since the implementation of the Paediatric Regulation acknowledges that submission of PIPs at an early stage of development might lead to unnecessary efforts, as research for a given product / indication might be discontinued. In this context, the timeframe for submission of an initial PSP (by max 60 days after EOP II meeting) be not be appropriate in all cases. We recommend that there be more flexibility. FDA is encouraged to consider the use of the provision to delay the submission of a PSP until such other time as may be agreed upon between the FDA and the sponsor as needed. By law Orphan designated indications are generally exempt from PREA. We recommend this be clearly reflected in this guidance. Additionally, we recommend if an Orphan designation review is pending at the EOP II meeting timeframe, the requirement for a PSP be deferred until a decision has been issued by the Office of Orphan Drugs. 166-168 A broad consideration of any possible therapeutic uses of the drug in children beyond the disease or indication being sought in adults may serve as the basis Under PREA the requirements for pediatric studies are limited to those uses as sought for by the sponsor in the adult population. Novartis recommends this discussion be the subject of a different guidance for implementation of BPCA. Novartis recommends deletion of any references to uses in children beyond the disease or

for a Written Request under section 505 A of the FD and C Act (21 USC 355a)). If a sponsor plans to submit a proposed pediatric study request asking the FDA to issue a Written Request in the future, that information should be included in the overview as appropriate indication being sought in adults as this is out of the scope of FDASIA PREA. 175-177 Extrapolation of efficacy from adult populations to pediatric populations may be appropriate if the course of the disease and the effects of the drug are sufficiently similar in adult and pediatric patients... This section should address any plans to extrapolate efficacy from adult to pediatric patients With more focus on (and approvals for) rare adult and pediatric conditions, the need to study extremely rare pediatric conditions under PREA may arise. This may be particularly important for indications where treatments are approved for small subsets of patients who express relevant molecular targets and where similar targets are also in the pediatric disease. The extreme rarity of these conditions raises significant limitations related to the number of patients potentially eligible for clinical trials, challenging the traditional clinical trials frameworks. We note that these situations may necessitate extrapolation of data from adult trials. Although the Agency has taken the position that safety cannot be extrapolated, there are certain safety information from the adult population that could be helpful e.g. liver enzyme elevation and drug metabolism information that may not require confirmation in a separate pediatric trial. Novartis recommends the guidance to include extrapolation of efficacy and safety from adult populations to pediatric populations, as appropriate, with the need for additional studies to be determined on a case by case basis. 201-212 Request for Drug Specific Waiver(s) footnote 27: Additional information on extrapolation can be found in Section VI of the draft guidance for industry How to Comply with the Pediatric Research Equity Act. Novartis recommends the criteria to apply for a potential waiver should be aligned with the Draft Guidance to Industry: How to Comply with the Pediatric Research Equity Act. For a full waiver request the current Draft guidance requires an extensive assessment. By contrast, the previous draft guidance required a checklist approach. We encourage full disease waivers to continue to be an option and the use of the previous checklist approach be available to conserve resources for industry and FDA. 207-208 Novartis notes that the statement It should be noted that requested waivers in the PSP will not be formally granted or denied until the application is approved is in conflict with the following line If studies will be waived because there is evidence that the drug Novartis proposes that when there is sufficient evidence for the Agency to grant a Waiver, the formal Waiver should be granted at the time of the initial 210-review cycle. If at the time of the submission of the initial PSP under PREA, it is determined by the applicable Division that a Waiver should be granted because there is available data supporting a lack of efficacy or a substantial risk related to safety across the pediatric age groups, delaying formal granting of Waiver status until an Application is approved, leads to

would be ineffective or unsafe in any pediatric age group, this information must be included in the product labelling. unnecessary uncertainty for the pharmaceutical industry, while delaying the inevitable. 207-210 This guidance does not provide a regulatory path if no agreement is reached regarding waivers, partial waivers, deferrals on the contents of a PSP during the 210 day review We encourage FDA to consider a PDUFA Type A meeting to help reach agreement for a PSP when an agreement is not reached at the end of the 210 day review. We also encourage FDA to make transparent the roles and responsibilities for reviewing the PSP and how the Agency will coordinate input from the Review Division and other FDA stakeholders (e.g., the referenced Pediatric and Maternal Health Staff, interested parties from other review divisions, scientific staff) and any external advisers and consultants. 244-260 The ICH guidances pertaining to the types of preclinical studies relevant to predicting safety in pediatric populations should be referenced, including differentiation between acceptable risks for experimental drugs treating life-threatening indications such as advanced cancers and those for more benign conditions. Please add, When selecting appropriate nonclinical studies, Sponsors should adhere to appropriate international guidances for life-threatening indications such as advanced cancers (ICH S9 Nonclinical evaluation for anticancer pharmaceuticals) or for less severe indications (ICH M3[R2] Nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals; ICH M3[R2] Nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals: Questions and Answers). 280 Whether the formulation being developed can be used for all paediatric populations requires an assessment of the formulation and metrics to measure appropriateness. Currently, there is neither consensus nor regulatory standard to determine such suitability from a regulatory body or industry. Novartis recommends that FDA convene public meetings to develop consensus around tools and standards to determine pediatric formulation suitability. To further advance pediatric research these findings should be written into Guidance to Industry. To repeat a suitability exercise on a company by company and product by product basis is a resource intensive and inefficient effort. 353-358 FDA requests that sponsors should include any agreements with other governments and any clinical investigations conducted under and IND for an indication other than the indication that is the subject of the initial PSP... If the Agency is requesting this information for a specific purpose, please provide an explanation within the Guidance on how this information will be used. Without further context to clearly state that this request is outside the provisions of PREA, Novartis recommends this section be deleted.

361-372 Contents of Requested Amendment to an Initial PSP Novartis request clarification for what constitutes an amendment that would require the submission of a PSP vs. an amendment that would only require a submission of a protocol amendment to the IND or an abbreviated version of the 210 day process. This process could represent a significant resource burden for industry and FDA. Sincerely, Chin Koerner Chin Koerner Executive Director US Regulatory and Development Policy Novartis Pharmaceuticals Corporation