Overview of Recently Approved 505(b)(2) New Drug Applications ( ): Role of Clinical Pharmacology

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1 Regulatory Overview of Recently Approved 505(b)(2) New Drug Applications ( ): Role of Clinical Pharmacology The Journal of Clinical Pharmacology XX(XX) , The American College of Clinical Pharmacology DOI: /jcph.350 Sheetal Agarwal, PhD, RAC, Wei Qiu, PhD, and Chandrahas Sahajwalla, PhD, FCP Abstract The role of clinical pharmacology(cp) in the approval of 505(b)(2) NDAs was explored with the goal of sharing with the drug development community, someofthecriticalcpaspectsthatneedtobeconsideredandaddressedduringtheplanningandsubmissionofa505(b)(2)nda.amongthe (b)(2) NDAs approved in (excluding those that were approved under the PEPFAR program), 25% included only CP information, no supportive clinical safety/efficacy was necessary for their approval and 43% included both clinical and CP information. A review of the pre-submission interaction discussion held for 58% of the non-pepfar NDAs, indicated that CP-related aspects discussed at this avenue included study design of the pivotal BA/BE study, biowaiver related discussion, need for additional or supportive pharmacokinetic information to be included in the NDA, selection of the most appropriate reference drug product for 505(b)(2) purpose, as well as acceptability of publicly available information to address data gaps in knowledge. Further, we also noted that 505(b)(2) NDAs that did not report having a pre-submission interaction with the Agency had twice the rate of receiving a complete response action in the first cycle as compared to the NDAs that did meet with the Agency. Keywords 505(b)(2), regulatory, drug development Every year, many 505(b)(2) new drug applications (NDAs) are submitted to the Food and Drug Administration(FDA or Agency). More 505(b)(2) NDAs are approved annually as compared to NDAs for new molecular entities (NMEs). Section 505(b)(2) was added to the Federal Food, Drug, and Cosmetic Act by the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Amendments). As included in the FDA 1999 Guidance 1 titled Guidance for Industry Applications Covered by Section 505(b)(2), a 505(b)(2) application is one for which one or more of the investigations relied upon by the applicant for approval werenotconductedbyorfortheapplicantandfor which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted (21 U.S.C. 355(b) (2)). This provision expressly permits FDA to rely, for approval of an NDA, on data not developed by the applicant. The applicant can rely on published literature or Agency s finding of safety and effectiveness for an approved drug, as sources of information for this purpose. Some examples of changes to approved drugs for which 505(b)(2) applications may be submitted include change in dosage form, strength, route of administration, or Rx to OTC switches, development of a fixed-dose combination product of multiple single-ingredient approved products, etc. As stated in the Guidance, if sponsors intend to submit a 505(b)(2) application that relies for approval on FDA s finding of safety and/or effectiveness for one or more listed drugs, they must establish that such reliance is scientifically appropriate, and must submit data necessary to support any aspects of the proposed drug product that represent modifications to the listed drug(s). The applicants must establish a bridge (e.g., via comparative bioavailability data) between their proposed drug product and each listed drug upon which they propose to rely to demonstrate that such reliance is scientifically justified. The role of clinical pharmacology as a discipline, in the submission and planning of a 505(b)(2) NDA is critical if sponsor is not planning to conduct a study-intensive clinical development programfortheirproduct.oneofthemostintegralpartsofa 505(b)(2) NDA application may be the pivotal bioavailability/bioequivalence (BA/BE) assessment that compares bioavailability (systemic exposure) of the sponsor s test Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA Submitted for publication 11 February 2014; accepted 19 June Corresponding author: Sheetal Agarwal, PhD, RAC, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Building 51, Room 3160, White Oak, New Hampshire Avenue, Silver Spring, MD 20993, USA Sheetal.Agarwal@fda.hhs.gov Disclaimer: The views expressed in this article are those of the authors and do not reflect the official views of the FDA. Correction added on July 17, 2014: Figure 2 legend was changed.

2 2 The Journal of Clinical Pharmacology / Vol XX No XX (2014) product to that of a US approved and marketed product that will be ultimately included as the reference (listed) drug in the application. In addition to providing a BA/BE pharmacokinetic (PK) or a PK-pharmacodynamic (PD) bridge to a US approved and marketed product(s), sponsors may conduct other assessments as needed or as recommended by the Agency to provide a complete 505(b)(2) NDA package for a drug product. Some examples of other clinical pharmacology assessments included in 505(b)(2) applications are evaluation of effect of food, drug drug interaction (DDI) potential, effect of organ impairment (hepatic or renal), appropriate dose ranging assessment with the proposed product, or inclusion of a population PK analysis 2 plan in large Phase 3 clinical trials to address effect of co-variates such as age, gender, body weight etc., on the systemic bioavailability of a drug. The need for such assessments is determined by the sponsors themselves or in discussion with the FDA reviewers during pre-submission interactions. Several sponsors make use of Agency assisted avenues such as written communication or formal face-toface meetings to discuss their 505(b)(2) development program and NDA submission plan with the Agency. In this report, we provide an overview of recently approved [ ] 505(b)(2) NDAs, focusing mainly on the clinical pharmacology-related aspects of the NDAs. We will summarize clinical pharmacology-related discussion from the pre-submission interactions as well as clinical pharmacology information included in the 505(b) (2) NDA packages. We will also describe any clinical pharmacology-related deficiencies that led to an initial complete response (CR) or a not approvable (NA) action for these NDAs. The goal of this report is to share with the drug development community, some of the critical clinical pharmacology aspects they need to consider and address during the planning so that a timely and efficient review of a 505(b)(2) NDA can take place once the NDA is submitted to the Agency. Methods Publicly available information available from Drugs@FDA 3 was harnessed to extract clinical pharmacology information included in the 505(b)(2) NDA applications approved during January 1, 2010 to December 31, 2012 (3 years). A total of (b)(2) NDAs were approved during this time, amongst which, 26 were approved under the U.S. President s Emergency Plan for AIDS Relief (PEPFAR) program. 4 The PEPFAR 505(b) (2) NDAs were excluded from analysis and comments related to clinical pharmacology discussion in this report as these NDAs typically tend to have specific study designs that are only applicable to PEPFAR based NDAs. The remaining (b)(2) NDAs that were not approved under the PEPFAR program are grouped as non-pepfar NDAs for the purpose of our report. Supplemental Table S1 includes the following information for all the 106 non-pepfar based NDAs: Date of approval, NDA #, brand and generic names, type of NDA, presence/absence of any post-marketing requirements or commitments in the approval letters of the NDAs, route of administration, dosage form and strengths approved, reference drug product(s), type of clinical pharmacology information included in the NDAs as well as presence/ absence of any clinical safety/efficacy studies conducted by the sponsor. Approval letters, discipline reviews (including quality, clinical, clinical pharmacology, and pharmacology/toxicology reviews) as well as summary reviews for the (b)(2) non-pepfar NDAs were accessed through Drugs@FDA. In addition, FDA internal database was employed to harness clinical pharmacology information and discussion included in pre-submission interaction records, and letters related to complete response (CR), refuse to file (RTF) as well as review extension actions; this information is only presented as a summary. Results and Discussion General Overview of 505(b)(2) NDAs Approved During 2010, 2011, and 2012 Over a span of 3 years, 69 new molecular entity (NME) NDAs and (b)(2) NDAs were approved by the Agency (Figure 1). The Agency classifies NDA applications into different categories depending on the type of information presented in the NDA. Besides Type 1 (NME) NDAs, the following categories of NDAs are listed on Drugs@FDA 5 which generally apply to 505(b) (2) NDAs, i.e., Type 2 for a new active ingredient, Type 3 for a new dosage form, Type 4 for a new combination, Type 5 for a new formulation or new manufacturer, Type 6 for a new indication, Type 7 for a drug already marketed without an approved NDA, Type 8 for an OTC (over-thecounter) switch and finally, Type 10 for a new indication submitted as a distinct NDA. Our survey indicated that most of the 505(b)(2) NDAs approved between 2010 and 2012 were classified as Type 5 (52/132, 40%) followed by Type 3 (39/132, 30%). Other types of approved 505(b)(2) NDAs included Type 4 (27/132, 20%), Type 7 (11/132, 8%), and Type 2 (2/132, 2%). Figure 1. NME NDAs vs. 505(b)(2) NDAs approved

3 Agarwal et al 3 A survey of the route of administration of the (b) (2) NDAs indicated (Figure 2) that most of these products were intended for delivery through the oral (77/132, 58%) and parenteral route including intravenous, subcutaneous, and intramuscular routes (36/132, 27%). Further, 4% (5/132), 3% (4/132), 2% each (3/132 each), 1.5% (2/132), and 1% each (1/132 each) of the approved products were intended for delivery through the transdermal route, topical route, nasal and sublingual routes, ophthalmic route, and buccal and intra-anal routes, respectively. Among the (b)(2) NDAs approved, 26/132 (20%) were approved by the Division of Anti-Viral Products (DAVP), followed by the Division of Analgesia, Anesthesia and Abuse Products (DAAAP), 19/132 (14%). The Division of Neurology Products(DNP) and Division of Reproductive and Urology Products (DRUP) approved 10/ (b)(2) NDAs each (8%). Although not listed individually, 505(b)(2) NDAs were approved in all the clinical divisions within the Office of New Drugs (Figure 3). Summary of Pre-Submission Interaction Information for the 505(b)(2) NDAs Our survey (FDA internal database) indicated that among the 106 non-pepfar 505(b)(2) NDAs approved between 2010 and 2012, the sponsors of 62 products (58%, 62/106) engaged in a pre-submission interaction 6 with the Agency. These interactions were recorded in the form of meeting minutes for teleconference or face-to-face meetings, or as written responses shared by the Agency with the sponsors. A review of these pre-submission interaction records indicated that several clinical pharmacology-related aspects were discussed at this avenue, a summary of which is presented below in no particular order of merit or frequency of discussion. Relative BA/BE study: The design of the pivotal bridging BA/BE study was discussed frequently. In general, the following aspects were discussed: crossover/parallel design, multiple-arm design Figure 2. Route of administration of 505(b)(2) NDAs approved (Total ¼ 132). evaluating effect of food or DDI potential, number of subjects to be included in the study (i.e., powering the study appropriately), the study population (healthy subjects vs. patients for which the drug product is indicated for), PK parameters to be included in the statistical analysis plan to establish relative BA or BE, moieties to be analyzed to demonstrate BE, ie, parent only or parent and major metabolite/s, and doses or dose strengths of the test and the reference product to be studied. Reference drug to be employed in the BA/BE study for bioavailability comparison: The route of administration, the indications sought for approval, the maximum approved dose of the product, the package insert format for the reference product (ie, old labeling format or physician labeling format (PLR 7 )), are some of the considerations for choosing the most relevant reference product. In some instances, we noted that if the original US approved product is discontinued from marketing in the US and as such, is unavailable to be employed in the relative BA/BE study, sponsors discussed the possibility of employing the approved generic version of the product while still referencing the original NDA product as their reference product for 505(b)(2) purpose. Biowaiver related discussion: Discussion regarding which types of in vivo BA studies may be waived took place frequently. In the context of 505(b)(2) NDAs, our review of the clinical pharmacology reviews indicated that in vivo BA/ BE studies for parenteral products that are simple solutions, dose proportionality studies as well as studies with lower dosage strengths of the test product are frequently waived based on provision for waivers of in vivo BA/BE studies (biowaivers) under conditions as provided in 21 CFR Discussion on using literature-based information to address missing data gaps: Data available in public database is frequently utilized by the sponsors and the Agency to address missing gaps in information as deemed relevant and necessary. In the context of clinical pharmacology, this is especially true for older drugs that have been marketed for many years and at the time of their approval, had not been adequately characterized (as compared to current standards) with respect to aspects such as drug distribution and elimination, metabolism pathways, DDI potential, etc. In addition, for drugs that have been previously approved, new information is published in the literature that may be relevant for general safe

4 4 The Journal of Clinical Pharmacology / Vol XX No XX (2014) Figure 3. OND division responsible for 505(b)(2) approvals (Total ¼ 132). and effective use of the drug. As such, sponsors discussed utilizing such publicly available information to address missing data gaps for their drug product. On certain occasions, the Agency could also direct the sponsors toward conducting a literature search for the most up-todate information on relevant aspects and request them to include such information in the NDA. PossibilityofcollectingPKdatainPhase3studies: In lieu of conducting dedicated PK studies to address effect of co-variates such as effect of age, gender, race, disease status, DDI potential etc., on the systemic bioavailability of the drug, sponsors frequently discussed their plan of incorporating a PK component(including population PK analysis) in a large Phase 3 trial. Specific feedback with respect to number of subjects to be sampled (in case of sparse PK sampling) or the different covariates to be included in the population PK analysis is also solicited from the Agency. Need for pediatric plan or pediatric studies: Some sponsors discussed their pediatric study plans or solicited Agency s views and expectations with respect to whether their product may or may not trigger pediatric rules and regulations for drug development. Product specific discussion: Some discussion is specific for a drug (i.e., based on expected pharmacological effects) or drug product (i.e., formulation). For e.g., the need or study design of an hypothalamic pituitary adrenal 8 (HPA) axis effect assessment may be discussed for corticosterioid drug products, the need for abuse liability studies may be discussed for habitforming drugs such as opioids etc. Similarly, drug product or formulation related discussion includes the need or study design for an assessment of dose dumping in presence of alcohol for extended-release products. Discussion related to format of the clinical pharmacology datasets in the NDA: Sponsors frequently obtain Agency s concurrence on their planned format of the 505(b)(2) NDA with respect to study reports and datasets to be submitted, for e.g., NONMEM or SAS datasets, modeling information for population PK analysis etc. This helps in avoiding the need for information request from the Agency, once the NDA is submitted. As noted above, several important clinical pharmacology-related aspects are brought up and discussed at the pre-submission interaction meeting which is an important avenue available to the sponsors to be able to interact with the Agency and obtain feedback before the NDA is submitted. This interaction can bring clarity to both the sponsors and the Agency reviewers in terms of each other s expectations and possibly help avoid unnecessary and overwhelming exchange of information between the sponsors and the Agency after the NDA is submitted or filed.

5 Agarwal et al 5 Clinical Pharmacology Information Included in 505(b)(2) NDAs We reviewed the type and extent of clinical pharmacology information included in the 106 non-pepfar 505(b)(2) NDAs to determine the extent of clinical pharmacology support in these NDAs. As indicated in Figure 4, we noted that 26 NDAs (26/106, 25%) included only clinical pharmacology information as the basis for approval; no supportive clinical safety/efficacy study was generated and provided by the sponsor. The majority of the non- PEPFAR 505(b)(2) NDAs however did include both clinical safety/efficacy and clinical pharmacology information, i.e., 43% of the NDAs (46/106). A request for biowaiver from conducting an in vivo BA/BE study was granted to 29/106 (27%) of these NDAs, as such these NDAs did not include any clinical safety/efficacy or clinical pharmacology information that was specifically generated by the sponsor. One of the NDAs (1/106) included clinical safety/efficacy information but was granted a biowaiver for the in vivo BA/BE study. The rest of the non-pepfar 505(b)(2) NDAs (4/106) did not require any clinical safety/efficacy or clinical pharmacology support as they were either literature based, or were co-packaged products (individually approved products co-packaged together for patient convenience) or were products for life threatening conditions with an established therapeutic profile. A survey of the type of clinical pharmacology information presented in the 26 non-pepfar 505(b)(2) NDAs that included only clinical pharmacology information in the NDA (no clinical safety/efficacy data was generated by the sponsor) indicated that the majority of these NDAs included a pivotal relative BA/BE study linking the test product to a US approved and marketed reference product via a PK bridge. However, in addition to the relative BA/BE study, several other clinical pharmacology assessments were included, such as, effect of food, effect of presence of alcohol on extended-release formulations (ie, dose dumping), DDI potential through in vitro or in vivo studies or reference to publications including this information, dosing in hepatic and renal impairment populations, characterizing PK in patient population, characterizing PK under special conditions such as effect of showering or moisturizing on drug absorption for transdermal products, characterizing effect on HPA axis (for corticosteroids), determining abuse potential (for habit-forming drugs) etc. The most elaborate clinical pharmacology programs among the 106 non-pepfar 505(b)(2) NDAs were noted for some of the new fixed-drug combination (FDC) products, i.e., Type 4 NDAs. From a clinical pharmacology perspective, although enough information may be established for each of the mono-therapy products in their target population and at the approved doses, a FDC of 2 or more individual drugs raises additional concerns, such as adequate dose-ranging with the new proposed FDC in the new target patient population, PD interaction or DDI potential among the individual components, effect of hepatic or renal impairment on the disposition of the FDC components, etc. As such, the clinical pharmacology programs of Type 4 NDAs tend to be more intensive as compared to single ingredient 505(b)(2) NDAs. Clinical Pharmacology also plays a unique role in most of the Type 7 NDAs, i.e., NDAs for US marketed but unapproved products, as the sponsors of these applications tend to rely heavily on published literature for available clinical pharmacology information for their drug products. Since some of these drugs have been generally marketed in the US for a long time, it is likely that relevant information is available in the public database. Sponsors tend to submit multiple literature articles and book chapters as supportive information for their drug product. We noted that clinical pharmacology reviews for marketed but unapproved drug products identified a few relevant published articles for review from many (sometimes hundreds) of the published articles submitted by the sponsors as many of these articles had not been identified as being relevant (for e.g., the ones Figure 4. Clinical/Clinical pharmacology information in non-pepfar 505(b)(2) NDAs Approved expressed as % (Total ¼ 106).

6 6 The Journal of Clinical Pharmacology / Vol XX No XX (2014) used for drug product labeling) or were simply provided as supportive information only. We further reviewed the clinical pharmacology reviews of the 106 non-pepfar 505(b)(2) NDAs to assess whether an Office of Scientific Investigations (OSI) inspection was requested for any clinical pharmacology studies included in these NDAs. Our review indicated that pivotal BA/BE studies (the only in vivo study that links the test product to the reference product, no clinical safety/efficacy support) were almost always inspected. In addition, BA/BE studies that linked a Phase 1 or 2 formulation to a Phase 3 formulation or those that linked a Phase 3 formulation to the final-to-be-marketed formulation were also frequently inspected. Clinical Pharmacology Associated Complete Response Actions for 505(b)(2) NDAs Our survey of the actions taken (FDA internal database) for the 106 non-pepfar 505(b)(2) NDAs indicated that a complete response 11 (CR, previously not approvable (NA)) action was taken at least once for 45 NDAs (45/ 106, 42%). A second CR action may be taken if the resubmitted information was not found to be adequate to address the deficiencies noted in the original review cycle. Of these 45 NDAs, we noted that only 20 had a presubmission interaction with the Agency and 25 did not. Considering that 62 NDAs (58%, 62/106) reported having a pre-submission interaction with the Agency, we note that 32% (20/62) of those NDAs that did interact with the Agency pre-submission received a CR/NA action as compared to 57% (25/44) of those NDAs that did not interact with the Agency pre-submission and received a CR action (Figure 5). This difference in an adverse outcome appears significant with almost a ~2-fold higher probability (57% vs. 32%) of receiving a CR action if the sponsor did not have a pre-submission interaction with the Agency. This result indicates that having pre-nda discussion with the Agency may bring about clarity in information needed to support the NDAs and thus may reduce the probability of an adverse action such as a CR for 505(b)(2) NDAs. Figure 5. Non-PEPFAR 505(b)(2) NDAs that received a CR/NA action (Total ¼45). A review of the CR/NA letters issued to sponsors (FDA internal database) was conducted to report clinical pharmacology-related aspects that have historically led to CR actions for 505(b)(2) NDAs either as stand-alone issues or in addition to other issues. This information is summarized below in no particular order of merit or frequency of occurrence. OSI inspection of the pivotal clinical pharmacology study (BA/BE study linking test product to reference or formulation bridging study) did not lead to a favorable outcome causing the pivotal bridging PK data to being deemed unacceptable. The pivotal BE study failed, i.e., higher or lower peak plasma concentrations or systemic exposure as compared to the reference drug, with no supportive information from either exposure response data or a Phase 3 study to be able to interpret how the changes in PK will affect the drug safety/efficacy. A significant effect of food on the 505(b)(2) drug product (as compared to the reference drug) may lead to concerns similar to those with failed BE, i.e., difficulty in interpretation of the data with respect to drug safety/efficacy in the absence of Phase 3 studies. Bioanalytical methods employed for testing parent or metabolites in the clinical pharmacology studies are not validated. Inappropriate bridging of different formulations employed throughout the drug development program. If a sponsor assumes that a biowaiver may be granted based on in vitro dissolution data and has not discussed this possibility with the Agency prior to NDA submission, it is possible that the Agency deems the change in the formulations to be major in which case an in vivo relative BA/BE study may be required to bridge the two formulations. Clinical Pharmacology Associated Refuse-to-File Actions and Review Extension Letters for 505(b)(2) NDAs We reviewed refuse to file (RTF) letters, as well as review extension letters (letters indicating that major amendments were submitted to the NDA during the review cycle that would lead to an extension in review time of the NDA) for the non-pepfar 505(b)(2) NDAs (FDA internal database) when available. We wanted to identify any clinical pharmacology-related aspects that were included in these letters and determine if some of those issues could be addressed before the NDA is submitted to avoid post-submission delays. The two major clinical pharmacology-related aspects that led to RTF action or a

7 Agarwal et al 7 major amendment submission during NDA review cycle are listed below: Missing datasets or bioanalytical methods/validation reports for the pivotal clinical pharmacology studies. Inadequate relative BA/BE study design: Some of the reasons that were identified include the study population is not representative of the US population, and the right dose was not studied or the proposed to be marketed dose was not supported. We note that both of these issues could be identified and resolved by the sponsors before the NDA is submitted to avoid delay in approval time. The study design may be discussed with the Agency pre-submission as noted previously. Clinical Pharmacology Associated Post-Marketing Requirements and Commitments Included in the Approval Letters of the 505(b)(2) NDAs Our survey of the approval letters for the 106 non- PEPFAR NDAs indicated that 51 NDAs (48%) included studies required as post-marketing requirement (PMR) or post-marketing commitment 9 (PMC) (Supplemental Table S1). Of the 51 NDAs that noted PMR/PMC studies in their approval letters, 35 (68%) included Pediatric Research Equity Act based studies, 10 and 7 (14%) included specific clinical pharmacology studies such as a renal impairment study, DDI studies, study assessing dose dumping in the presence of alcohol for extendedrelease formulations, and PK studies to assess drug/ metabolites in the plasma and urine of pregnant women and to measure residual drug after application of transdermal products. This observation indicates that in the absence of critical clinical pharmacology information in the 505(b)(2) NDAs, the Agency does require the sponsors to follow up with studies post-approval to assure safe and effective use of the drug under labeled usage conditions. Conclusion Many 505(b)(2) NDAs are approved by the Agency every year, more so than NDAs for NMEs. Based on our review, the role of clinical pharmacology seems pivotal in the approval of many 505(b)(2) NDAs. Our review of presubmission interaction records indicates that although sponsors frequently tend to utilize this avenue for an active discussion with the Agency before the NDA is submitted, many sponsors do not. Sponsors are encouraged to utilize the pre-submission meeting space to their benefit when possible and discuss their development program with the Agency pro-actively. Our review of the CR action letters indicate that several clinical pharmacology-based aspects that may elevate to significant review issues during the NDA review such as study design issues with the pivotal BA/BE bridging study, can be addressed before an NDA is submitted such that the NDAs can be reviewed efficiently once submitted to the Agency. For marketed and unapproved products or other products relying upon publicly available information for clinical pharmacology support, it would be most helpful if the sponsors could clearly indicate which articles are the most relevant for their drug product (for e.g., articles from which data is proposed to be used for drug product labeling or articles that provide the pivotal PK data) and which articles are only provided for support. In addition, as many of the pivotal BA/BE studies are routinely inspected, sponsors should ensure that the respective clinical and analytical facilities are prepared for the inspections so that the inspections go through smoothly. Based on this report, we hope to have provided some assistance to sponsors of 505(b)(2) NDA applications with respect to the critical clinical pharmacology-related aspects that should be considered for efficient 505(b)(2) NDA submissions. Acknowledgments The authors wish to thank the following reviewers in the Office of Clinical Pharmacology for their assistance: Dr. David Lee for review of the manuscript and Dr. Zhihong Li for help with data collection. Conflict of Interest The authors declare no conflict of interest. References 01. Guidance for Industry Applications Covered by Section 505(b)(2) (Online Source). 02. Guidance for Industry Population Pharmacokinetics (Online Source). 03. Drugs@FDA (Online Source). 04. The PEPFAR program (Online Source). 05. Types of NDAs (Online Source). 06. Guidance for Industry Formal Meetings Between the FDA and Sponsors or Applicants (Online Source). 07. Guidance for Industry Labeling for Human Prescription Drug and Biological Products - Implementing the PLR Content and Format Requirements (Online Source). 08. Guidance for Industry Orally Inhaled and Intranasal Corticosteroids: Evaluation of the Effects on Growth in Children (Online Source). 09. Guidance for Industry Postmarketing Studies and Clinical Trials Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (Online Source). 10. Guidance for Industry How to Comply with the Pediatric Research Equity Act (Online Source). 11. Complete Response Letter Rule (Online Source). Supporting Information Additional supporting information may be found in the online version of this article at the publisher s web-site.