Discovery, Development and Approval of New Chemical Entities: An Overview

Dr. HemenwayJeffrey N. Hemenway, Ph.D.
Gilead Sciences Inc., Foster City, CA, USA

Organizations within Pharmaceutical R&D such as Discovery, Pharmaceutical Development and Clinical Development, work together in a highly collaborative effort to develop safe and efficacious new drugs.  The pharmacological activity and toxicity potential of new chemical entities (NCEs) are evaluated in animals to identify the most suitable compounds for clinical development.  When a new drug candidate is identified for further development, the appropriate form and a suitable manufacturing process for the drug substance are identified, and a formulation and process for the drug product are selected for early-stage clinical studies.  An Investigational New Drug (IND) application must be filed in order to initiate first in human studies, which includes the proposed clinical protocols, along with animal pharmacology and toxicology data, details about the drug substance and drug product.  Phase I clinical studies test the new drug in single ascending dose (SAD) and multiple ascending dose (MAD) studies in a small group of (usually) healthy volunteers to determine a safe dosage range.  Phase II studies test the drug in a larger group of patients to see if it is effective for the indication and further evaluate safety.  Phase III studies are conducted in large groups of patients to confirm the drug’s effectiveness and safety relative to the current best-available treatment.  Ongoing pharmaceutical development is conducted in parallel with clinical studies.  The final form of the drug substance is selected and enabling formulation technologies may also be evaluated.  Manufacturing processes for the drug substance and drug product must be developed and scaled.  Significant changes in the drug product throughout the development process are not uncommon.  The results from the clinical and pharmaceutical development of an NCE are summarized in a New Drug Application (NDA), which must be approved to grant marketing authorization.  Phase VI studies continue to monitor the safety of new drugs as greater numbers of patients are treated, often in conjunction with post approval commitments.    This presentation will provide an overview of the necessary development activities and regulatory requirements for new drug development and approval at various stages of clinical development and commercialization.  Case studies will be presented to exemplify some key considerations and decisions that must be made during the development process for early and late stage programs.

Jeffrey Hemenway, Ph.D. is currently a Senior Scientist in Formulation and Process Development at Gilead Sciences Inc.  He received his bachelor’s in Chemistry from University of Missouri, Kansas City, and his doctorate in Pharmaceutical Chemistry from the University of Kansas, where he was trained in the area of prodrug design and characterization.  He joined the Biopharmaceutics Department at Bristol Meyers Squibb, where he worked in the areas of solid oral formulation and manufacturing process development, scale up and tech transfer for early and late stage programs.  He is a member of the AAPS and currently serves as the Secretary/Treasurer for the FDD Section.  In his current position at Gilead Sciences, he leads a team of scientists responsible for discovery pharmaceutics, preformulation, formulation and manufacturing process development, scale up, outsourced GMP manufacturing and CMC regulatory documentation for preclinical, early and late stage programs.   
Redefining Biopharmaceutical R&D: Interface between Industry and Academia for Effective Discovery & Development of Drugs

Dr. SunkaraGangadhar Sunkara, Ph.D., MBA

There has been a significant shift in the overall drug discovery and development strategy in the last decade due to the advances in the understanding of disease targets, evolution of computational tools and the formation of new integrated scientific disciplines. The overall shift has been influenced by the efforts from the Industry and Academic institutes along with the contribution from regulatory authorities and various scientific focus groups/associations. On the other hand, the collaboration models/approaches between the Industry and Academic institutes in the drug discovery and development have not been evolving the rate at which the drug discovery and development approach is changing. In this presentation, key representative examples of areas of evolved scientific areas will be reviewed; and few scenarios will be shared how the Industry and Academia can enhance their collaboration approach to enhance the overall efficiency and productivity of drug discovery and development.

Dr. Gangadhar Sunkara is an Executive Director at Novartis Institute for Biomedical Research and is responsible for providing drug metabolism and pharmacokinetic/pharmacodynamic (PK/PD) strategy to projects in early and late stage development or post-marketing programs in the therapeutic areas of cardiovascular disorders, tropical diseases and established medicines.  Dr. Sunkara, as the Head of Asia PK/PD, is also responsible for providing clinical PK/PD input to new drug applications in China and Japan.  Dr. Sunkara earned his B.Pharm and M.Pharm (Pharmaceutics) degrees from Kakatiya University in India and Ph.D. in pharmaceutical sciences from the University of Nebraska Medical Center, USA.  Dr. Sunkara has excellent publication record and has often been an invited speaker.
Advances in Parenteral Drug Nanodispersions:  Processing, Characterization and Case Studies

Dr. ConstantinidesPanayiotis "Panos" P. Constantinides, Ph.D.
Biopharmceutical and Drug Delivery Consulting, LLC, Gurnee, IL

There have been major advances and achievements in the use of nanoparticles for parenteral drug delivery and targeting especially for cancer drugs and biologics. Of particular interest are drug nanodispersions and include, liposomes, nanoemulsions, solid lipid nanoparticles, polymeric micelles, dendrimers, nanocrystals and nanosuspensions. Directing therapeutics to  intracellular targets and selectively killing disease cells is the primary driving force behind the rapid evolution of nanoparticle-based approaches.   A brief overview of nanoparticle design, manufacturing, characterization and in vitro/in vivo assessment, including Quality-by-Design (QbD) aspects, will be discussed during the first part of the talk. Case studies will then be presented with parenteral small molecules, approved drugs or New Molecular Entities (NMEs) employing nanoemulsions, liposomes, polymeric micelles, solid lipid nanoparticles, and nanosuspensions. Improvements in the manufacturing methods and better understanding of the factors controlling stability will certainly expand the use of nanodispersions in parenteral drug delivery and drug products.

Dr. Panayiotis (Panos) P. Constantinides is the President of Biopharmaceutical & Drug Delivery Consulting, LLC and Affiliated Professor of Biopharmaceutical Sciences at Roosevelt University, College of Pharmacy in Schaumburg, Illinois, with 25 years of experience in drug delivery and pharmaceutical development. He received a University Diploma in Chemistry from Athens University in 1977 and PhD in Biochemistry from Brown University in 1983. He was a postdoctoral fellow in the Pharmacology Department and Associate Research Scientist in the Comprehensive Cancer Center of Yale University School of Medicine (1983-1987). Past industrial positions held included: Vice President of R&D with DOR Biopharma and Morton Grove Pharmaceuticals (2001-2004), Director of Research at SONUS Pharmaceuticals (1997-2000) and from 1987 to 1997 a number of R&D positions of increasing responsibilities with LipoGen, SmithKline Beecham Pharmaceuticals and Abbott Laboratories. In addition, he serves as scientific advisor in early stage companies and contract research organizations. He has held adjunct faculty appointments with the Pharmaceutics Department of Washington University in Seattle, WA and the Department of Biochemistry of the University of Tennessee, in Knoxville, TN.  He is affiliated with the School of Pharmacy of the University of Wisconsin and serves as faculty in the annual Biotechnology Entrepreneurship Boot Camp program of the BIO International Convention. He is inventor in 33 patents and patent applications, has authored more than 130 publications and has been invited speaker at many national and international conferences, biotech/pharma companies and universities. Dr. Constantinides is AAPS Fellow, current Chair-Elect of the AAPS Formulation Design and Development (FDD) Section and Past Chair of the Lipid-Based Drug Delivery Systems and the Nanotechnology Focus Groups.
Right Dosage Form to Fit Patient Better

Dr. GaoDanchen Gao, Ph.D.
AbbVie, North Chicago, IL

505(b)(2) is a hybrid of a full NDA and an ANDA. It is a unique U.S. regulatory pathway to provide additional routes in patient care after FDA approval of a new drug product. In return, it offers opportunity for a pharmaceutical company to maximize the value of a marketed product. Dosage form change is one of the common approaches under 505(b)(2). In this presentation, various innovation ideas around dosage form design will be reviewed from conception, regulatory strategy to commercialization. Integration between science and NPV is key to provide the right dosage form to fit patient better.

Dr.  Danchen Gao rejoined Abbott Laboratories, now AbbVie, in 2011 to take on the role of director of intellectual property strategy. Starting her career as a solid dose formulator at Abbott in 1995, Danchen has grown with increased responsibilities in various functions of both large and specialty pharmaceutical companies, including site leader for difficult to deliver drug candidates in Pharmacia/Pfizer, Sr . director of R&D at Morton Grove Pharmaceuticals and the founding director of NDA division at Anchen Pharmaceuticals. In her 19 years pharmaceutical industry career, she has designed and led NDA and 505(b)(2) programs, evaluated business development opportunities, worked as a global project manager, acted as company agent to FDA, supported general counsels and reported to CEOs. Danchen is an inventor or a co-inventor of numerous dosage form design patent applications, among them, the Celebrex® composition patent has been granted by more than 60 countries.  Danchen holds a Ph.D. in Pharmaceutical Chemistry from College of Pharmacy at The University of Kansas. 
Impact of Pharmaceutical Excipients on Drug Product Stability, Bioavailability, and Manufacturability

Dr. NarangAjit S. Narang, Ph.D.
Bristol-Myers Squibb, Co., New Brunswick, NJ

Excipients in drug products impact stability, manufacturability, and bioavailability. These considerations are critical to not only formulation and drug product design, but also the control strategy elements of drug product development and commercial manufacture. The ability to scale-up and reproducibly manufacture a drug product on the commercial scale (manufacturability) is impacted by formulation design and process engineering, including the application of in-line process analytical technologies. Case study of a wet granulation process will be presented to highlight the importance of process understanding in designing a control strategy. Improving drug product stability by excipient selection, control, and package design assures maximization of drug product shelf-life. Role of impurities in excipients on drug product stability and interaction of excipient properties with manufacturing process will be discussed. Excipients can impact bioavailability by affecting physiology, drug product, or drug substance properties. Examples of excipient impact on oral drug bioavailability will be presented to highlight the importance of excipient selection during formulation design. The importance of mechanistic understanding in drug product design and control would be highlighted through case studies.

Ajit Narang works for the Drug Product Science & Technology Department of Bristol-Myers Squibb, Co. (BMS) in New Brunswick, NJ in the development of oral solid dosage forms. He also serves as Adjunct Faculty at the Universities of Tennessee and Phoenix; Industrial Advisory Board member of Western Michigan University; and Editor of Journal of Applied Biopharmaceutics and Pharmacokinetics and BioMed Research International. He earned his Ph.D. from the University of Tennessee in Memphis and holds over 12 years of pharmaceutical industry experience in the development of oral dosage forms and drug delivery platforms working for BMS, Ranabxy, and Wockhardt in different capacities. He has published over 40 peer reviewed articles; 2 books; 5 patent applications; 40 poster presentations and 8 podium presentations at various scientific meetings; and has contributed to the development of several marketed drug products. His current research interests include innovations in dosage form development and drug delivery technologies that enable pharmaceutical development of challenging molecules to resolve stability, manufacturability, and bioavailability issues.
Enabling Oral Drug Delivery Technologies

Dr. KetnerRod Ketner, Ph.D.
Bend Research, Bend, OR

The increasing prevalence of poorly soluble drugs in pharmaceutical industry pipelines has led to the development of a variety of enabling oral drug-delivery technologies. These technologies include amorphous-dispersion, attrition-milling, lipid, and liquid formulations.  This presentation will look at the rational selection of technologies for solubilization using the compound’s physical properties (e.g., melting temperature, glass-transition temperature, log P, and solubility) and product specifications (e.g., dose, pharmacokinetics, permeability).  Maps and guidance surfaces will be used to identify formulation approaches with limited experimental work.

A primary focus of this presentation will be the science behind the use of amorphous solid dispersions (“spray-dried dispersions” or SDDs) and related technologies to improve the oral bioavailability of hundreds of low-solubility drugs.  Advancements in SDD technology have ranged from rapid feasibility testing with milligram quantities of drug through large-scale Phase III clinical trials involving the manufacture of metric tons of material.  This presentation will cover in vitro test methods that differentiate the species and activity of drug in biorelevant solutions and suspensions, common manufacturing processes, and the formulation of the drug-product intermediate into conventional oral solid dosage forms.  In addition, stage-appropriate physical-stability models, which have been developed and verified for the prediction of long term stability for SDD formulations, are described, as are applicability maps that identify the physical-property boundaries of drug molecules where “conventional” SDD technology is applied.  The spray-drying manufacturing discussion illustrates a process-development paradigm and design space application from development through commercial scale up.

Rod is Director of Pharmaceutical Sciences at Bend Research, a division of Capsugel Dosage Form Solutions, where he has worked for 15 years. In his current role, Rod manages Bend’s large pharmaceutical alliance partners. He has been a key contributor to the development of Bend Research’s amorphous spray dried dispersion (SDD) and other novel drug delivery technologies. His work has largely focused on solving challenging problems related to chemical and physical stability. Rod received a Ph.D. in Physical Organic Chemistry from UC Santa Cruz and did his post-doctoral work at UC Berkeley. He holds multiple U.S. and international patents on drug delivery technologies. Rod also directs Bend Research’s charitable outreach programs and is actively involved in supporting science education in Central Oregon.

Pharmacokinetic and Pharmacodynamic Aspects of Small vs. Large Molecule Drugs

Dr. DiaoLei Diao, Ph.D.
Biogen Idec, Inc., Cambridge, MA

Biotech drugs including proteins, peptides, monoclonal antibodies, antisense oligonucleotides constitute a major focus in pharmaceutical R&D recent years. Inherently mechanistic-based, biotech drugs have unique pharmacokinetics (PK) and pharmacodynamics (PD) features including target mediated disposition, background endogenous substance, and immunogenicity, compared to traditional small molecule drugs. The presentation is intended to discuss the similarity and difference of PK and PD for biotech drugs compared to small molecule drugs, and the impact of such difference in the discovery and development of biotech versus small molecule drugs.

Lei Diao is a scientist in the Department of Clinical Pharmacology and Pharmacometrics at Biogen Idec since 2012. He obtained his PhD in Pharmaceutical Sciences from the University of Maryland Baltimore in 2011 and underwent postdoctoral training in pharmacometrics at the University of Tennessee College of Pharmacy.  Lei’s current role in Biogen Idec includes representing clinical pharmacology for therapeutic protein in late stage clinical development, conducting population PK and PK/PD analysis to support regulatory registration and product launch, and contributing to clinical trial designs. Recent publications include “Pharmacokinetics and Pharmacokinetic–Pharmacodynamic Correlations of Therapeutic Peptides” and “Population Pharmacokinetic Modelling of Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Patients with Haemophilia B”, both published in Clinical Pharmacokinetics.
Accelerated Stability Assessment Program (ASAP): Using Science to Set Expiry

Dr. WatermanKenneth C. Waterman, Ph.D.
President, FreeThink Technologies, Inc.

ASAP employs isoconversion (time to hit the specification limit at each condition) with designed temperature/RH conditions (based on a humidity-corrected Arrhenius equation) to build a model for degradant formation or potency loss for drug products and drug substances. Once the model is built, the shelf-life inside packaging can be determined based on the calculated RH inside the packaging.  These methodologies provide for far better predictions of shelf-life (expiry) than previously possible at a significantly reduced time frame (2-3-weeks).  ASAPprime® employs this science in combination with statistical tools to enable accurate estimations of shelf-life with many factors determined computationally (e.g., packaging, storage conditions, storage excursions).

Ken Waterman studied physical-organic chemistry, completing his undergraduate at UCLA, his graduate at UC Berkeley and his post-doctorate at Columbia University.  Dr. Waterman worked 12-years at Polaroid, then 13 years at Pfizer working on drug stability, drug delivery, biopharmaceutics and prodrugs, before starting FreeThink Technologies in 2011.  FreeThink launched its software ASAPprime and opened its R&D laboratories in 2012.  He is the author of over 75 publications and was made an AAPS Fellow in 2011.

New Modalities in BioPharma
Dr. SmithRonald L. Smith
Merck, West Point, PA

Ronald L. Smith, Ph.D., is Distinguished Scientist in Pharmaceutical Sciences at Merck Research Laboratories heading the Exploratory Products & Technologies group.  Dr. Smith joined Merck in 2008 as Executive Director of Pharmaceutical Research in West Point, PA and was most recently Executive Director of Product Value Enhancement.   Prior to Merck, Dr. Smith led Exploratory Biopharmaceutics & Drug Delivery at Bristol-Myers Squibb Company where he also had responsibility for drug substance and drug product stability for small molecules and biologics. He began his career with the Procter & Gamble Company leading the research and product development of several patented technologies for intranasal, buccal, mucoadhesive and transdermal drug delivery.  Dr. Smith is a past-Chair of the Pharmaceutics & Drug Delivery Section of AAPS and the Board of Scientific Advisors for the Controlled Release Society.  He has held Adjunct faculty appointments at the University of Cincinnati College of Pharmacy and the School of Pharmacy at West Virginia University. He received a B.S. degree in Chemistry from West Chester University and a Ph.D. in Chemistry from the University of Iowa. 

Global Operations and Outsourcing Considerations 
Dr. RueggerColleen E. Ruegger, Ph.D.
Novartis Pharmaceuticals Corporation

Dr. Ruegger received a BS in Pharmacy from Rutgers College of Pharmacy and a Ph.D. in Pharmaceutical Science from Rutgers University.  She joined Novartis (legacy Ciba-Geigy) in 1995 as a Senior Scientist and has held positions of increasing responsibility in the Pharmaceutical and Analytical Development section of Technical Research and Development.  Dr. Ruegger is currently Global Head of Oral Pharmaceutical Development where she is responsible for pharmaceutical product development, clinical manufacturing, technology transfer and project management.  Her interests include Quality by Design, compaction simulation, and formulation development of poorly soluble compounds.  Dr. Ruegger is a member of the American Association of Pharmaceutical Scientists and is a past chair of the Manufacturing, Science and Engineering section of AAPS.

Research and Development of Therapies for Rare Inherited Diseases

Dr. ChengSeng H. Cheng, Ph.D.
Genzyme, a Sanofi Company, MA

Over the past decade, there has been increasing interest by academic and biopharmaceutical organizations to support the research and development of therapies for rare or orphan diseases. This is borne of many factors including the realization that approximately 6-10% of the general population can be affected by a rare disease. Moreover, effective therapies are available for only approximately 300 of the estimated 7000 rare diseases that have been recorded to date. As such, this disease area represents one with significant unmet medical need. Our experience at developing enzyme augmentation therapy for the lysosomal storage disorders have provided important lessons as to how we should approach drug discovery for rare diseases. Foremost is the need to have a good understanding of the underlying biology of the disease, as this can reduce the risk of successfully developing a drug. In addition, if the disease mechanism is well understood and there is an outstanding medical need, there is an increased probability of creating a transformative medicine. Transformative medicines are pharmacoeconomically compelling, which in turn can help drive discussions around approval, pricing and access. Early engagement with stakeholders such as patient groups and organizations as well as scientific and medical experts in the respective disease areas is also an important consideration. I will provide examples of our strategies at selecting disease targets and different technology platforms (biologics, small molecules and nucleic acids) that may be brought to bear in the management of these rare ailments. I will also highlight additional benefits that may be realized from researching rare diseases. For example, there is a growing realization that since the metabolic and biological pathways associated with some rare diseases are shared with those that are more common, that a study of such orphan diseases may provide greater insights into the pathogenesis of the more common and complex diseases. I will illustrate examples of how some of these links have afforded the possibility of re-purposing therapies developed initially for rare indications for otherwise unrelated diseases that are significantly more prevalent.

Seng Cheng is Head of Research and Early Development of the Rare Diseases Division at Genzyme, a Sanofi Company. Dr. Cheng received his BSc, and PhD degrees in Biochemistry from the University of London, U.K. He trained as a postdoctoral fellow at the National Institute for Medical Research in London, U.K., in the field of tumor biology. He was a Staff Scientist at Integrated Genetics Inc., and later joined Genzyme Corporation to work on several discovery projects including the structure and function of the cystic fibrosis transmembrane conductance regulator. As Group Vice President of Genetic Diseases Science at Genzyme, he also managed the development of novel gene delivery systems as well as translational research in genetic diseases, a number of which transitioned to clinical testing. Areas of focus included inherited metabolic, muscle, lung and neurodegenerative diseases. He has published over 240 research articles and reviews, and is a named co-inventor on 45 issued patents in the area of biotechnology. In his current position, he is responsible for directing the translational research and early clinical development activities in rare genetic diseases.

PK-PD Considerations Through Different Stages of Drug Development 

Dr. BrandquistChristine Brandquist, Pharm.D., M.S.
Celerion, Lincoln, NE

With the trend of advancing compounds to the proof-of-concept stage as early, safe, and cost-effective as possible, there is value in characterizing the pharmacokinetic (PK) and factors affecting PK in the early stages of clinical development. First-in-human (FIH) studies, and in particular single-ascending and multiple-ascending dose (SAD/MAD) designs, provide an opportunity to explore the impact of intrinsic (e.g. obesity, age) and extrinsic (e.g. food-effect, smoking) factors on formulation performance, PK in general, and safety of the new drug product through adaptive-like approaches. Per the FDA Guidance, “an adaptive design clinical study is defined as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study. Analyses of the accumulating study data are performed at prospectively planned timepoints within the study…”. The inclusion of interim evaluations of PK and safety, combined with an adaptive-like study design approach, provides advantages in terms of optimizing dose levels tested in these studies while minimizing the risk of administering doses which will result in either poor PK characterization or safety concerns. Employing modeling and simulation in adaptive early clinical research trials is good approach which can be helpful in guiding some decisions at the pre-specified points in the study design, specifically as a tool in making these adaptive changes and improving the understanding of the investigational product. This talk will illustrate challenges in FIH SAD/MAD and examine some trends toward adaptive-like study designs, while providing real examples to demonstrate the advantages and limitations of such approaches.  

Christine is currently a Senior Managing Principal Scientist in the Clinical Pharmacology Sciences Department at Celerion in Lincoln, Nebraska. Christine received her BS in Chemistry and Biology at Nebraska Wesleyan University (Lincoln, Nebraska) and received a PharmD and a MS in Pharmaceutical Sciences from the University of Nebraska Medical Center, College of Pharmacy (Omaha, NE). Dr. Brandquist completed a postdoctoral fellowship in the area of Clinical Pharmacokinetics/Pharmacodynamics at the University of North Carolina, Chapel Hill, and GlaxoSmithKline (Research Triangle Park, NC). After completing her undergraduate work, she work as an Analytical Scientist at Harris Laboratories and after obtaining her PharmD, Dr. Brandquist worked as a Registered Pharmacist with Walgreens. Since completing her postdoctoral training, Dr. Brandquist has worked in the Pharmaceutical Industry as a Pharmacokinetic Scientist/Senior Scientist with Contract Research Organizations, Globomax/Icon Development Solutions and MDS/Celerion. Her work has been primarily with phase I clinical trails.