Pharmacists in Drug Discovery & Development
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Young pharmaceutical scientists are and can get involved in all aspects of new drug discovery and development. They have to be appropriately qualified, trained and experienced though,
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Pharmacists in Drug Discovery & Development
- 1. Dr. Bhaswat S. Chakraborty Sr. VP, R&D, Cadila Pharmaceuticals Ltd. Former Senior Reviewer, Health Canada Pharmacists in Drug Discovery & Development Presented at the International Conference of Pharmacy (ICP) 2017 at the School of Pharmaceutical Sciences, Lovely Profesional University, Phagwara, Punjab, India, April 7-8, 2017 Dr. Leslie Benet, Pharmacist Remington Honor Medal, 2016
- 2. Contents • Global use of medicines • Drug Discovery & Development (DDD) R&D spending • DDD models • Areas of Interest / Expertise • R&D Pharmacists • Education, training & skills; Adaptation; Teamwork • DDD Basics • MNC Pipeline example • Areas of Drug Discovery & Development for Pharmacists • Molecular biology, immunology, pharmacology; Genomics, proteomics & metabolomics; Preclinical • Pharmacognosy & Chemistry; Pharmaceutics, NDDS • Clinical research • Conclusions 2
- 3. Famous Pharmacists 3 John Stith Pemberton American pharmacist, Inventor of Coca-Cola Hubert Humphrey Jr. Pharmacist, 38th Vice President of the USA Caleb Bradham American pharmacist, Inventor of Pepsi Charles Walgreen American pharmacist, Founder of Walgreens Eugène Soubeiran French pharmacist, Discoverer of Chloroform M.L. Shroff Indian pharmacist, Educationist Jyotish Chandra Ghosh Indian pharmacist, Pioneer Bishnu Mukherjee Indian pharmacist, Pioneer Indravadan Modi Indian pharmacist, Industrialist Pankaj Patel Indian pharmacist, Industrialist
- 4. Global Use of Medicines 4 Recent Past: 2012-2016 • New Molecular Entity Launches 160-185 • Global spending Growth CAGR 3-6% • U.S. Spending Growth CAGR 1-4 % • Emerging Country Spending Growth CAGR 12-15% • “Patent Dividend”$ 106Bn 2016 Numbers • Spending - $ 1.2 Trillion • Spending on Brands $615-645Bn • Spending on Generics $400-430Bn • Developed Country Spending Per Person $609 • Emerging Country Spending Per Person $91
- 5. Left chart, EvaluatePharma. Right chart: Genetic Engineering & Biotechnology News, March 2014 5
- 6. Pharmaceutical R&D Effectiveness & Efficiency 6 Paul et al (2010). Nature Reviews/Drg Discovery, 9:203-214
- 7. Comprehensive Cost Analysis 7 Paul et al (2010). Nature Reviews/Drug Discovery, 9:203-214
- 8. Two Models of DDD 8 Paul et al (2010). Nature Reviews/Drug Discovery, 9:203-214
- 9. Organizational Areas of Interest / Expertise 9
- 10. Pharmacists’ Areas of Interest / Expertise Pharmaceutics Pharmacology Chemistry (Medicinal/Organic/ Analytical) Clinical Trials/ Biopharmaceutics Project/R&D Management Other areas 10
- 11. Education, Training and Skills Required to Start with • Most of the pharmaceutical scientists (pharmacists) have a post graduate training • from a recognized academic institution in their respective fields • ~10-20% of these individuals are PhD degree holders and rest have a Masters or a Pharm.D. degree • recently a management plus Masters degree is offered in institutions • desirable: high IQ, goal setting, problem solving and team playing skills • also, an eye for details • writing expressly in technical English or any other vernacular • being aware of their intellectual and other gifts 11ChakrabortyB.S.(2013).PharmaTech, 3:18-20
- 12. Adaptation of Fresh Graduates in Functional Roles • The total number of pharmacy, biotech and medical devices R&D scientists are estimated >400,000 people globally • Vast majority get a job orientation following their graduation from academia and only after joining their employment • Get surprised as they get a formal training in on-going projects and SOPs by the minute stepwise descriptions of processes and rigidity of specifications • The hierarchy of reporting and the reality of owning the responsibilities are also strikingly novel for entry level scientists • A suitable mentor can hold the hands of a fresh graduate during these bewildering times 12ChakrabortyB.S.(2013).PharmaTech, 3:18-20
- 13. Teamwork • Pharma R&D teams: management, operational and expertise • management teams: leading and co-ordinating • operational teams: actual delivery of projects and problem solving • expert teams: critical input and depth expertise wherever needed • Mentoring process should establish an equal dignity and importance of all roles such that there is no artificial competition and dissatisfaction • Clear SOPs should be written up for the development of team playing skills • myth: soft skills (mentoring included or implied) cannot be written as procedures. This is not true. Mentoring objectives and essentials of the processes must be written down to enhance clarity • e.g., leadership role: use authority in a positive way; implementer role: delivering projects on time and building quality in projects • both utilizing the skills for a common larger team 13ChakrabortyB.S.(2013).PharmaTech, 3:18-20
- 14. Learning Teamwork in Large Multidisciplinary Setting • A large company (MNC) engages in R&D of many therapeutic areas • may or may not be candidate’s preference • may have to adjust rather than express her talent • Scholarly oriented PhD scientists in pharmacy face challenges of • general co-ordination • time, scope and budget bound focus on R&D projects • Emphasis on eventual commercial success and profit • Leadership roles in pharma R&D are complex • Team playing roles and expectations may not be transparent 14ChakrabortyB.S.(2013).PharmaTech, 3:18-20
- 15. Drug Discovery & Development (DDD) Basics 15ChakrabortyB.S.(2012).PharmaTech, 3:22-26
- 16. Drug Discovery & Development (DDD) Basics.. 16ChakrabortyB.S.(2012).PharmaTech, 3:22-26
- 17. R&D Pipeline of an MNC (Pfizer) 17
- 18. Areas of Drug Discovery & Development for Pharmacists 18
- 19. Era of Molecular Knowledge & MoA 19 Eder et al (2014). Nature Reviews Drug Discovery, 13: 577–587 • Target: A validated biological entity, which is characterized, efficacious, safe, meet clinical and commercial needs & ‘druggable’ • e.g., proteins, receptors, genes and RNA • certain targets are more amenable to small molecule, eg, G-protein-coupled receptors • others to large molecules: antibodies are good at blocking protein/protein interactions • Chemocentric: systems-based approaches originate from a known compound or compound class
- 20. Drug Discovery Screening Assays 20 Hughes et al (2011). British Journal of Pharmacology, 162:1239–1249
- 21. Genomics, Proteomics & Metabolomics 21 • Genomics, proteomics and metabolomics are recent advances in DDD • Genomics use novel and next-generation sequencing techniques and discovers normal and diseased-state tissues, transcription and/or expression profiling, side-effect profiling, pharmacogenomics and biomarkers • Proteomics carry out target and lead identification, compound optimization, throughout the clinical trials process and after market analysis • isotope coded affinity tags, stable isotopic labeling by amino acids in cell culture, isobaric tags for relative and absolute quantification, multidirectional protein identification technology, activity- based probes, protein/peptide arrays, phage displays and two-hybrid systems etc. • Metabolomics use systems biology approaches • characterization of metabolites and metabolism in biological systems • diagnose disease, understand disease mechanisms, identify novel drug targets, customize drug treatments and monitor therapeutic outcomes
- 22. Genomics and Proteomics 22 • Most genes code for proteins, which interact to form pathways • Pathways interact with sub-cellular mechanisms to generate function at cellular and higher levels • The upward pointing arrow is the usual way in which these interactions are viewed • There is downward causation too • Higher-level properties determine which sub-cellular pathways are activated and which genes are expressed Noble D. (2003). TRENDS in Biotechnology, 21: 333-337
- 24. 24
- 25. 25 Preclinical Studies: Drug Candidate Confirmation
- 26. 26 Preclinical Studies: Preclinical Drug Characterization
- 27. Pharmacology 27
- 28. Pharmacognosy & Chemistry • Drug discovery from medicinal plants: lengthier and more complicated than other drug discovery methods • Many pharmaceutical companies have eliminated or scaled down their natural product research • Department of AYUSH in India, however, provide financial support and necessary skill, expertise, knowledge and resources for pharmacognosy based drugs • In USA, National Center for Natural Products Research at the University of Mississippi and NIH Botanical Centers at the University of Illinois at Chicago are recent positive developments • `New high throughput screening techniques and faster characterization of plant based drugs are available 28Balunas & Kinghorn (2005). Life Sciences, 78:431–441
- 29. 29 Source: Mike Sumner, internet
- 30. Pharmaceutics Lipinski's Rule of Five (most medication drugs are relatively small and lipophilic molecules) • Lipinski’s rule states that, in general, an orally active drug has no more than one violation of the following criteria: • Not more than 5 hydrogen bond donors (expressed s as the sum of OHs and NHs) • Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms) • A molecular mass less than 500 D • An octanol-water partition coefficient log P not >5 • Compound classes that are substrates for biological transporters are exceptions to the rule 30 • Structural Characterization • Impurity Identification • Solubility assessment • Prototype formulation • Stability testing • NDDS • IVIVC
- 31. New Drug Delivery Systems (NDDS) 31Allen and Cullis (2004). Science, 303:1818-1822 Problem Implication Effect of DDS Poor Solubility Hydrophobic drugs may precipitate in aqueous media Toxicities are associated with use of excipients DDS like liposomes provide both hydrophobic and hydrophilic environments, enhancing drug solubility Tissue Damage on Extravasation Leads to tissue damage Regulated drug release from DDS can reduce/eliminate tissue damage Rapid breakdown of the drug in vivo Loss of activity of drug follows administration DDS protects drug from premature degradation and functions as a sustained release system Unfavourable pharmacokinetics Drug is cleared too rapidly, requiring high doses or continuous infusion DDS can substantially alter PK of drug, reducing clearance Poor Biodistribution Widespread distribution can affect normal tissues, resulting in dose-limiting side effects DDS lowers the volume of distribution, and helps to reduce side effects in sensitive, nontarget tissues Lack of selectivity for target tissues Distribution of drug to normal tissues leads to side effects Low concentrations of drugs in target tissues will result in suboptimal effects DDS can increase drug concentrations in diseased tissues by the EPR effect Ligand-mediated targeting of DDS also increases selectivity
- 32. New Drug Delivery Systems (NDDS) 32 (A) Liposomes containing an anticancer drug extravasate in in tumor tissue (dark green), but not in normal tissue (light green) (B) Drug is released from the liposomes in the vicinity of the tumor cells and taken up into the cells (C) Liposomes containing anticancer drugs (or plasmid DNA or antisense oligonucleotides) bind to cell surface receptors (dark green triangles), which triggers internalization of the DDS into endosomes Allen and Cullis (2004). Science, 303:1818-1822
- 34. Well Designed Ph II RCT 34 Belani, Chakraborty, Modi & Khamar (2016) Annals of Oncology
- 35. Concluding Remarks • The discovery or isolation of the drug, whether small or large molecule is a complex process of studying its structure (along with 1000s of related compounds), mechanism of action, and proof of concept of efficacy and safety • The preclinical phase actually decides which few candidates will go further to be tested clinically in humans – healthy and patients • Research & Development Pharmacists can dedicate themselves in any one or more than one areas of specialty in DDD • Clinical studies test the drug to see whether it should be approved for wider use in the relevant patient population • outcome measures in clinical trials describe and quantitate the benefits (and risks) of the drug • I am highly optimistic about the current and future glory of Indian pharma R&D scientists. Approximately one out of six pharma scientists in the US is of Indian origin! • Along with domain expertise, team playing skills are now essential for pharmaceutical DD scientists 35
- 36. 36 Thank You Very Much
Editor's Notes
- Dimensions of r&D productivity. To improve R&D productivity, it is crucial to understand the interdependencies between inputs (for example, R&D investments), output (for example, new molecular entity launches) and outcomes (for example, valued outcomes for patients). This figure outlines the key dimensions of R&D productivity and the goals tied to R&D efficiency and effectiveness. An effective R&D productivity strategy must encompass both of these components. Value will be created by delivering innovative products with high-quality information.
- R&D model yielding costs to successfully discover and develop a single new molecular entity. The model defines the distinct phases of drug discovery and development from the initial stage of target-to-hit to the final stage, launch. The model is based on a set of industry-appropriate R&D assumptions (industry benchmarks and data from Eli lilly and Company) defining the performance of the R&D process at each stage of development (see supplementary information s2 (box) for details). R&D parameters include: the probability of successful transition from one stage to the next (p(Ts)), the phase cost for each project, the cycle time required to progress through each stage of development and the cost of capital, reflecting the returns required by shareholders to use their money during the lengthy R&D process. With these inputs (darker shaded boxes), the model calculates the number of assets (work in process, WIP) needed in each stage of development to achieve one new molecular entity (nME) launch. Based on the assumptions for success rate, cycle time and cost, the model further calculates the ‘out of pocket’ cost per phase as well as the total cost to achieve one nME launch per year (Us$873 million). lighter shaded boxes show calculated values based on assumed inputs. Capitalizing the cost, to account for the cost of capital during this period of over 13 years, yields a ‘capitalized’ cost of $1,778 million per nME launch. It is important to note that this model does not include investments for exploratory discovery research, post-launch expenses or overheads (that is, salaries for employees not engaged in R&D activities but necessary to support the organization).
- The quick win, fast fail drug development paradigm. This figure illustrates the traditional paradigm of drug development (a) contrasted with an alternative development paradigm referred to as quick win, fast fail (b). In this alternative, technical uncertainty is intentionally decreased before the expensive later development stages (Phase II and Phase III) through the establishment of proof-of-concept (POC). This results in a reduced number of new molecular entities (nMEs) advancing into Phase II and III, but those that do advance have a higher probability of success (p(Ts)) and launch. The savings gained from costly investment in late-stage R&D failures are re-invested in R&D to further enhance R&D productivity. Cs, candidate selection; FED, first efficacy dose; FHD, first human dose; PD, product decision.