Analysis of the paths of pharmaceutical innovation takes place within the context of the pharmaceutical ecosystem. The market growth rate skyrocketed due to the expansion of the number of top-selling drugs, improving the pharmaceutical industry's position in the global economy [2].
Government and Policies
The pharmaceutical ecosystem could be defined as the convergence of networks of cross-interacting subsystems across the drug product pipeline that have a stake in the effectiveness of drug development and access to the marketed drug.
Drug Discovery Research and Development
The preclinical R&D phase involves quality assurance professionals, assay development researchers, safety pharmacologists and toxicologists. Clinical R&D involves clinical research staff, pharmacologists, biostatisticians, molecular biologists, pharmacovigilance professionals and drug safety researchers.
Economics Models
The Civic Society
The Processes
Pharmaceutical Policy and Regulation
4 THE ENTREPRENEUR EFFECT OF THE PHARMACEUTICAL SYSTEM AND COMPANY. drug sales) that have successfully passed drug approval cycles. This delays a drug's entry into the generic market and, as such, will also limit the low price effect [9].
Access to Drugs
Federal laws allow for linkages between the drug approval process and the registration of patents in most of North America and other countries scattered around the globe. There is a direct correlation between drug prices and availability of generic drugs in the sense that the entry of a generic drug into the market is accompanied by a drop in drug prices.
Drug Pricing and Payment
Access to pharmaceuticals can be defined as the timely availability, subject to economic and physical conditions, of quality, safe and effective medicines to those patients who need them. Many interwoven factors determine the level of access to quality medicines, such as the availability of financial resources, government policies, infrastructure conditions, private and public sector insurance programs, appropriate use, supply management and manufacturing capacity1.
Communication
The goal is to communicate values, opportunities and challenges that will help transform the future of public health worldwide. Funding of patient advocacy organizations resulted in the protection of the interests of the funding partners.
Drug Repositioning or Repurposing
Quite often, extensive funding has been invested in advertising at the expense of the end user, who indirectly pays for this practice through the purchase of drugs with built-in advertising costs on price tags [19]. However, there are divided interests regarding the choice of the recycled drug and the purpose of such an endeavor [21].
Stratified/Personalized Medicine
The core processes (inner circle) and the strategic/social issues (outer circle) form a bridge between the drug discovery processes and society. All aspects of human culture, law and philosophy have a mutual relationship with drug discovery and development, and thus the latter cannot exist independently of the social system and its organizational features.
Pharmaceutical Regulation
The Role of Government in the Business of Drug Discovery
- INTRODUCTION
- Evolution of the Pharmaceutical Regulatory System The initial restructuring of the federal regulation of drugs in the United
- THE LEGAL INSTRUMENTS
- The Act/Enabling Act
- Regulations
- Guidelines
- THE NATIONAL REGULATORY AUTHORITIES AND ADMINISTRATION
- The Food and Drug Administration
- Health Canada
- European Medicines Agency
- Pharmaceuticals and Medical Devices Agency of Japan The Pharmaceuticals and Medical Devices Agency (PMDA, KIKO) is an in-
- ANALYTICAL FRAMEWORK FOR REGULATORY APPROVAL: BENEFIT–RISK ASSESSMENT
- THE PHARMACEUTICAL PRODUCT LIFE CYCLE
- Modules for Drug Regulatory Assessment
Examples are the United States' FD&C Act, Canada's Food and Drug Act, and Japan's Pharmaceutical Affairs Act (PAA). The heads of the Medicines Agencies cooperate with the EMA and the European Commission in the operation of the European Medicines Regulatory Network (the "Network") [5].
The Decision Points 1.5.1.1 Decision Point I
- Patents
- Labeling
- THE GLOBAL PHARMACEUTICAL INDUSTRY
- International Conference on Harmonisation of Technical Requirements for Registration of
- Government Regulations: Prospects for Multinational Clinical Trials
- MODERNIZATION OF THE GLOBAL PHARMACEUTICAL SYSTEMS: REGULATORY STRATEGIES, ROADMAP
- The Critical Path Initiative
- The European Medicines Agency’s Roadmap to 2015 The EMA’s Roadmap published “A Strategy for the Heads of Medi-
- The Progressive Licensing Model of Health Canada
- Global Initiatives
- World Health Partnerships
After drug marketing, there is continuous monitoring of aspects related to drug safety. Guidelines are found in the Association of British Pharmaceutical Industry Guidelines for Phase I Clinical Trials.
Trends in Innovation and the Business of Drug Discovery
INTRODUCTION
- Pharmaceutical Innovation
- The Global Pharmaceutical Business
In the rest of the world Teva (Israel) and Takeda, Astellas, Daiichi Sankyo (Japan) rank highest. Currently, drug spending has decreased from 58% to 48% in the United States and Europe, and the size of the African pharmaceutical market is expected to double in.
EVOLUTIONARY TRENDS IN PHARMACEUTICAL INNOVATION
- The Global Pharmaceutical Discoveries of the Twentieth Century (Table 2.1)
Trends in innovation and drug discovery33 Table 2.1 The global pharmaceutical discoveries of the twentieth century. Incremental improvements in the new classes of drugs tend to address the limits of the already existing ones.
ADVANCES IN PHARMACEUTICAL INNOVATION TECHNOLOGY
Collaborative Drug Discovery (CDD) enables managing and sharing chemical and biological data and collaborating with internal or external partners through the CDD vault interface. Social media identifies patient behavior in response to treatment and monitoring applications that identify lifestyle trends.
SELECT MEDICAL MILESTONES OF 2014
Their use has created a lot of value and contributed to many years of economic growth and strong profits from new medicines. The National Institutes of Health (NIH), America's largest sponsor of biomedical research, has invested enormously in cancer research, contributing to the increasing amount of cancer drugs on the market.
FACTORS CONTRIBUTING TO PHARMACEUTICAL INNOVATION SETBACK
- Research and Development Productivity
- Complex Biological Systems
- The Challenge of Adverse Drug Reactions
- Economic Strategies
- Between Risk and Return: The “Valley of Death”
- Poor Product Strategies
- Patent Protection
- Clinical Development Challenges
- Regulatory Burden
Pharmaceutical R&D in these areas has not been “discovered” and is considered high-risk and expensive projects – the worst-feared discovery issues. Fewer validated new drug candidates fill the pipelines due to the reduction in the number of well-validated options.
CASE: CHALLENGES IN ANTIMICROBIAL DRUG DISCOVERY
New compounds are produced under heavy regulatory guidelines and the large financial investment makes it a major challenge [46]. Strict regulatory standards are adding more and more filters that tend to narrow all gateways to drug licensing.
CONSEQUENCE OF INNOVATION SETBACK
STRATEGIES AND APPROACHES TO ADDRESSING INNOVATION FAILURE
- Regulatory Approach
- Mergers, Acquisitions, and Outsourcing
- Pharmaceutical Research and Development
- New Avenues of Personalized Medicine: Application of Pharmacogenomics Technology in Drug Development
- Drug Repositioning/Repurposing
- Building the Pharmaceutical Ecosystem
Abbott drew on the drug discovery tools at Cambridge to complement its intrinsic strengths. Effective integration of all aspects of the pharmaceutical ecosystem will lead to high performance standards.
CONCLUDING REMARKS
Available from: http://triplehelixblog.com/2014/07/the-patent-cliff-implications-for-the-pharmaceutical-industry/#sthash.ILnShoIC.ReC80vJx.dpuf [accessed. Available at: http://triplehelixblog.com/2014/07/the-patent-cliff-implications- for-the-pharmaceutical-industry/#sthash.ILnShoIC.dpuf [accessed.
Cash Flow Valley of Death
A Pitfall in Drug Discovery
INTRODUCTION
Drug discovery and development projects reach a financial pause as drug development companies face declining interest from investors or venture capitalists, which seriously affects business stability [1]. In the pharma business, this is referred to as the separation period between basic research and the second phase of clinical trials that prove the PoC, due to funding constraints that hinder the pipeline's progress to commercialization.
PRODUCT VALUATION AS AN INVESTMENT DECISION-MAKING TOOL
A number of venture capital firms, such as Prospect and Excalibur, have already pulled out of biotech investments. For example, in the UK, the former venture capital model consisted of tiers of funding up to the initial public offering, which the exit strategy has phased out.
CHALLENGES ASSOCIATED WITH THE VALLEY OF DEATH
- Organization Proportions and Impact in Drug Discovery Organization size and capacity have an inverse relationship with their ability
- Vulnerability of Biotech and Small Companies
- Key Research Activities in the Stage of Lowest Funding Translational science mainly plays the role of transforming activity into
- Unpredictability of Pharmaceutical Innovation Science In the pharmaceutical industry, most of the proposed research projects are
- Academic Discovery and Research Limitations
- Target Selection
The venture capitalists did not have access to the company's wealth, so they used the exit strategy to cash in on their investment. The most common problems are experienced in the early and start-up phases of R&D, when the investment risk is high, which deters risk-averse potential investors: the fear of a lack of profitability [10].
FIRMS INVOLVED IN THE PHARMACEUTICAL VALUE CHAIN
- Big Pharmaceutical Industries (Big Pharma)
- Biotechnology-Based Industries (Biotech)
- Biopharmaceutical Industries
- Contract Research Organizations
Contract research organizations (CROs) are outsourcing companies, vendors that perform more precise and focused research and development functions for the pharmaceutical or biotechnology industries. Their main mission is to close the "time-to-market" gap by effectively using innovation and incorporating a full spectrum of services for small biotech companies.
STRATEGIES FOR BRIDGING THE VALLEY OF DEATH AND INNOVATION FAILURE
- The Changing Drug Discovery Landscape
- Product Forecasting
- Investment in the Discovery Science
- Advancing Corporate Productivity: Partnerships .1 Big Pharma – Early Stage/Biotech Company Partnerships
- Communication
- Importance of the Biotechnology Incubators
- Addressing Investment Limitations
Product forecasting refers to predicting the success rate of the new drug product in the market. In the early stage of drug discovery, a prior knowledge of the attributes of the drug compound is essential to understand the marketing prospects of the drug product.
FUNDING MODELS
- US Financing Models
- Canadian Financing Models
The National Research Council of Canada is the Canadian government's principal research and development organization. Canada's HIV Technology Development Program attracts SMEs to further develop HIV vaccines and promote more intensive efforts or medical solutions for HIV.
NONGOVERNMENTAL FUNDING MODELS .1 Large Pharmaceutical Companies
- Venture Capital
- Public-Venture Philanthropy
- Angel Investment .1 Private-Angel Investment
- Private-Corporate Investment
- Crowdfunding
OTHER FINANCIAL CONCEPTS
- Not-for-Profit/Nonprofit Organizations
- Cash Flow
- Cash Flow Return on Investment
- Derisking
The risk-adjusted NPV takes into account the risk of the specific stage of drug development. Free cash flow is possible when minimal expenses are made during the establishment of the company.
PRIVATE–PUBLIC SECTOR GROUPS
- National Centre for Advancing Translational Sciences NCATS is supported by the NIH to promote innovative methods and tech-
- Innovative Medicines Initiative
- European Federation for Pharmaceutical Sciences
- The Centre for Drug Research and Development
Available at: http://www.ddw-online.com/business/p191021-the-challenges-of-the-changing-drug-discovery-model-fall-12.html. 52] Available from: http://www.ncats.nih.gov/research/rare-diseases/bridgs/bridgs.html [53] Genome Canada.
Prediscovery Research
Challenges and Opportunities
INTRODUCTION
The conventional view is that the functioning of biological systems is mostly network-based, in other words arising from the whole and not parts. These have been called "emergent" properties because they arise from the whole and are not properties of the individual parts.
MODELS OF HUMAN DISEASE BIOLOGY .1 Target-Based Drug Discovery
Since the completion of the Human Genome Project, targeted drug discovery has dominated modern pharmaceutical research due to its complementary advantage over phenotypic drug discovery. The decision is justified by obtaining information about alternative therapies, compliance and tolerance, evidence and strength of the obtained information.
DISEASES CONSIDERED IN BIOPHARMACEUTICAL RESEARCH AND DEVELOPMENT
The Lilly-sponsored Phenotypic Drug Discovery (PD2) initiative was established to screen external molecules in phenotypic modules to find compounds with therapeutic potential and collaboration opportunities [ 15 ].
MODERN TRENDS IN DRUG DISCOVERY
- Extracellular RNA Communication as an Emerging Paradigm in Drug Discovery
- The Applicability of Systems Biology in Drug Discovery Drug discovery traditionally is based on animal models, cells, and tissue screens
- The Omics Technology
- Network: A Systems Biology Approach to Drug Discovery
- Mapping the Disease Association Networks
- Polypharmacological Profiling: A Novel Approach to Drug Discovery
- Multiple Transporters Drug Targeting
An example of the use of systems biology in clinical medicine is the RNA expression profiles of diffuse B-cell lymphoma. This takes into account genetic heterogeneity, metabolic variation and epigenetic modulation, which could be addressed in the early stages of the drug discovery process.
CURRENT CHALLENGES IN EARLY DRUG DISCOVERY .1 Setbacks in Identification and Selection of New Targets
- Network/System Biology Application-Limitations
- The Impact of the Pharmaceutical Ecosystem
- Effect of Size and Capability
This can cause variations as the concentration of the drugs and activity levels are not controlled. Systems biology, which enables the determination of biological complexity at the level of the whole system, is a very promising strategy in drug discovery.
The Significance of Discovery Screening and Structure
Optimization Studies
- INTRODUCTION
- SCREENING TOOLS IN DRUG DISCOVERY .1 High Throughput Screening in Drug Discovery
- Setbacks in HTS Application
- Bioassays
- IN SILICO MODELS IN DRUG DISCOVERY AND DESIGN Biology has experienced an increased use of highly sophisticated systems
- Virtual Screening
- Computer-Aided Drug Design
- Structure–Activity Relationship in Drug Discovery
- Pharmacophore Models of Drug Targeting
- Cheminformatics and Bioinformatics Technology
- FROM HIT TO LEAD: SUMMARY OF COMPOUND OPTIMIZATION IN DRUG DISCOVERY
High throughput screening (HTS) is one of the leading technological breakthroughs in drug research. In silico SNP analysis and bioinformatics tools: a review of state-of-the-art technology to aid drug discovery.
Preclinical In Vitro Studies
Development and Applicability
- INTRODUCTION
- PREDICTABILITY OF PRECLINICAL DISEASE MODELS Most of the predicaments of the early drug discovery projects were mostly
- TRENDS IN PRECLINICAL DRUG DEVELOPMENT
- RELEVANCE OF ADME/PK STUDIES
- Important Considerations in Evaluating Human Drug Toxicity
- EXPERIMENTAL TOOLS USED IN PRECLINICAL DEVELOPMENT
- Intestinal Absorption Studies Models: Caco-2 Cells
- Advances in Cell Culture Systems
- DRUG ELIMINATING AGENTS AND MECHANISMS
- Metabolizing Enzymes: CYPs (P450)
- Drug–Drug Interactions
- Transporters
- APPLICATION OF ZEBRAFISH AS A MODEL WHOLE ORGANISM: A LANDMARK IN PRECLINICAL
ADMET refers to the absorption, distribution, metabolism, excretion and toxicity characteristics of the drug candidate. Response refers to the PD response to the drug, which is the biological activity or pharmacological effect of the drug.
Animal Utilization in Drug Development: Clinical, Legal,
- INTRODUCTION
- THE SCIENTIFIC VALUE OF ANIMAL STUDIES
- LABORATORY ANIMALS MODEL IN THE FRONTIERS OF DRUG DISCOVERY
- RELATIONSHIPS IN ANIMAL TAXONOMY
- THE EFFECT OF SPECIES DIFFERENCES ON STUDY RESULTS
- Pain Cognition/Recognition or Expression
- Effect of Dosage Regimen
- Effects of Genetic Modification
- Cytochrome P450 (CYP)-Mediated Drug Metabolism and Inhibition
- HOW RELIABLE IS THE ANIMAL TOXICITY
- Extrapolation of Animal Data to Humans
- LANDMARKS IN PRECLINICAL DEVELOPMENT
- Animal Models of Depressions: Minipig and Beagle Animal Models
- Animal Models of Cancer
- Animal Models of Alzheimer’s Disease in Drug Development
- Insect Models: The Fruit Fly
- ANIMAL MODELS IN THE DEVELOPMENT OF BIOPHARMACEUTICALS: THE EXCEPTIONAL
- LEGAL ACCOMMODATIONS ON THE USE OF ANIMALS IN PHARMACEUTICAL RESEARCH AND DEVELOPMENT
- Canada
- Europe
- ANIMAL ALTERNATIVES IN DRUG DEVELOPMENT
- Replacement
- Reduction
- Refinement
According to [5] "Good practice guidelines - selection of non-rodent species for pharmaceutical toxicology", documentation of animal studies should be completed for rodents and a non-rodent and 6-9 months repeated dosing was recommended as sufficient to provide adequate toxicity information. There is a mismatch of biochemical composition between the mouse model and the brain of Alzheimer's disease, which has contributed to the failure to develop an important pathological signature of Alzheimer's - neurofibrillary tangles [35].
Pharmaceutical Formulation and Manufacturing Development
Strategies and Issues
INTRODUCTION
In the manufacturing phase, the drug in development or new drug entity (NDE) becomes the active pharmaceutical ingredient (API). Chemical synthesis is a continuous process that parallels NDE maturation throughout the development phase of the drug discovery program.
REGULATORY ASPECTS OF PHARMACEUTICAL DEVELOPMENT
- Overview
- The International Conference on Harmonisation Technical Documents for Pharmaceutical Development
All these activities are rooted in the International Conference on Harmonization (ICH) guidelines that must be followed for the investigational new drug (IND) to be considered qualified to progress to the next stage (Figure 8.1). In general, ICH Q8, 9 and 10 are a combination of technical requirements that must be strictly adhered to to cover all the processes involved in pharmaceutical development and manufacturing.
FORMULATION AND MANUFACTURING IN PHARMACEUTICAL DEVELOPMENT
- Formulation Development
- Manufacturing Development
- Issues Pertaining to Drug Formulations
They deal with the synthetic route selection for the drug substance and product, the mechanism of API impurity formation and the suitability of the optimization studies. Critical process parameters exist for each step or stage of the manufacturing process and are optimized as needed.
- CLINICAL TRIALS MATERIALS
- Phase I
- Phase II
- Phase III
- CONCEPTS USED IN PHARMACEUTICAL DEVELOPMENT
- DRUG SHORTAGES
- MANUFACTURING PROBLEMS LEADING TO DRUG SHORTAGES
- Impurities in Manufacturing Development
- Impurity in Drug Formulation
- Genotoxic Impurities in Developing Drugs
- Issues of Repetitive Cycle in Drug Manufacturing
- Sterility Issues
- ADDRESSING DRUG SHORTAGES: STRATEGIES
In the pilot phase, critical processing steps and parameters must be defined to enable the validation of the production process. Those of the key intermediates may or may not be converted into other impurities in the active pharmaceutical ingredients.
